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

TITLE=BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.833171

DOI=10.3389/fcvm.2022.833171

ISSN=2297-055X

ABSTRACT=<sec><title>Objective</title><p>Animal models suggest that <italic>BRCA1/2</italic> mutations increase doxorubicin-induced cardiotoxicity risk but data in humans are limited. We aimed to determine whether germline <italic>BRCA1/2</italic> mutations are associated with cardiac dysfunction in breast cancer survivors.</p></sec><sec><title>Methods</title><p>In a single-center cross-sectional study, stage I-III breast cancer survivors were enrolled according to three groups: (1) <italic>BRCA1/2</italic> mutation carriers treated with doxorubicin; (2) <italic>BRCA1/2</italic> mutation non-carriers treated with doxorubicin; and (3) <italic>BRCA1/2</italic> 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 <italic>in vitro</italic> study was performed to assess the impact of <italic>BRCA1</italic> loss of function on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) survival following doxorubicin exposure.</p></sec><sec><title>Results</title><p>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 <italic>BRCA1/2</italic> mutation status (<italic>p</italic> = 0.03). In doxorubicin-treated <italic>BRCA1/2</italic> 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<sub>2max</sub> were observed across the three groups (p<sub>overall</sub> = 0.07). Doxorubicin caused a dose-dependent reduction in viability of iPSC-CMs <italic>in vitro</italic> without differences between <italic>BRCA1</italic> mutant and wild type controls (<italic>p</italic> &gt; 0.05).</p></sec><sec><title>Conclusions</title><p><italic>BRCA1/2</italic> 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 <italic>BRCA1/2</italic> mutations in women with breast cancer.</p></sec>