BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors

Biniyam G Demissei; WenJian Lv; Nicholas S Wilcox; Karyn Sheline; Amanda M Smith; Kathleen M Sturgeon; Chris McDermott-Roe; Kiran Musunuru; Bénédicte Lefebvre; Susan M Domchek; Payal Shah; Bonnie Ky

doi:10.3389/fcvm.2022.833171

BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors

Front Cardiovasc Med. 2022 Feb 15:9:833171. doi: 10.3389/fcvm.2022.833171. eCollection 2022.

Authors

Biniyam G Demissei¹, WenJian Lv¹, Nicholas S Wilcox¹, Karyn Sheline¹, Amanda M Smith¹, Kathleen M Sturgeon², Chris McDermott-Roe¹, Kiran Musunuru¹, Bénédicte Lefebvre^{1

3}, Susan M Domchek^{3

4}, Payal Shah^{3

4}, Bonnie Ky^{1

3

5}

Affiliations

¹ Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
² Department of Public Health Sciences, Pennsylvania State College of Medicine, Hershey, PA, United States.
³ Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
⁴ Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
⁵ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.

Abstract

Objective: Animal models suggest that BRCA1/2 mutations increase doxorubicin-induced cardiotoxicity risk but data in humans are limited. We aimed to determine whether germline BRCA1/2 mutations are associated with cardiac dysfunction in breast cancer survivors.

Methods: In a single-center cross-sectional study, stage I-III breast cancer survivors were enrolled according to three groups: (1) BRCA1/2 mutation carriers treated with doxorubicin; (2) BRCA1/2 mutation non-carriers treated with doxorubicin; and (3) BRCA1/2 mutation carriers treated with non-doxorubicin cancer therapy. In age-adjusted analysis, core-lab quantitated measures of echocardiography-derived cardiac function and cardiopulmonary exercise testing (CPET) were compared across the groups. A complementary in vitro study was performed to assess the impact of BRCA1 loss of function on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) survival following doxorubicin exposure.

Results: Sixty-seven women with mean (standard deviation) age of 50 (11) years were included. Age-adjusted left ventricular ejection fraction (LVEF) was lower in participants receiving doxorubicin regardless of BRCA1/2 mutation status (p = 0.03). In doxorubicin-treated BRCA1/2 mutation carriers and non-carriers, LVEF was lower by 5.4% (95% CI; -9.3, -1.5) and 4.8% (95% CI; -9.1, -0.5), respectively compared to carriers without doxorubicin exposure. No significant differences in VO_2max were observed across the three groups (p_overall = 0.07). Doxorubicin caused a dose-dependent reduction in viability of iPSC-CMs in vitro without differences between BRCA1 mutant and wild type controls (p > 0.05).

Conclusions: BRCA1/2 mutation status was not associated with differences in measures of cardiovascular function or fitness. Our findings do not support a role for increased cardiotoxicity risk with BRCA1/2 mutations in women with breast cancer.

Keywords: BRCA1/2; HER2 therapy; anthracycline; breast cancer; cardiomyocyte; heart failure.