Prospective evaluation of candidate snps of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC) patients treated with first-line folfiri plus bevacizumab (BV).

ABSTRACT Introduction Despite several attempts, no predictors of benefit from BV have been so far identified. We reported the association of VEGF rs833061 T/T to a worse outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI+BV, but not in a historical cohort treated with FOLFIRI. Recent post-hoc analyses on randomized trials suggested the potential prognostic and/or predictive role of other VEGF and VEGFR1/2 SNPs. Methods Moving from our retrospective finding, we designed a prospective validation trial in mCRC pts treated with first-line FOLFIRI+ BV to detect a HR for PFS of 1.7 for VEGF rs833061 T/T compared to C- variants. With two-sided alpha=0.05 and beta=0.200, 199 events were required. Accrual was faster than expected and in the meanwhile promising results about other SNPs were reported and we therefore included a confirmatory analysis of VEGF rs699946 A/G, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS rs4145836 A/G SNPs. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. Results Four-hundred-twenty-four pts were included. At a median follow up of 24 months, median PFS was 10.5 months. At the univariate analysis, no differences in PFS according to VEGF rs833061 C/T variants were observed (p=0.38). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants (N=118) were associated to shorter PFS compared to TT (N=306) (HR: 1.40 [95%CI: 1.07-1.84], p=0.015). In the multivariate model, this association retained significance (HR: 1.402 [95%CI: 1.079-1.822], p=0.012), that was lost by applying multiple testing correction. Conclusion This prospective experience failed to validate the hypothesized predictive impact of VEGF rs833061 variants. Also other previous retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic rather than predictive impact was previously reported, correlated with PFS. We suggest that future studies on biomarkers of benefit from BV should look at the complexity of tumoral angiogenesis at different levels and not only from the genetic perspective.