Originally published as JCO Early Release 10.1200/JCO.2007.13.5467 on February 4 2008

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Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial

Edith A. Perez, Vera J. Suman, Nancy E. Davidson, George W. Sledge, Peter A. Kaufman, Clifford A. Hudis, Silvana Martino, Julie R. Gralow, Shaker R. Dakhil, James N. Ingle, Eric P. Winer, Karen A. Gelmon, Bernard J. Gersh, Allan S. Jaffe, Richard J. Rodeheffer

From the Mayo Clinic, Jacksonville, FL; Mayo Clinic, Rochester, MN; Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD; Indiana University Cancer Center, Indianapolis, IN; Dartmouth Hitchcock Medical Center, Lebanon, NH; Memorial Sloan-Kettering Cancer Center, New York, NY; Cancer Institute Medical Group, Santa Monica, CA; University of Washington, Seattle, WA; Cancer Center of Kansas, Wichita, KS; Dana Farber Cancer Institute, Boston, MA; BC Cancer Agency, Vancouver, BC, Canada

Corresponding author: Edith A. Perez, MD, Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: perez.edith{at}mayo.edu

Purpose To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.

Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months.

Results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%.

Conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

published online ahead of print at www.jco.org on February 4, 2008

Supported in part by a grant from the National Institutes of Health CA25224; Genentech, Inc; and The Breast Cancer Research Foundation.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; at the 28th San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005; and at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007.

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

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