Originally published as JCO Early Release 10.1200/JCO.2006.09.1611 on July 23 2007

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Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial

Thomas M. Suter, Marion Procter, Dirk J. van Veldhuisen, Michael Muscholl, Jonas Bergh, Chiara Carlomagno, Timothy Perren, Rodolfo Passalacqua, Claudia Bighin, Jan G.M. Klijn, Fail T. Ageev, Erika Hitre, Juergen Groetz, Hiroji Iwata, Malgorzata Knap, Michael Gnant, Susanne Muehlbauer, Alison Spence, Richard D. Gelber, Martine J. Piccart-Gebhart

From the Swiss Cardiovascular Center, University Hospital Bern; F. Hoffmann-La Roche, Basel, Switzerland; Frontier Science, Kincraig, Kingussie, Scotland; Department of Cardiology, University of Groningen, Groningen; Department of Medical Oncology, Daniel den Hoed Cancer Center/Erasmus MC, Rotterdam, the Netherlands; Kardiologische Praxis, Munich; Cardiology Wilhelm-Marx-Haus and Krankenhaus Gerresheim, Duesseldorf; Department of Cardiology, University Hospital Hamburg-Eppendorf, Germany; Department of Oncology, Karolinska Institute and University Hospital, Stockholm, Sweden; Department of Molecular and Clinic Endocrinology and Oncology, Università Federico II, Napoli; Division of Medical Oncology, Istituti Ospitalieri, Cremona; Medical Oncology, National Cancer Institute, Genoa, Italy; Cancer Research UK Clinical Centre Leeds; St James's University Hospital, Leeds, United Kingdom; Cardiology Research Complex, Moscow, Russia; National Institute of Oncology, Budapest, Hungary; Aichi Cancer Center Hospital, Nagoya, Japan; Medical University of Vienna, Austria; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and the Department of Medicine and Breast International Group, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium

Address reprint requests to Thomas M. Suter, MD, Swiss Cardiovascular Center, University Hospital Bern, Inselspital, CH-3010 Bern, Switzerland; e-mail: thomas.suter{at}insel.ch

Purpose: The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy.

Patients and Methods: The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2–positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction.

Results: Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m² v 257 mg/m²) or epirubicin (480 mg/m² v 422 mg/m²) and had a lower screening LVEF and a higher body mass index.

Conclusion: Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.

published online ahead of print at www.jco.org on July 23, 2007.

Supported by F. Hoffmann-La Roche (Roche), Basel, Switzerland.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Correspondence

• Trastuzumab-Related Cardiotoxicity in the Herceptin Adjuvant Trial
  Filippo Montemurro, Stefania Redana, Giorgio Valabrega, Rossella Martinello, Massimo Aglietta, and Renato Palmiero
  JCO 2008 26: 2052-2053 [Full Text]

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