Prospective Validation of Candidate SNPs of <i>VEGF/VEGFR</i> Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab

<div><p>Purpose</p><p>The potential impact of different SNPs of <i>VEGF/VEGFR</i> pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of <i>VEGFA</i> rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of <i>VEGF/VEGFR</i> pathway genes was included.</p><p>Experimental design</p><p>To detect a HR for PFS of 1.7 for <i>VEGFA</i> rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. <i>VEGFA</i> rs699946 A/G, rs699947 A/C, <i>VEGFR1</i> rs9582036 A/C and rs7993418 A/G, <i>VEGFR2</i> rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and <i>EPAS1</i> rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing.</p><p>Results</p><p>Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to <i>VEGFA</i> rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only <i>VEGFR2</i> rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05–1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95–1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082–1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14).</p><p>Conclusion</p><p>This prospective experience failed to validate the hypothesized predictive impact of <i>VEGFA</i> rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only <i>VEGFR2</i> rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.</p>