Genetic variations in semaphorin/neuropilin signaling to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab-based chemotherapy.

Abstract

11608 Background: Neuropilin ( NRP) is known to be an important VEGF co-receptor that acts as a key mediator of angiogenesis. Its ligands, semaphorins ( SEMA), compete with VEGF for NRP binding and can themselves have angiogenic activity. Plexins are also receptors of SEMAs, and have the GTPase activating proteins (GAPs) domain for RAS. NRPs are shown to signal through RAS pathways. We aimed to evaluate whether single nucleotide polymorphisms (SNPs) of genes involved in the SEMA/NRPpathways predict clinical outcome in bevacizumab-treated mCRC pts. Methods: Associations between nine SNPs in 7 genes ( SEMA3A, SEMA3D, SEMA3F, NRP1, NRP2, PLXNA1 and PLXND1) and clinical outcomes were evaluated in mCRC patients receiving first-line FOLFIRI-bevacizumab in a phase III trial: TRIBE ( N= 228). Associations between genotype and RAS mutation status with clinical outcomes was also examined. Main characteristics were the following: male/female = 138/90; median age = 60; RAS-wildtype/mutant = 55/116; median PFS = 9.7 months; median OS = 26.1 months, median follow-up time = 49.3 months. Results: NRP1 rs2228638 Any A ( N= 40) showed a significantly longer PFS compared to G/G variant ( N= 188) in the univariate (11.6 months (M) vs. 9.5 M, HR = 0.64, 95%CI = 0.43-0.95, p = 0.022) and the multivariate analysis (HR = 0.59, 95%CI = 0.38-0.90, p = 0.016). SEMA3F rs12632110 A/A ( N= 20) showed a significantly shorter PFS compared to any G variant (N = 205) in the multivariate analysis (HR = 1.89, 95%CI = 1.02-3.49, p = 0.043). Among RAS-mutant pts, SEMA3F rs12632110, SEMA3F rs1046956, SEMA3D rs7800072, NRP1 rs228638, PLXNA1 rs4679323 and PLXND1 rs2255703 polymorphisms were significantly associated with PFS in the univariate and multivariate analysis. PLXNA1 rs4679323 was also significantly associated with OS in the univariate and multivariate analysis. There was no association between these polymorphisms and outcome in patients with RASwildtype tumors. Conclusions: Genetic variants within SEMA/NRP pathways may be prognostic markers in RAS mutant mCRC patients treated with bevacizumab-based chemotherapy.