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

BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors

Biniyam G Demissei  1 , WenJian Lv  1 , Nicholas S Wilcox  1 , Karyn Sheline  1 , Amanda M Smith  1 , Kathleen M Sturgeon  2 , Chris McDermott-Roe  1 , Kiran Musunuru  1 , Bénédicte Lefebvre  1   3 , Susan M Domchek  3   4 , Payal Shah  3   4 , Bonnie Ky  1   3   5
Affiliations

BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors

Biniyam G Demissei et al. Front Cardiovasc Med. .

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 VO2max were observed across the three groups (poverall = 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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Age-adjusted marginal mean (95% Confidence Interval) estimates of echocardiography and cardiopulmonary exercise testing measures according to exposure group. The figure presents the age-adjusted marginal mean (95% confidence interval) estimates based on analysis of covariance for measures of systolic function, diastolic function and cardiopulmonary exercise testing according to exposure group including (a) BRCA1/2 mutation carriers exposed to doxorubicin, (b) BRCA1/2 mutation carriers not exposed to doxorubicin, and (c) BRCA1/2 mutation non-carriers exposed to doxorubicin. For longitudinal and circumferential strain, absolute values are presented, where by a higher value represents greater function.
Figure 2
Figure 2
BRCA1 mutation and cardiomyocyte cell viability following doxorubicin. The figure presents comparisons of cell viability between BRCA1 mutant [BRCA1 (+/indel)] and wild type [BRCA1 (+/+)] human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) following exposure to 1–500 nM doxorubicin concentration.
See this image and copyright information in PMC

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