Genetic markers of bevacizumab-induced hypertension

Abstract

Purpose There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. Experimental design Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. Results Ten SNPs were associated with bevacizumabinduced hypertension (P B 0.05), but none surpassed the threshold adjusted for multiple testing (P \ 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). Conclusions The genes described in this large genetic analysis using pooled datasets warrant further functional 123 Angiogenesis (2014) 17:685-694 DOI 10.1007 investigation regarding their role in mediating bevacizumab-induced hypertension.

Bevacizumab‐induced hypertension is a predictive marker for improved outcomes in patients with recurrent glioblastoma treated with bevacizumab

“…26 These authors also demonstrated that 6 different SNPs at loci involving the VEGF-A pathway, including VEGFR-1, VEGFR-2, VEGFR-3, EPAS1, and EGLN3, were associated with the development of bevacizumab-induced hypertension. 27 Schneider et al have evaluated SNPs at the VEGF-A locus in patients with metastatic breast cancer and their association with outcome and the development of hypertension. 9 Specifically, they found that 2 VEGF promoter SNP alleles, VEGF-2578AA and VEGF-1154A, were associated with better OS whereas 2 additional VEGF promoter SNP alleles, VEGF-634CC and VEGF-1498TT, were protective against hypertension.…”

Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy

“…Fifteen SNPs known to increase patients' susceptibility to hypertension and thrombosis were also included. These were not analyzed for their effect on bevacizumab treatment outcome, but for correlation with bevacizumab-induced hypertension; results were published recently [32]. After testing for minor allele frequency and the homogeneity of the observed allele frequency (Supplementary Fig.…”

Biological agents in gastrointestinal cancers: adverse effects and their management

“…The development of hypertension is hypothesized to be due to reduced nitric oxide production and rarefaction of vessels (9,10). Hypertension in response to bevacizumab may also have a genetic component (11,12).…”