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Targeting Vascular Endothelial Growth Factor Pathway in First-Line Treatment of Metastatic Colorectal Cancer: State-of-the-Art and Future Perspectives in Clinical and Molecular Selection of Patients F. Loupakis*,1,3, G. Bocci#,2,3, G. Pasqualetti3,4, L. Fornaro1,3, L. Salvatore1,3, C. Cremolini1,3, G. Masi1, R. Danesi2,3, M. Del Tacca3,4 and A. Falcone1,3 1
Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy; 2Division of Pharmacology, Department of Internal Medicine, University of Pisa, Italy; 3Azienda Ospedaliero-Universitaria Pisana and Istituto Toscano Tumori, Italy; 4 Clinical Pharmacology Centre for Drug Experimentations, Azienda Ospedaliero-Universitaria Pisana, Italy Abstract: Targeting vascular endothelial growth factor (VEGF) pathway represents a successful strategy in the treatment of metastatic colorectal cancer (mCRC). Since the approval of the first antiangiogenic drug, the anti-VEGF monoclonal antibody bevacizumab, a number of other molecules have been tested in preliminary trials and are currently under investigation in phase III randomized studies. At present, no clinical tools are available to select patients more likely to benefit from VEGF pathway inhibitors nor to exclude those who are proner to suffer from specific adverse events, so that almost all mCRC patients are potentially candidate to receive an antiangiogenic-containing regimen. To overcome this substantial limit, a consistent aid is awaited by the identification of molecular tools of selection. Retrospective analyses and translational studies have been conducted and are currently ongoing to address this major question, investigating molecular, biological and genetic markers. This review aims at resuming the state-of-the-art about the role of VEGF pathway inhibitors in the treatment of mCRC and at focusing on the present knowledge about candidate biomarkers as predictors of activity and toxicity.
Keywords: Colorectal cancer, VEGF, predictive factors, biomarkers. INTRODUCTION Angiogenesis is a complex process regulated by numerous endogenous factors that stimulate or inhibit neovascularization of both healthy and pathologic tissues. The impressive disregulation of the angiogenic process in tumors, driven by the significant imbalance between pro- and antiangiogenic factors, is one of the major determinants of tumoral progression and growth, metastatic spreading and disease aggressiveness. Targeting proangiogenic factors has become an effective strategy to inhibit tumor growth in preclinical studies and, more recently, a successful clinical tool in oncologic practice [1]. In particular, the vascular endothelial growth factor (VEGF) pathway plays a crucial role in the development of new blood vessels and is, therefore, a key target for novel biologic agents [2]. In February 2004, the Food and Drug Administration (FDA) approved the use of the anti-VEGF monoclonal antibody (moAb) bevacizumab in the treatment of metastatic colorectal cancer (mCRC) patients, in combination with fluoropyrimidine-based chemotherapy. This approval was granted on the basis of a phase III randomized trial *Address correspondence to this author at the Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy; Tel: +39050992451; Fax: +39050992069; E-mail:
[email protected] # Guido Bocci is supported by a grant from the Italian Association for Cancer Research (AIRC). 1568-0096/10 $55.00+.00
demonstrating that the addition of bevacizumab to conventional first-line chemotherapy improved overall survival [3]. None of the pre-specified subgroups of patients 1 benefited more than others , neither none of the potential molecular determinants that have been so far retrospectively investigated influenced the outcome [4-6]. For such reasons, at present, there are no predictors of benefit from bevacizumab. It has also been suggested that the definition of response as tumoral shrinkage, according to RECIST criteria, may represent an inappropriate parameter of benefit, in order to appraise a real antiangiogenic effect [7, 8]. At the same time, it has been shown that non-responding patients may derive an advantage in terms of disease control from the addiction of bevacizumab to chemotherapy similar to that obtained by those achieving a consistent tumoral shrinkage [9]. Such observations, coupled with discouraging results from main pharmacogenomic analysis [4, 5], deaden expectations for defining predictors of outcome for patients candidate to receive bevacizumab. Nevertheless, the identification of biomarkers that might predict the efficacy of antiangiogenic drugs should be a useful and even necessary strategy in the very first clinical development (phase I-II). Indeed, many antiangiogenic drugs failed to demonstrate a clear efficacy in phase III trials in contrast to promising preclinical and early clinical results [1]. On the other hand, for already approved agents such as bevacizumab, the unavailability of validated 1
Fyfe, G.; Hurwitz, H.; Fehrenbacher, L.; Cartwright, T.; Hainsworth, J.; Heim, W. Bevacizumab plus irinotecan/5-FU/leucovorin for treatment of metastatic colorectal cancer results in survival benefit in all pre-specified patient subgroups. J. Clin. Oncol. 2004, 22, (14S (July 15 Supplement)).
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biomarkers for predicting and assessing antiangiogenic/ antitumor activity, compromises a well-advised integration into the therapeutic armamentarium, since the decision of which patients are good candidate for anti-VEGF target therapy is actually based only on gross clinical characteristics. This review will focus on: i) the actual role of VEGF pathway inhibitors in treating mCRC, ii) the clinical criteria for patients’ selection and, ultimately, iii) the present status of knowledge and future perspectives for developing molecular tools to foresee and monitor antiangiogenic activity. VEGF PATHWAY INHIBITION IN PRACTICE: WHERE DO WE STAND?
CLINICAL
Different studies explored the value of adding the antiVEGF moAb bevacizumab to conventional cytotoxic regimens ascertaining its role in the current management of mCRC. On the other hand, the approval of bevacizumab rised a number of still unanswered questions. First of all, if is there an optimal chemotherapeutic scheme for combination with the antiangiogenic agent. The pivotal phase III AVF2107 study conducted by Hurwitz et al. [3] in previously untreated mCRC patients, demonstrated improved activity and efficacy with the combination of bolus FU and irinotecan (IFL) plus bevacizumab in comparison to chemotherapy alone {response rate (RR) 44.8% vs 34.8%, p=0.004; median progression-free survival (PFS) 10.6 vs 6.2 months, HR=0.54, p150% from baseline plasma VEGF levels within the first cycle of treatment correlated with clinical outcome [38]. Other serum biomarkers were assessed such as activated endothelial cells, Eselectin and a transmembrane tyrosine kinase, TIE-2 but they did not show strong correlations with clinical outcome, precluding a conclusion about their potential utility. These findings differ from those observed with bevacizumab considering the results obtained with immunodepletion (decrease of VEGF after treatment) [27, 34]. Indeed, tyrosine kinase inhibitors (TKI) block the phosphorylation of VEGF receptor but do not directly affect the binding between the ligand (VEGF) and its high affinity extracellular domain of the receptor (VEGFR-2). The molecular basis of VEGF increase are still unknown but TKIs might up-regulate the receptor ligand as an attempt by endothelial cells to overcome the inhibition of VEGF pathway.
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Other possible biomarkers studied by Willett et al. [32] are tumor microvascular density, measured by immunohistochemistry and blood flow parameters by perfusion CT, the number of viable CECs and CEPs. Bevacizumab decreased tumor microvascular density and both the number of viable CECs and CEPs consistently with an antivascular effect. CEPs were detected at concentrations that were two orders of magnitude lower than those of viable CECs. The decrease in blood concentration of viable CECs was observed on day 12 after the administration of bevacizumab (which corresponds approximately to the half-life of the drug in blood circulation) [32]. CECs and CEPs are currently being assessed as potential biomarkers of anti-angiogenic therapy. Prior studies have shown that anti-angiogenic agents suppress the mobilization and blood levels of CECs and CEPs, and that treatment with a VEGFR-2 antibody causes a dosedependent reduction in viable CEPs that correlates to its antitumor activity [39]. However, flow cytometric CECs and CEPs evaluation requires a complex four-color approach with technical difficulties to store fresh clinical samples and, above all, very high costs and could provide an advantage to other molecular approaches that can be used as surrogates of angiogenesis and antiangiogenic drug activity. Interestingly, a possible alternative has been found by Rabascio et al. [40] who showed that increased circulating VE-cadherin (a specific endothelial protein) RNA in patients with cancer indicated viability of CECs. Moreover, CD133, a specific surface marker for bone marrow-derived CEPs, could be another possible biomarker for antiangiogenic therapies in CRC since Lin et al. [41] found that elevated CD133 mRNA levels predicted CRC recurrence independent of TNM stage IV disease. The Pharmacogenetic Approach A pharmacogenetic approach might help in understanding some of the differences in clinical outcomes using antiVEGF drugs. Indeed, several polymorphisms of VEGF gene have been described and many of these seem to be closely related to the growth factor expression and plasma concentration. It is conceivable that a cancer patient, bearing a VEGF SNP that affects gene expression, may have a tumor growth independent or poorly dependent on VEGF for its vascularization and resistant to an anti-VEGF treatment [42]. Indeed, many other growth factors can stimulate vascular growth and compensate the lack of VEGF, such as FGFs. In this way, a cancer patient who has low level of plasma VEGF or low expression of VEGF in tumor tissue may not benefit from bevacizumab. Renner et al. investigated the complete 3´-untranslated region (nucleotide 700–2622) of the VEGF gene for sequence variations by single-strand conformation polymorphism analysis [43]. The frequencies of allele mutation were determined in 119 healthy subjects. Three polymorphisms (702C/T, 936C/T, 1612G/A) were found, and allele frequencies of 702T, 936T and 1612A were 0.017, 0.160 and 0.471, respectively. Patients harboring the 936T allele had VEGF plasma levels significantly lower than noncarriers, whereas the SNPs 702C/T and the 1612G/A revealed no associations with VEGF plasma concentrations.
Targeting Vascular Endothelial Growth Factor Pathway
VEGF SNPs and their link with high VEGF expression were shown in NSCLC specimens and normal lung. Low VEGF-A expression in tumor cells was significantly correlated with the presence of the -2578CC, -634GG and 1154AA and GA alleles of VEGF gene. The vascular density measurement showed that tumors with -2578CC had a significantly lower value if compared with the CA, whereas the AA cases had an intermediate vascularization. Furthermore, 634GG and -1154AA VEGF SNP had also significantly lower vascular density [44]. VEGF expression may be influenced also by promoter haplotypes [45]. Four different common haplotypes (including the location of SNPs -2578, -2549, -2489, -2447, -1498, 1198, -1190, -1154, -634, and -7 from the translation start point) have been identified in the promoter region and at least one (-2578, -1154 and -634; AAG/AAG or AGG/AGG) modulates VEGF production [45]. Recently, it has been described for the first time a relationship between VEGF polymorphisms of tumor tissues and efficacy of bevacizumab treatment. Indeed, Schneider et al. [46] showed that VEGF -2578AA genotype was associated with a superior median OS in metastatic breast cancer patients treated with paclitaxel and bevacizumab. The VEGF 1154A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm. Other experiences focused on other genes and their genetic variants to evaluate their influence on bevacizumab clinical activity. Schultheis et al. [47] suggested that the IL-8 -251A/T polymorphism may be a molecular predictor of response to bevacizumab-based chemotherapy in a study of 53 ovarian cancer patients treated with bevacizumab and low dose cyclophosphamide. Genetic variants may also influence the occurrence of specific adverse events. As reported above, CRC patients treated with bevacizumab may suffer from venous and arterial thromboembolism, pulmonary embolism, gastrointestinal perforations, bleeding, proteinuria and hypertension Interestingly, in the above mentioned study by Schneider et al. two genotypes, the VEGF -634CC and VEGF -1498TT, have been associated with significantly lower incidence of grade 3 or 4 hypertension.
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done since the early phases of development of newer drugs, to move from the present paradigm of demonstrating small advantages for unselected populations to the future one of verifying substantial differences for molecularly selected patients. ABBREVIATIONS AZD2171
= cediranib
bFGF
= basic fibroblast growth factor
bFOL
= bolus 5 fluorouracil plu oxaliplatin
CapeIRI
= capecitabine plus irinotecan
CapeOXA
= capecitabine plus oxaliplatin
CECs
= circulating endothelial cells
CEPs
= circulating endothelial cell progenitors
CI
= confidence interval
CRC
= colorectal cancer
CT
= chemotherapy
DCR
= disease control rate
EGFR
= epidermal growth factor receptor
FDA
= Food and Drug Administration
FOLFIRI
= infusional 5-fluorouracil plus irinotecan
FOLFOX
= infusional 5-fluorouracil plus oxaliplatin
FOLFOXIRI = infusional fluorouracil, oxaliplatin and irinotecan FU or 5-FU
= 5-fluorouracil
GONO
= Gruppo Oncologico Nord Ovest
HR
= hazard ratio
IFL
= bolus 5-fluorouracil plus irinotecan
IgG1
= immunoglobulin G1
IL-8
= interleukin 8
LDH
= lactate dehydrogenase
mCRC
= metastatic colorectal cancer
mFOLFOX6 = modified FOLFOX6 CONCLUSION VEGF pathway inhibition is one of the most successful treatment strategy ever developed for the treatment of mCRC. At present almost all patients are candidate to receive bevacizumab. Nevertheless clinicians do not know, among other questions: i) if every patient is going to benefit from it (and if not, who does), ii) which patients are proner to suffer from serious adverse events, iii) how long to treat patients (until progression? beyond progression?). It seems difficult that trials exclusively clinical may answer all these questions and an aid is awaited from the molecular profiling of patients (at basal and during treatment). Since no validated predictive or surrogate markers of benefit from antiangiogenic therapy are still available for routine clinical use, the quest for them is a major challenge in translational cancer research and in clinical oncology. Such effort should be
mIFL
= modified IFL
moAb
= monoclonal antibody
NSCLC
= non small cell lung cancer
OS
= overall survival
PDGFR
= platelet-derived growth factor receptor
PFS
= progression-free survival
PlGF
= placental growth factor
PTK ZK
= PTK787/ZK222584 or vatalanib
RECIST
= Response Evaluation Criteria In Solid Tumors
RR
= response rate
SCID
= severe combined immunodeficient
44 Current Cancer Drug Targets, 2010, Vol. 10, No. 1
SNP
= single nucleotide polymorphism
TKI
= tyrosine kinase inhibitors
TTP
= time to progression
VEGF Trap
= aflibercept
VEGF
= vascular endothelial growth factor
VEGFR
= VEGF receptor
XELOX
= xeloda plus oxaliplatin
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Revised: December 24, 2009
Accepted: December 24, 2009
