Abstract 4131: Genetic variant associations with treatment outcome and safety in metastatic colorectal cancer patients treated with sorafenib and bevacizumab (BEV) as salvage therapy

Abstract

Abstract Purpose: Polymorphisms in genes involved in the angiogenesis pathway have been investigated as predictive markers for efficacy and tolerability to anti-angiogenesis treatment, such as BEV. This study examines single nucleotide polymorphisms (SNPs) in VEGF, VEGFR2, and HIF-1α for their potential association with outcome and safety in metastatic colorectal cancer (mCRC) patients treated with the combined vertical blockade of VEGF signaling (i.e., sorafenib and BEV) as salvage therapy. Experimental procedures: Genomic DNA was extracted from peripheral blood for 78/79 evaluable patients in the North Central Cancer Treatment Group (NCCTG) Phase II study, N054C (Grothey, et al., ASCO 2010). TaqMan or direct sequencing was used for genotyping VEGF (rs25648, rs3025039, rs2010963, rs1005230, rs833061, rs699947, rs1570360), VEGFR2 (rs2305948, rs2219471, rs2071559, rs1870377), and HIF-1α (rs11549465, rs11549467) SNPs. Chi-square or Fisher's exact test was used to determine genotype associations with the study's primary endpoint, progression-free rate at 3 months of follow-up, as well as genotype associations with the most common grade 3+ adverse events at least possibly related (AE rels) to treatment (i.e., fatigue, hypertension, skin reaction). Results summary: The presence of a mutant T allele in the 5’ UTR of VEGF (rs25648; C534T) was associated with fewer successes in progression-free rate at 3 month follow-up (Fisher's exact test, p=0.0187). In addition, the presence of a C allele in the promoter region of VEGFR2 (rs2071559, T-604C) was associated with fewer grade 3+ hypertension AE rels (Fisher's exact test, p=0.0101). However, after correcting for multiple comparisons using the method of Benjamini & Hochberg none of the p-values were significant at a 0.05 level. At the same time, no differences were observed between the genotype subgroups and either progression-free rate at 3 months or the most common grade 3+ AE rels for the remaining SNPs that were analyzed, before or after correction. Conclusions: This study provides preliminary evidence that mCRC patients with the VEGF C534T (rs25648) variant may not benefit from combined treatment of sorafenib and BEV, whereas patients with the VEGFR2 T-604C (rs2071559) polymorphism may experience fewer grade 3+ AE rels. Further prospective validation of these SNPs and their association with this treatment combination in mCRC is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4131. doi:10.1158/1538-7445.AM2011-4131