Cardiac function in BRCA1/2 mutation carriers with history of breast cancer treated with anthracyclines
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Animal data suggest that defects in BRCA1/2 genes significantly increase the risk of heart failure and mortality in mice exposed to doxorubicine. Women with BRCA1/2 mutations who develop breast cancer (BC) may receive anthracyclines but their risk of cardiac dysfunction has not been investigated. Our study tested the hypothesis that women with history of BRCA1/2 mutation-associated BC treated with anthracyclines have impaired parameters of cardiac function compared to similarly treated women with history of sporadic BC. Women with history of BC and anthracycline treatment underwent an echocardiographic exam for assessment of primary outcomes, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). The sample size of 81 provided 79 % power with two-sided two-sample t test and alpha of 0.05 to detect a clinically meaningful difference in cardiac function of absolute 5 % points difference for LVEF and 2 % points difference for GLS. Of 81 normotensive participants, 39 were BRCA1/2 mutation carriers and 42 in the sporadic group. Mean age was 50 ± 9 years in both groups (P = 0.99) but BRCA1/2 mutation carriers had longer anthracycline treatment-to-enrollment time (7.5 ± 5.3 vs. 4.2 ± 3.3 years, P = 0.001). There were no significant differences in LVEF (P = 0.227) or GLS (P = 0.53) between the groups. LVEF was normal in 91 % of women and subclinical cardiac dysfunction defined as absolute GLS value <18.9 % was seen in 4 (10 %) BRCA1/2 mutation carriers and 7 (17 %) sporadic participants. In this first prospective examination of cardiac function in BRCA1/2 mutation carriers, we found no significant differences in sensitive echocardiographic parameters of cardiac function between BRCA1/2 mutation carriers and women with history of sporadic BC who received anthracycline treatment. In contrast to laboratory animal data, our findings indicate lack of elevated cardiac risk with the use of standard-doses of adjuvant anthracyclines in treatment of BRCA1/2 mutation carriers with early stage BC.
KeywordsBRCA1/2 mutation Breast cancer Anthracycline Cardiotoxicity Echocardiography
The authors would like to thank Maria Tupas-Habib (BS, RDCS) and Alton Henry (BS, RDCS), research sonographers from the MHRI Cardiovascular Core Laboratory, for their contribution in performing echocardiography studies. We also want to thank all the patients who participated in the study including FCR and LRPR participants, and Elizabeth Poggi (MS, CRA) and Jessica Whitley (BA) from Lombardi Comprehensive Cancer Institute, for their contribution in identifying and contacting FCR and LRPR participants. This research was also supported by the Nontherapeutic Subject Registry Shared Resource of the Lombardi Comprehensive Cancer Center (P30-CA051008).
This project was supported by a grant from Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research at the Georgetown Lombardi Comprehensive Cancer Center (to AB and KLS). AB is supported by Georgetown-Howard Universities Center for Clinical & Translational Science post-doctoral KL2 Award (5KL2TR000102-04).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest related to this manuscript. Sandra M. Swain serves as a consultant for Genentech Inc. and Claudine Isaacs received remuneration from Genentech. Inc.
This study was performed in compliance with laws of the United States of America. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ana Barac and Filipa Lynce had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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