Purpose: The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.
Methods: Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5'UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.
Results: VGPs -2578, -1512, -1451, -1411, and -460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs -152 (G/G vs. G/A + A/A) and -1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP -1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP -634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed.
Conclusions: Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.