Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar 1;5(3):309-317.
doi: 10.1001/jamacardio.2019.5586.

Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer

Anthony F Yu  1   2 , Jessica R Flynn  3 , Chaya S Moskowitz  3 , Jessica M Scott  1   2 , Kevin C Oeffinger  4 , Chau T Dang  1   2 , Jennifer E Liu  1   2 , Lee W Jones  1   2 , Richard M Steingart  1   2
Affiliations

Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer

Anthony F Yu et al. JAMA Cardiol. .

Abstract

Importance: Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer.

Objective: To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer.

Design, setting, and participants: This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019.

Main outcomes and measures: Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2).

Results: A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (β coefficient, -0.75; 95% CI, -1.32 to -0.18).

Conclusions and relevance: Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Yu reported receiving grants from American Heart Association and the National Institutes of Health (NIH) during the conduct of the study and consulting fees from Glenmark Pharmaceuticals and Genentech, Inc, outside the submitted work. Dr Scott reported receiving grants from AKTIV Against Cancer and the NIH during the conduct of the study. Dr Dang reported receiving grants from institutional research funding provided to Memorial Sloan Kettering Cancer Center (MSKCC) from Puma Biotechnology, Inc, and Roche Group/Genentech, Inc, and serving as a compensated advisory board member to Roche Group/Genentech, Inc, Eli Lilly and Company, Daiichi Sankyo Company, and Puma Biotechnology, Inc, during the conduct of the study. Dr Liu reported receiving consulting fees from Bay Labs outside the submitted work. Dr Jones reported owning stock in Pacylex Pharmaceuticals, Inc, outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Cardiopulmonary Function as Assessed by Resting Left Ventricular Ejection Fraction (LVEF), Resting Global Longitudinal Strain (GLS), and Peak Oxygen Consumption (Peak VO2)
Box-plot analysis of resting LVEF, resting GLS, and peak VO2 among the patients who developed cardiotoxicity during trastuzumab treatment (TOX group), those with no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group), and age-matched healthy controls (HC group). The horizontal line within each box indicates the median, while the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box mark the 90th and 10th percentiles. The blue dot represents outliers.
See this image and copyright information in PMC

References

    1. Romond EH, Jeong JH, Rastogi P, et al. . Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30(31):3792-3799. doi:10.1200/JCO.2011.40.0010 - DOI - PMC - PubMed
    1. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. ; Herceptin Adjuvant (HERA) Trial Study Team . 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021-1028. doi:10.1016/S0140-6736(13)61094-6 - DOI - PubMed
    1. Tarantini L, Cioffi G, Gori S, et al. ; Italian Cardio-Oncologic Network . Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world women with breast cancer. J Card Fail. 2012;18(2):113-119. doi:10.1016/j.cardfail.2011.10.015 - DOI - PubMed
    1. Slamon D, Eiermann W, Robert N, et al. ; Breast Cancer International Research Group . Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283. doi:10.1056/NEJMoa0910383 - DOI - PMC - PubMed
    1. Guarneri V, Lenihan DJ, Valero V, et al. . Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience. J Clin Oncol. 2006;24(25):4107-4115. doi:10.1200/JCO.2005.04.9551 - DOI - PubMed

Publication types