1412 POSTER Genetic Markers in Relation to Bevacizumab-induced Hypertension

Abstract

Background: There are currently no biomarkers predicting outcome or toxicity associated with bevacizumab treatment for advanced solid tumours. Here, we combined biomarker studies from several phase III trials with bevacizumab to systematically assess whether genetic variation in VEGFA pathway genes and other genes is associated with bevacizumab-induced hypertension. Methods: Germline DNA was available from 628 patients diagnosed with advanced primary colorectal (NO16966), pancreatic (AVITA), non-small cell lung (AVAiL), renal (AVOREN) and breast (AVADO) cancer and treated with bevacizumab. Toxicities were identified from clinical trial reports and graded according to common toxicity criteria. Overall, 113 patients had grade 1-4 bevacizumab-induced hypertension (assessed across trials with CTCAE v2-3). A total of 158 single nucleotide polymorphisms (SNPs) located in VEGFA, VEGFA-receptors (FLT1 and KDR) and other genes were selected using a SNP tagging approach and genotyped using MALDI-TOF mass spectrometry. A logistic regression on individual patient data was performed after stratification for cancer type and other covariates. Results: Ten SNPs were associated with bevacizumab-induced hypertension (p < 0.05), but none of these surpassed the threshold for multiple testing (p < 0.0003). The three SNPs showing the strongest association (p < 0.01) were: rs2305949 in KDR (allelic OR 0.93, 95% CI 0.88-0.98, p = 0.0059), rs4444903 in EGF (allelic OR 1.06, 95% CI 1.02-1.11, p = 0.006); and rs1680695 in EGLN3 (allelic OR 1.07, 95% CI, 1.02-1.12, p = 0.008). Interestingly, rs2305949 and rs4444903 were closely linked to amino acid changes occurring on position 273 and 708 of KDR and EGF, suggesting that these changes may functionally affect both genes and thereby contribute to hypertension. Notably, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (allelic OR 1.06, 95% CI 1.01-1.11, p = 0.02), thereby supporting previous observations in a limited number of patients [Frey et al. ASCO 2008].ents [Frey et al. ASCO 2008]. Conclusions: Our study represents a large genetic analysis of bevacizumab-induced hypertension using pooled data sets. The genes described warrant further investigation for their potential role in the safety profile of bevacizumab.