Single nucleotide polymorphism analysis and outcome in advanced-stage cancer patients treated with bevacizumab

Abstract

Background: There are no validated biomarkers predicting benefit from bevacizumab (bev) therapy. In an effort to identify such markers, biomarker studies have been integrated into several Phase III trials with bev in an attempt to correlate genetic variability in VEGFA pathway genes with the therapeutic efficacy of bev. Methods: Germline DNA was available from 1346 subjects diagnosed with advanced primary colorectal (NO16966), pancreatic (AVITA), non-small cell lung (AVAiL), renal (AVOREN) and breast (AVADO) cancer. Overall, 628 subjects received bev. Common single nucleotide polymorphisms (SNPs) located in the hypoxia-inducible factors (HIF-1A and EPAS1), VEGFA, VEGFA-receptors (VEGFR1 and VEGFR2) and several other genes were selected using a SNP tagging approach. A total of 158 SNPs were genotyped using MALDI-TOF mass spectrometry. A meta-analysis of individual patient (pt) data was performed, after stratification for cancer type and other covariates. Genetic associations were assessed using Cox Proportional Hazard Regression for progression-free survival (PFS) and overall survival (OS). Results: The rs4145836 SNP in EPAS1 was most significantly associated with improved PFS in both bev-treated pts (allelic HR 0.6895% CI 0.56- 0.82, p = 0.0001) and placebo pts, suggesting that this SNP may be a prognostic marker for outcome independent of bev. The rs699946 SNP, located in the VEGFA promoter, was associated with improved PFS in bevtreated subjects with an allelic HR of 1.27 (95% CI 1.08-1.49, p = 0.003). No effect was seen in placebo subjects, suggesting that rs699946 may be a predictive marker for favourable outcome with bev treatment. The nearby rs699947 SNP in VEGFA, which has previously been associated with bev treatment outcome in breast cancer [Schneider et al. 2008], was not associated with a PFS advantage in our study. In terms of OS, the rs12505758 SNP in VEGFR2 was most significantly associated with improved OS in bev-treated pts (allelic HR 1.50, 95% CI 1.21-1.85, p = 0.0002). No effects for rs12505758 were seen in placebo pts. Conclusions: Our study represents a large genetic analysis of SNPs in correlation to bev outcome, based on pooled data sets. The observed associations suggest certain genetic loci as potential markers for favourable prognosis, regardless of bev treatment, and prediction of benefit from bev. Further studies will be necessary to assess the potential clinical value of these preliminary associations.