Breast Cancer Research and Treatment

, Volume 155, Issue 2, pp 285–293 | Cite as

Cardiac function in BRCA1/2 mutation carriers with history of breast cancer treated with anthracyclines

  • Ana BaracEmail author
  • Filipa Lynce
  • Karen L. Smith
  • Mihriye Mete
  • Nawar M. Shara
  • Federico M. Asch
  • Madeline P. Nardacci
  • Lynette Wray
  • Pia Herbolsheimer
  • Raquel A. Nunes
  • Sandra M. Swain
  • Robert Warren
  • Beth N. Peshkin
  • Claudine Isaacs
Clinical trial


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.


BRCA1/2 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.

Ethical standards

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.


  1. 1.
    Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329–1333PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Mai PL, Chatterjee N, Hartge P et al (2009) Potential excess mortality in BRCA1/2 mutation carriers beyond breast, ovarian, prostate, and pancreatic cancers, and melanoma. PLoS ONE 4:e4812PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Mersch J, Jackson MA, Park M et al (2015) Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121:269–275PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Arts-de Jong M, Maas AH, Massuger LF, Hoogerbrugge N, de Hullu JA (2014) BRCA1/2 mutation carriers are potentially at higher cardiovascular risk. Crit Rev Oncol Hematol 91:159–171CrossRefPubMedGoogle Scholar
  5. 5.
    Haider N, Arbustini E, Gupta S et al (2009) Concurrent upregulation of endogenous proapoptotic and antiapoptotic factors in failing human hearts. Nat Clin Pract Cardiovasc Med 6:250–261CrossRefPubMedGoogle Scholar
  6. 6.
    Haudek SB, Taffet GE, Schneider MD, Mann DL (2007) TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest 117:2692–2701PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Olivetti G, Abbi R, Quaini F et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141CrossRefPubMedGoogle Scholar
  8. 8.
    Shukla PC, Singh KK, Quan A et al (2011) BRCA1 is an essential regulator of heart function and survival following myocardial infarction. Nat Commun 2:593PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Singh KK, Shukla PC, Quan A et al (2012) BRCA2 deficiency exaggerates doxorubicin-induced cardiomyocyte apoptosis and cardiac failure. J Biol Chem 287:6604–6614Google Scholar
  10. 10.
    Kosmala W, Jellis CL, Marwick TH (2015) Exercise limitation associated with asymptomatic left ventricular impairment: analogy with stage B heart failure. J Am Coll Cardiol 65:257–266CrossRefPubMedGoogle Scholar
  11. 11.
    Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH (2014) Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 63:2751–2768CrossRefPubMedGoogle Scholar
  12. 12.
    National Comprehensive Cancer Network (2015) Breast version 3. 2015Google Scholar
  13. 13.
    Kishi S, Teixido-Tura G, Ning H et al (2015) Cumulative blood pressure in early adulthood and cardiac dysfunction in middle age: the CARDIA Study. J Am Coll Cardiol 65:2679–2687CrossRefPubMedGoogle Scholar
  14. 14.
    Marwick TH, Venn AJ (2015) The strain of detecting early target organ damage in hypertension. J Am Coll Cardiol 65:2688–2690CrossRefPubMedGoogle Scholar
  15. 15.
    Szelenyi Z, Fazakas A, Szenasi G et al (2015) The mechanism of reduced longitudinal left ventricular systolic function in hypertensive patients with normal ejection fraction. J Hypertens 33:1962–1969CrossRefPubMedGoogle Scholar
  16. 16.
    Hlatky MA, Boineau RE, Higginbotham MB et al (1989) A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 64:651–654CrossRefPubMedGoogle Scholar
  17. 17.
    Tang WH, Topol EJ, Fan Y et al (2014) Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients. J Am Heart Assoc 3:e000960PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Merz CN, Kelsey SF, Pepine CJ et al (1999) The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol 33:1453–1461CrossRefPubMedGoogle Scholar
  19. 19.
    Shaw LJ, Olson MB, Kip K et al (2006) The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. J Am Coll Cardiol 47:S36–S43CrossRefPubMedGoogle Scholar
  20. 20.
    Lang RM, Badano LP, Mor-Avi V et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28(1–39):e14PubMedGoogle Scholar
  21. 21.
    Tan-Chiu E, Yothers G, Romond E et al (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811–7819CrossRefPubMedGoogle Scholar
  22. 22.
    Yingchoncharoen T, Agarwal S, Popovic ZB, Marwick TH (2013) Normal ranges of left ventricular strain: a meta-analysis. J Am Soc Echocardiogr 26:185–191CrossRefPubMedGoogle Scholar
  23. 23.
    Ho E, Brown A, Barrett P et al (2010) Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart 96:701–707CrossRefPubMedGoogle Scholar
  24. 24.
    Lin LI (1989) A concordance correlation coefficient to evaluate reproducibility. Biometrics 45:255–268CrossRefPubMedGoogle Scholar
  25. 25.
    Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1:307–310CrossRefPubMedGoogle Scholar
  26. 26.
    Ismail-Khan R, Sajjad M, Sun W et al (2012) An exploratory study to determine if BRCA1 and BRCA2 mutation carriers have higher risk of cardiac toxicity. J Clin Oncol 30(suppl):abstr 1585Google Scholar
  27. 27.
    Kalam K, Otahal P, Marwick TH (2014) Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction. Heart 100:1673–1680CrossRefPubMedGoogle Scholar
  28. 28.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97:2869–2879CrossRefPubMedGoogle Scholar
  29. 29.
    Von Hoff DD, Layard MW, Basa P et al (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710–717CrossRefGoogle Scholar
  30. 30.
    Gulati M, Pandey DK, Arnsdorf MF et al (2003) Exercise capacity and the risk of death in women: the St James Women Take Heart Project. Circulation 108:1554–1559CrossRefPubMedGoogle Scholar
  31. 31.
    Wei M, Kampert JB, Barlow CE et al (1999) Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA 282:1547–1553CrossRefPubMedGoogle Scholar
  32. 32.
    Jones LW, Courneya KS, Mackey JR et al (2012) Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. J Clin Oncol 30:2530–2537PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Jones LW, Haykowsky M, Pituskin EN et al (2007) Cardiovascular reserve and risk profile of postmenopausal women after chemoendocrine therapy for hormone receptor–positive operable breast cancer. Oncologist 12:1156–1164CrossRefPubMedGoogle Scholar
  34. 34.
    Lejskova M, Alusik S, Valenta Z, Adamkova S, Pitha J (2012) Natural postmenopause is associated with an increase in combined cardiovascular risk factors. Physiol Res 61:587–596PubMedGoogle Scholar
  35. 35.
  36. 36.
    Bairey Merz CN, Olson M, McGorray S et al (2000) Physical activity and functional capacity measurement in women: a report from the NHLBI-sponsored WISE study. J Womens Health Gend Based Med 9:769–777CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ana Barac
    • 1
    • 2
    Email author
  • Filipa Lynce
    • 2
    • 3
  • Karen L. Smith
    • 4
  • Mihriye Mete
    • 5
  • Nawar M. Shara
    • 5
  • Federico M. Asch
    • 1
    • 5
  • Madeline P. Nardacci
    • 2
  • Lynette Wray
    • 5
  • Pia Herbolsheimer
    • 6
  • Raquel A. Nunes
    • 6
  • Sandra M. Swain
    • 6
  • Robert Warren
    • 2
    • 3
  • Beth N. Peshkin
    • 2
  • Claudine Isaacs
    • 2
    • 3
  1. 1.Division of Cardiology, MedStar Washington Hospital CenterMedStar Heart and Vascular InstituteWashington DCUSA
  2. 2.Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashington DCUSA
  3. 3.Division of OncologyMedStar Georgetown University HospitalWashington DCUSA
  4. 4.Johns Hopkins Kimmel Cancer CenterSibley Memorial HospitalWashington DCUSA
  5. 5.MedStar Health Research InstituteWashington DCUSA
  6. 6.Division of OncologyMedStar Washington Hospital CenterWashington DCUSA

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