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 Edward H. Romond, Jong-Hyeon Jeong, Priya Rastogi, Sandra M. Swain, Charles E. Geyer Jr, Michael S. Ewer, Vikas Rathi, Louis Fehrenbacher, Adam Brufsky, Catherine A. Azar, Patrick J. Flynn, John L. Zapas, Jonathan Polikoff, Howard M. Gross, David D. Biggs, James N. Atkins, Elizabeth Tan-Chiu, Ping Zheng, Greg Yothers, Eleftherios P. Mamounas, and Norman Wolmark See accompanying editorial on page 3769 Author affiliations appear at the end of this article. Submitted October 26, 2011; accepted July 16, 2012; published online ahead of print at www.jco.org on September 17, 2012. Supported by Grants No. U10-CA- 12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 from the National Cancer Institute, Department of Health and Human Services, Public Health Service, and by Genentech. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical trial information: NCT00004067. Corresponding author: Priya Rastogi, MD, National Surgical Adjuvant Breast and Bowel Project, East Commons Professional Building, Four Allegheny Center, 5th Floor, Pittsburgh, PA 15212; e-mail: rastogip@upmc.edu. © 2012 by American Society of Clinical Oncology 0732-183X/12/3031-3792/$20.00 DOI: 10.1200/JCO.2011.40.0010 A B S T R A C T Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline- related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab. J Clin Oncol 30:3792-3799. © 2012 by American Society of Clinical Oncology INTRODUCTION Trastuzumab given concurrently with or after adju- vant chemotherapy has been shown to improve disease-free survival (DFS) and overall survival in early-stage human epidermal growth factor receptor 2 (HER2) –positive breast cancer. 1-3 Cardiac dys- function (CD) is the most concerning toxicity asso- ciated with these regimens, especially when the chemotherapy includes an anthracycline. We previ- ously reported a detailed analysis of cardiac safety with a median follow-up of 27 months for Na- tional Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-31, which randomly assigned patients with HER2-positive, node-positive breast cancer to receive four cycles of doxorubicin (60 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 30  NUMBER 31  NOVEMBER 1 2012 3792 © 2012 by American Society of Clinical Oncology