IJC International Journal of Cancer
Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers Michael Wilhelmsen1, Ib J. Christensen1, Louise Rasmussen1, Lars N. Jørgensen2, Mogens R. Madsen3, Jesper Vilandt4, €nner9, Susan Gawel10, Xiaoqing Yang10, Thore Hillig5, Michael Klærke6, Knud T. Nielsen7, Søren Laurberg8, Nils Bru 10 11 11 Gerard Davis , Annemieke Heijboer , Frans Martens and Hans J. Nielsen1 1
Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark Department of Surgical Gastroenterology, Bispebjerg Hospital, University of Copenhagen, København, Denmark 3 Department of Surgical Gastroenterology, Herning Hospital, University of Copenhagen, Herning, Denmark 4 Department of Surgical Gastroenterology, Hillerød Hospital, University of Copenhagen, Hillerød, Denmark 5 Department of Clinical Biochemistry, Hillerød Hospital, Denmark 6 Department of Surgical Gastroenterology, Horsens Hospital, University of Copenhagen, Horsens, Denmark 7 Department of Surgical Gastroenterology, Randers Hospital, University of Copenhagen, Randers, Denmark 8 Department of Surgical Gastroenterology, Aarhus Hospital, University of Copenhagen, Aarhus, Denmark 9 Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark 10 Cancer Core R&D, Abbott Diagnostics Division, Abbott Park, Chicago, IL, USA 11 Department of Clinical Biochemistry, VU medical center, Amsterdam, The Netherlands
Tumor Markers and Signatures
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Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined R automated immunoassay platform. Primary endpoints were detection of (i) CRC in EDTA-plasma using the Abbott ARCHITECTV and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N 5 4,698) were consecutively included during 2010–2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had ‘clean’ colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value Key words: colorectal cancer, blood-based biomarkers, detection Additional Supporting Information may be found in the online version of this article. Grant sponsor: The Andersen Isted Fund; Grant sponsor: The Augustinus Foundation; Grant sponsor: The Beckett Fund; Grant sponsor: The Inger Bonnen Fund; Grant sponsor: The Hans & Nora Buchard Fund; Grant sponsor: CEO Jens Bærentsen (private donation); Grant sponsor: The Walter Christensen Family Fund; Grant sponsor: The P.M. Christiansen Family Fund; Grant sponsor: The Aase & Ejnar Danielsen Fund; Grant sponsor: The Erichsen Family Fund; Grant sponsor: The Knud & Edith Eriksen Fund; Grant sponsor: The Svend Espersen Fund; Grant sponsor: The Elna and Jørgen Fagerholt Fund; Grant sponsor: The Sofus Carl Emil Friis Fund; Grant sponsor: The Torben & Alice Frimodt Fund; Grant sponsor: The Eva & Henry Frænkel Fund; Grant sponsor: The Gangsted Fund; Grant sponsor: The Thora & Viggo Grove Fund; Grant sponsor: The H Foundation; Grant sponsor: The Erna Hamilton Fund; Grant sponsor: The Sven & Ina Hansen Fund; Grant sponsor: The Søren & Helene Hempel Fund; Grant sponsor: The Henrik Henriksen Fund; Grant sponsor: The Jørgen Holm Family Fund; Grant sponsor: Foundation Jochum; Grant sponsor: The KID Fund; Grant sponsor: The Kornerup Fund; Grant sponsor: The Linex Fund; Grant sponsor: The Dagmar Marshall Fund; Grant sponsor: The ‘Midtjyske Bladfund’; Grant sponsor: The Axel Muusfeldt Fund; Grant sponsor: The Børge Nielsen Family Fund; Grant sponsor: The Michael Hermann Nielsen Fund; Grant sponsor: The Arvid Nilsson Fund; Grant sponsor: The Obel Family Fund; Grant sponsor: The Krista & Viggo Petersen Fund; Grant sponsor: The Willy & Ingeborg Reinhard Fund; Grant sponsor: The Kathrine & Vigo Skovgaard Fund; Grant sponsor: The Toyota Fund; Grant sponsor: The Vissing Fund; Grant sponsor: The Wedell-Wedellsborg Fund; Grant sponsor: Hvidovre University Hospital (The Capital Region of Denmark) DOI: 10.1002/ijc.30558 History: Received 15 July 2016; Accepted 8 Nov 2016; Online 8 Dec 2016 Correspondence to: Michael Wilhelmsen, Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, 2650 Hvidovre, Denmark, E-mail:
[email protected]; Tel: 145 38622436
C 2016 UICC Int. J. Cancer: 140, 1436–1446 (2017) V
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was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC.
Introduction Globally, colorectal cancer (CRC) is the third most frequent cancer disease with >1.4 million new cases and >690,000 deaths annually.1 Although 80% of the patients will undergo intended curative resection, half of these will be diagnosed with recurrent or metastatic disease within the ensuing 5 years.2 Patients, who undergo intended curative resection have a 5-year stage-dependent survival rates ranging from 35 to 90%, whereas long-term survival is rarely seen in patients with stage IV disease. Obviosly, the survival rates would be significantly improved if more patients could be identified with early stage disease.3 Hitherto, it has been possible to increase the number of patients with early stages by various screening methods. Direct colonoscopy appears to be the optimal method, but due to limited cost/benefit and compliance issues the method cannot be recommended for screening of entire populations and must be restricted to ‘at risk’ subjects.4,5 Such subjects may be identified by using various stool-based screening methods, of which the guaiac fecal occult blood test (gFOBT) has been used for more than a decade in Europe and USA. The test have specificities of 85–90%, while the sensitivity range between 40 and 90%.4 However, these high ranges have been contradicted by new data from a major observational study showing sensitivites for nonadvanced adenoma, advanced adenoma and CRC of 5.3, 8.6 and 24.2%, respectively.6 In addition, compliance rates using gFOBT are often limited to
