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Genetics and Genomics

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).

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Fig. 1: CONSORT and quality control flowchart for CALGB 80303, 40503, 90401 and 40502, and ECOG-ACRIN E5103.
Fig. 2: Cumulative incidence of grade ≥ 2 hypertension for rs6770663 in KCNAB1.
Fig. 3: Cumulative incidence of grade ≥ 2 proteinuria for rs339947 between DNAH5 and TRIO and grade ≥ 2 composite toxicity for rs16945809 in YWHAE.

Data availability

The datasets generated during and/or analysed during the current study are available in the NHGRI-EBI GWAS Catalog under study accession numbers GCST90026609, GCST90026610 and GCST90026611.

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Acknowledgements

We acknowledge the PI of ECOG-ACRIN E5103, Kathy Miller, MD.

Funding

This work was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U24CA196171, UG1CA233253, UG1CA233327 and UG1CA233373. JCFQ was supported by the São Paulo Research Foundation-FAPESP (2018/04491-2). Also supported in part by funds from Abraxis BioScience, Bristol Meyers Squibb, Celgene and Genentech. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://acknowledgments.alliancefound.org

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JCFQ, ASE and FI wrote the manuscript; FI designed the research; JCFQ, JW, ABS, CJ, ASE, FS, FM, JNP, DLH, ECD, HLM, MB, HR, HLK, WKK, MJR, DLK, KO, BS, DL and F.I. performed the research; JCFQ, JW, ABS, CJ, ASE, GJ, KO and FI analyzed the data; JW, ABS, CJ, ASE and DL contributed new reagents/analytical tools.

Corresponding author

Correspondence to Federico Innocenti.

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Ethics approval and consent to participate

All participants provided written informed consent for sample collection and pharmacogenetic analysis, and all trials were conducted in accordance with recognised ethical guidelines. The study was performed in accordance with the Declaration of Helsinki and was approved by the local IRB.

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Not applicable.

Competing interests

JCFQ, JW, DL, KO and FI are coinventors of a patent application, serial number 16/932,002. FI is an advisor for Emerald Lake Safety. These relationships have been disclosed to and are under management by UNC-Chapel Hill.

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Quintanilha, J.C.F., Wang, J., Sibley, A.B. et al. Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01557-w

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