Role of VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) in predicting treatment-induced hypertension (HTN) and clinical outcome (CO) in metastatic clear cell RCC (mccRCC) patients (pts) treated with sunitinib.

Abstract

4629 Background: We previously reported that VEGF SNP-634 is associated with development of sunitinib-induced HTN in mccRCC pts (J Clin Oncol 27:15s, 2009). We have now expanded this analysis to include a panel of established SNPs within VEGF [-2578 C/A (rs 699947), -1154 G/A (rs 1570360), 936 C/T (rs 3025039)] and VEGFR2 [889 G/A (rs 2305948), 1416 A/T (rs 1870377)]. We tested the hypothesis that VEGF and VEGFR2 SNPs differ for association with HTN and CO [tumor shrinkage (TS), progression-free survival (PFS) and overall survival (OS)] in mccRCC pts receiving sunitinib. Methods: mccRCC pts receiving sunitinib (50mg 4/2) with germline DNA were retrospectively identified. Genomic DNA was isolated from peripheral blood lymphocytes and amplified using primers designed to flanking sequences for the respective SNPs. Genotypes were assigned following sequence analysis. Data was analyzed using the Wilcoxon rank sum and Cochran-Armitage trend tests, and proportional hazards models. Results: Sixty-four pts were identified of which 63 had SNP data. Pt characteristics included 78% male; median age 60 (range, 35-80); 67% ECOG performance status 0; 89% prior nephrectomy and 63% previously treated with cytokines (48%) and/or a tyrosine kinase inhibitor (TKI; 24%). Among candidate VEGF SNPs, 936 was associated with median TS (C/T – 48% and C/C – 24%, p=0.04) and -2578 was associated with prevalence of sunitinib-induced HTN (C/C – 100%, A/C – 89%, A/A – 69%, p=0.03). None of the VEGF SNPs were associated with PFS or OS. In contrast, VEGFR2 SNPs were not associated with HTN or TS. However, the most favorable combined VEGFR2 genotype [G/A (889) and A/A (1,416)] had significantly better OS (p=.03) than pts with less favorable combined genotypes. The impact of the combined genotype on OS remained significant after adjusting for Cleveland Clinic TKI risk group (p=.04). Conclusions: In mccRCC pts treated with sunitinib, VEGF SNPs (-2578 and -634) are associated with HTN, and 936 is associated with TS, while VEGFR2 SNPs (889 and 1,416) are correlated with OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer