Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients

Abstract

Background: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities.

Methods: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex.

Results: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10^-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10^-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10^-7).

Conclusions: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).

Fig. 1. CONSORT and quality control flowchart for CALGB 80303, 40503, 90401 and 40502, and ECOG-ACRIN E5103.

MAF minor allele frequency, HWE Hardy-Weinberg Equilibrium.

Fig. 2. Cumulative incidence of grade ≥ 2 hypertension for rs6770663 in KCNAB1.

The numbers next to each genotype correspond to the number of patients with hypertension grade ≥2 / total patients (%). One patient in CALGB 80303 and one patient in CALGB 90401 have the GG genotype of rs6770663 and did not report bevacizumab-induced grade ≥ 2 hypertension.

Fig. 3. Cumulative incidence of grade ≥ 2 proteinuria for rs339947 between DNAH5 and TRIO and grade ≥ 2 composite toxicity for rs16945809 in YWHAE.

rs339947 was not present in the genotype platform of CALGB 40503. The numbers next to each genotype correspond to the number of patients with hypertension grade ≥2 / total patients (%).