Originally published as JCO Early Release 10.1200/JCO.2007.12.1665 on November 12 2007

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Cardiovascular Adverse Events During Adjuvant Endocrine Therapy for Early Breast Cancer Using Letrozole or Tamoxifen: Safety Analysis of BIG 1-98 Trial

Henning Mouridsen, Aparna Keshaviah, Alan S. Coates, Manuela Rabaglio, Monica Castiglione-Gertsch, Zhuoxin Sun, Beat Thürlimann, Louis Mauriac, John F. Forbes, Robert Paridaens, Richard D. Gelber, Marco Colleoni, Ian Smith, Karen N. Price, Aron Goldhirsch

From the Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen, Denmark; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Harvard School of Public Health; Frontier Science and Technology Research Foundation, Boston, MA; IBCSG Coordinating Center and Inselspital; Swiss Group for Clinical Cancer Research, Bern; Senology Center of Eastern Switzerland, Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; School of Public Health, University of Sydney, Sydney; Australian New Zealand Breast Cancer Trials Group, University of Newcastle, Calgary Mater Newcastle, Newcastle, New South Wales, Australia; French Breast Cancer Group, Institut Bergonié, Bordeaux, France; Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Belgium; European Institute of Oncology, Milan, Italy; and The Royal Marsden Hospital, London, United Kingdom

Address reprint requests to Henning Mouridsen, MD, Department 2501, Righospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; email: henning.mouridsen{at}rh.hosp.dk

Purpose: Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98.

Patients and Methods: Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms).

Results: Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)—an excess only partially attributable to prior hypercholesterolemia—and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events.

Conclusion: The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.

published online ahead of print at www.jco.org on November 12, 2007.

The coordinating group for the BIG 1-98 trial is the International Breast Cancer Study Group (IBCSG). The IBCSG receives funds from Novartis to coordinate the trial and also receives grant support from the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, US National Cancer Institute (Grant No. CA-75362), Oncosuisse/Cancer Research Switzerland, and the Foundation for Clinical Cancer Research of Eastern Switzerland.

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

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