Abstract 2199: Associations of genetic polymorphisms in VEGFR1 with progression-free and overall survival in patients with neuroendocrine tumors treated with the VEGFA inhibitor bevacizumab.

Abstract

Abstract Background: Neuroendocrine tumors (NET) have been shown to be responsive to treatment with VEGF pathway inhibitors. We hypothesized that genetic variation in VEGFA, VEGFR1 or VEGFR2 is associated with progression free survival (PFS) and/or overall survival (OS) in patients with metastatic NET treated with bevacizumab, a monoclonal antibody targeting VEGFA. Methods: We selected 61 functional and tagging SNPs with a minor allele frequency of 5% or greater, with full gene coverage of VEGFA, VEGFR1 and VEGFR2. We pooled data from two genotyped datasets, selecting 82 patients with metastatic NET who received bevacizumab administered either as a single agent or as part of a combination regimen. Using a Cox proportional hazards regression analysis, and an additive genetic model, we tested the SNPs’ associations with PFS and OS adjusting for age and stage at diagnosis, gender, tumor origin, grade of differentiation, and genotyping dataset. Results: We found that 4 intronic tagging SNPs in VEGFR1, rs7987649, rs9508021, rs9513095 and rs2104330 were associated with PFS at p<0.05. The association between rs7987649 and PFS (multivariate Hazard Ratio 0.55 (0.38, 0.81) p=0.002) remained significant after adjusting for multiple testing. One of the four SNPs associated with PFS, rs7987649, as well as another SNP in VEGFR1, rs3794339, were associated with OS at p<0.05 although these associations did not remain significant after multiple testing adjustment. No SNPs in either VEGFR2 or VEGFA were associated with PFS or OS. Conclusions: In patients with neuroendocrine tumors treated with bevacizumab, the VEGFR1 SNP rs7987649 appears to be associated with progression-free survival. We note that three SNPs identified in our analysis, rs9508021, rs9513095 and rs2104330, are in strong linkage disequilibrium with SNPs rs7993418 and rs9582036, which have been associated with increased VEGFR1 expression and with PFS and OS in pancreatic adenocarcinoma (Lambrechts, 2012). Further study of loci within this region of VEGFR1 is warranted to discover potential causal variants affecting NET survival. Citation Format: Monica Ter-Minassian, ZhiRong R. Qian, Jennifer A. Chan, Susanne M. Hooshmand, Lauren K. Brais, Rachel Heafield, Xihong Lin, Geoffrey Liu, David C. Christiani, Matthew H. Kulke. Associations of genetic polymorphisms in VEGFR1 with progression-free and overall survival in patients with neuroendocrine tumors treated with the VEGFA inhibitor bevacizumab. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2199. doi:10.1158/1538-7445.AM2013-2199