Genomic Analysis of Bevacizumab-induced Hypertension

Bevacizumab use in the treatment of cancer can lead to the development of hypertension in some patients, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. In the present study, whole exomes and flanking regulatory regions of candidate genes associated with vasodilation and blood pressure were sequenced in bevacizumab-treated subjects with the objective of identifying genes harboring multiple variants associated with severe, early-onset bevacizumab-induced hypertension.]]> To identify SNPs associated with bevacizumab-induced hypertension risk, sequencing was performed on 61 European bevacizumab-treated patients (38 male, 23 female) selected from the CALGB 80405 study. Nineteen cases had developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment. Whole exomes and flanking regulatory regions of 174 candidate genes (selected based on their documented role in VEGF signaling, endothelial cell biology, nitric oxide signaling, or hypertension) were sequenced on the Illumina HiSeq 2500 System. The results presented are from a case-control association analysis of common variants in the candidate genes (exons + flanking regions). Covariates are sex, age, body mass index, preexisting hypertension, and preexisting diabetes. The data are in the public ftp site. ]]>The patient cohort for this study was selected from the bevacizumab arm of CALGB 80405, a phase III trial conducted to determine if the addition of cetuximab vs bevacizumab to FOLFIRI or FOLFOX is superior as first-line therapy in advanced or metastatic KRAS wild-type colorectal cancer. Subjects fulfilled all previously described (https://www.ncbi.nlm.nih.gov/pubmed/28632865) eligibility criteria for the study, including the requirement that any existing hypertension must be well controlled (<160/90 mmHg) on a regimen of anti-hypertensive therapy. Patients received 5 mg/kg bevacizumab every two weeks followed by FOLFOX or FOLFIRI every two weeks. Blood pressure was measured prior to randomization, at day 1 of each eight week treatment cycle, and every two weeks during treatment. Serious adverse events, including hypertension, were reported during each treatment cycle. The severity of hypertension was assessed on a scale of 1-5 according to the NCI Common Terminology Criteria for Adverse Events version 3. DNA was available from patients who were also enrolled in a pharmacogenetic companion study (CALGB 60501) embedded within CALGB 80405. Cases and controls were selected to compare severe, early-onset hypertension patients to those with no reported hypertension. Cases were defined as having at least one grade 3 or higher hypertension event during the first three treatment cycles. Controls were defined as having no reported hypertension during the first six treatment cycles while completing a minimum of four uninterrupted cycles with no gaps in adverse event form coverage.]]>