A pooled analysis of the cardiac events in the trastuzumab adjuvant trials

  • Evandro de AzambujaEmail author
  • Noam Ponde
  • Marion Procter
  • Priya Rastogi
  • Reena S. Cecchini
  • Matteo Lambertini
  • Karla Ballman
  • Alvaro Moreno Aspitia
  • Dimitrios Zardavas
  • Lise Roca
  • Richard D. Gelber
  • Martine Piccart-Gebhart
  • Thomas Suter
Clinical trial



Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity.


This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study.


A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10 years (119.2–137.2 months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity.


One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.


Trastuzumab LVEF Cardiotoxicity Breast cancer 



The authors would like to acknowledge the teams of HERA, NSABP B-31, NCCTCG N9831, and PACS004 for their help in making this project possible.


The NSABP B-31 Trial was supported by NCI Grants: U10CA180868, -180822, UGICA-189867, and U24CA-196067.

Compliance with ethical standards

Conflict of interest

Evandro de Azambuja has received honoraria and advisory board from Roche/GNE and Seattle Genetics; travel grants from Roche/GNE and GSK/Novartis and research grants to his Institute: Roche/GNE; AstraZeneca, GSK/Novartis, Servier. Noam Pondé has received honoraria from AZ and Eli Lilly and travel grants from Eli Lilly and Novartis. Marion Procter has declared that her institution received funding from Roche in respect to the HERA and APHINITY trials. Matteo Lambertini has received honoraria from Theramex and consulting fee from TEVA. Pryia Rastogi has received travel and accommodations supported by Lilly, AZ, and GNE/Roche. Martine Piccart has been declared board Member (Scientific Board): Oncolytics, Radius; consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, Seattle Genetics; research grants to her Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. Thomas Suter has declared research support from Novartis and Amgen; consultant from Pfizer and advisory Board from Alnylam. Richard D Gelber declares that his institution receives support for his salary from Roche, AstraZeneca, Merck, Novartis, Ipsen, Celgene, Pfizer, and Ferring. Dimitrios Zardavas has declared employment from BMS. Karla V. Ballman has declared consulting or Advisory Role from ARIAD; Medtronic; Takeda; Agenus; Patents, Royalties, Other Intellectual Property: Prostate cancer signature patent (Inst); Expert Testimony—Janssen Oncology; Lilly. Lise Roca, Alvaro Moreno Aspitia, and Reena Cecchini have no conflict of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in each of the studies (HERA, NSABP B-31 (NRG Oncology) and NCCTG N9831 (Alliance)).

Supplementary material

10549_2019_5453_MOESM1_ESM.docx (138 kb)
Supplementary material 1 (DOCX 137 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Evandro de Azambuja
    • 1
    Email author
  • Noam Ponde
    • 1
    • 2
  • Marion Procter
    • 3
  • Priya Rastogi
    • 4
  • Reena S. Cecchini
    • 5
  • Matteo Lambertini
    • 1
    • 6
  • Karla Ballman
    • 5
  • Alvaro Moreno Aspitia
    • 7
  • Dimitrios Zardavas
    • 8
  • Lise Roca
    • 9
  • Richard D. Gelber
    • 10
  • Martine Piccart-Gebhart
    • 1
    • 8
  • Thomas Suter
    • 11
  1. 1.Institut Jules Bordet, Université Libre de Bruxelles (U.L.B)BrusselsBelgium
  2. 2.AC Camargo Cancer CenterSao PauloBrazil
  3. 3.Frontier Science (Scotland)KincraigUK
  4. 4.NRG Oncology, and The University of Pittsburgh Medical CenterPittsburghUSA
  5. 5.NRG Oncology, and the University of PittsburghPittsburghUSA
  6. 6.IRCCS Ospedale Policlinico San Martino and University of GenovaGENOVAItaly
  7. 7.Mayo ClinicJacksonvilleUSA
  8. 8.Breast International Group (BIG)BrusselsBelgium
  9. 9.Institut Regional du Cancer Montpellier Val d’AurelleMontpellierFrance
  10. 10.Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health, and Frontier Science and Technology Research FoundationBostonUSA
  11. 11.University Hospital BernBernSwitzerland

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