Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Peripheral Vascular Disease, Cardiovascular System & Cardiology, Anti-angiogenesis, Bevacizumab, Hypertension, Single nucleotide polymorphism, Predictive biomarker, ENDOTHELIAL GROWTH-FACTOR, PHASE-III TRIAL, METASTATIC COLORECTAL-CANCER, PACLITAXEL PLUS BEVACIZUMAB, BLOOD-PRESSURE, 1ST-LINE THERAPY, NITRIC-OXIDE, FACTOR RECEPTOR, DOUBLE-BLIND, PLACEBO, Antibodies, Monoclonal, Humanized, Demography, Endpoint Determination, Female, Genetic Markers, Genetic Predisposition to Disease, Humans, Incidence, Male, Middle Aged, Placebos, Polymorphism, Single Nucleotide, Signal Transduction, Treatment Outcome, Vascular Endothelial Growth Factor A, 1112 Oncology and Carcinogenesis, 1117 Public Health and Health Services, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis

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 bevacizumab-induced hypertension (P ≤ 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 investigation regarding their role in mediating bevacizumab-induced hypertension.