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Translational Therapeutics

Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE

British Journal of Cancer volume 130, pages 1348–1355 (2024)Cite this article

Subjects

Abstract

Background

Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions.

Methods

We performed post-hoc analyses to evaluate the association in 3124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n = 346) and SBP ≥ 180 mmHg (hypertensive crisis) (n = 69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis.

Results

Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10−9; OR = 5.2).

Conclusion

Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity.

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Fig. 1: Patient flow diagram.
Fig. 2: Kaplan–Meier survival curve for the patients with vs. without bevacizumab-induced hypertensive crisis (SBP ≥ 180 mmHg).
Fig. 3: Germline genetic associations with bevacizumab-induced hypertensive crisis (SBP ≥ 180 mmHg) from patients of European ancestry in E5103 and BEATRICE.
Fig. 4: Germline genetic associations with bevacizumab-induced hypertensive crisis (SBP ≥ 180 mmHg) in patients of European ancestry in E5103 and BEATRICE from whole-exome (WES) analysis.

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Data availability

Unidentified genome wide genotyping data and raw sequence data can be accessed at dbGaP (accession number phs003201.v1.p1).

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Funding

This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820 and U10CA180794. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation. Susan G. Komen for the Cure (SAC110056) (BPS) and Vera Bradley Foundation Center (BPS). Bevacizumab and matching placebo were provided free of charge by Roche/Genentech.

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Author notes

  1. These authors contributed equally: Fei Shen, Guanglong Jiang.

Authors and Affiliations

  1. Indiana University School of Medicine, Indianapolis, IN, USA

    Fei Shen, Guanglong Jiang, Santosh Philips, Erica Cantor, Laura Gardner, Gloria Xue, Geneva Cunningham, Nawal Kassem, Kathy D. Miller & Bryan P. Schneider

  2. Dana Farber Cancer Institute – ECOG-ACRIN Biostatistics Center, Boston, MA, USA

    Anne O’Neill

  3. Edinburgh Cancer Research Centre, Edinburgh, United Kingdom

    David Cameron

  4. Swiss Cardiovascular Center, Bern University Hospital, Inselspital, Bern, Switzerland

    Thomas M. Suter

  5. Caris Life Science, Dalla, TX, USA

    George W. Sledge

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Contributions

Conceptualization, FS and BPS; Methodology, FS, JJS, SP, EC, LG, GX, GC, NK and BPS; Formal Analysis, JJS and SP; Investigation, FS, JJS, SP and BPS; Resources, AO, DC, TMS, KDM, GWS and BPS; Data Curation, AO; Writing—Original Draft, all authors; Funding Acquisition, BPS.

Corresponding author

Correspondence to Bryan P. Schneider.

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Competing interests

BPS has received research support from Roche/Genentech for drug supply. The remaining authors declare no competing financial interests.

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This study involves secondary research of coded biological samples and clinical data for which patient consent was not required. It was determined exempt from Institutional Review Board (IRB) review as described in 45CFR 46.104 from the Indiana University IRB (application# 1311859668).

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Shen, F., Jiang, G., Philips, S. et al. Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE. Br J Cancer 130, 1348–1355 (2024). https://doi.org/10.1038/s41416-024-02602-0

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