Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function



HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years.


Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40–49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients.


Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines.


Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

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Data availability

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.


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This work was supported by Genentech, Inc., a member of the Roche group [ML28685]; the National Cancer Institute at the National Institutes of Health [P30CA051008 to Site P.I., L.M. Weiner]; a Conquer Cancer Foundation of ASCO Young Investigator Award, supported by The Breast Cancer Research Foundation [F.L.]; a Georgetown-Howard Universities Center for Clinical & Translational Science Post-doctoral KL2 Award [A.B.]; and Genentech, Inc. provided study drugs: ado-trastuzumab emtansine (T-DM1), pertuzumab, and trastuzumab in-kind. Any opinions, findings, and conclusions expressed in this work are those of the authors and do not necessarily reflect those of the American Society of Clinical Oncology, the Conquer Cancer Foundation, The Breast Cancer Research Foundation, the National Cancer Institute at the National Institutes of Health, or the National Institutes of Health.

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K.K., F.L., A.B., X.G., C.D., A.Y., K.S., C.G., P.P., R.N., P.H., R.W., M.S., M.F., F.A., M.T., C.I., and S.S. contributed to the analysis of the results and to the writing of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sandra M. Swain.

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Conflict of interest

K. Khoury, X. Geng, R. Warren, M. Srichai, M. Hofmeyer, and F. Asch, report no competing interests. F. Lynce reports consulting/advisory role from Bristol-Myers Squibb, Jounce Therapeutics (unpaid), AstraZeneca and Pfizer/EMD Serono, association with the speakers’ bureau for ASCO, travel, accommodations and expenses from Bristol-Myers Squibb and Genentech, has received research funding from Pfizer, Bristol-Myers Squibb and Inivata, and institution-associated research funding from Calithera Biosciences, Immunomedics, Chugai Pharma USA, Regeneron, Inivata, and Tesaro. A. Barac reports consulting/advisory role from Takeda Science Foundation. C. Dang reports consulting/advisory role and travel, accommodations and expenses and has received honoraria from Genentech/Roche, Puma Biotechnology, Lilly, and has received research institution-associated funding from Genentech/Roche and Puma Biotechnology. A. Yu reports consulting/advisory role from AstraZeneca and Genentech for himself and an immediate family member, and research funding from AstraZeneca received for an immediate family member. K. Smith reports stock and ownership interest in Abbvie and Abbott laboratories, and has received institution-associated funding from Pfizer. C. Gallagher reports consulting/advisory role from Seattle Genetics, and association with the speakers’ bureau for Daiichi-Sankyo. P. Pohlmann reports consulting/advisory role from Personalized Cancer Therapy, OncoPlex Diagnostics, Immunonet BioSciences, Pfizer, HERON, Puma Biotechnology, Sirtex Medical, Caris Life Sciences, SeaGen and Juniper, association with the speakers’ bureau for Genentech/Roche, patents: United States Patent no. 8,486,413, United States Patent no. 8,501,417, United States Patent no. 9,023,362, United States Patent no. 9,745,377, stock/ownership and leadership in Immunonet BioSciences, received honoraria from ASCO and Dava Oncology, and institution-associated research funding from Genentech/Roche, Fabre-Kramer, Advanced Cancer Therapeutics, Caris Centers of Excellence, Pfizer, Pieris Pharmaceuticals, BOLT, SeaGen, Byondis, and Cascadian Therapeutics. R. Nunes reports consulting/advisory role from Agendia (unpaid), and has received research funding from bioTheranostics. P. Herbolsheimer is an employee of AstraZeneca, and reports travel, accommodations and expenses and stock/ownership from AstraZeneca. M. Tan reports consulting/advisory role from American Gene Technologies, has received honoraria from AstraZeneca, Incyte, Otsuka, and Sanofi Pasteur, travel and accommodations from Otsuka, and research funding from Genentech. C. Isaacs reports consulting/advisory role from Pfizer, Genentech/Roche, Novartis, AstraZeneca, Puma Biotechnology, Context Therapeutics, and Seattle Genetics, association with the speakers’ bureau for Genentech, Pfizer, and AstraZeneca, received honoraria from Genentech/Roche, AstraZeneca, and Pfizer, and institution-associated research funding from Novartis, Pfizer, Genentech, and Tesaro. S. Swain reports consulting/advisory or non promotional speaking role from Exact Sciences (Genomic Health), Genentech/Roche, Daiichi Sankyo, Athenex, Natura, and Silverback Therapeutics, IDMC from AstraZeneca, support for third party writing assistance from Genentech/Roche, and institution-associated research funding from Genentech and Kailos Genetics. The COI’s described above include competing interests of greater than 1 year.

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Khoury, K., Lynce, F., Barac, A. et al. Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function. Breast Cancer Res Treat 185, 863–868 (2021). https://doi.org/10.1007/s10549-020-06053-y

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  • HER2-targeted therapy
  • Breast cancer
  • Cardiac dysfunction
  • Cardiac safety
  • Cardioprotective medications