Originally published as JCO Early Release 10.1200/JCO.2007.11.6798 on March 10 2008

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Late Extended Adjuvant Treatment With Letrozole Improves Outcome in Women With Early-Stage Breast Cancer Who Complete 5 Years of Tamoxifen

Paul E. Goss, James N. Ingle, Joseph L. Pater, Silvana Martino, Nicholas J. Robert, Hyman B. Muss, Martine J. Piccart, Monica Castiglione, Lois E. Shepherd, Kathleen I. Pritchard, Robert B. Livingston, Nancy E. Davidson, Larry Norton, Edith A. Perez, Jeffrey S. Abrams, David A. Cameron, Michael J. Palmer, Dongsheng Tu

From the Massachusetts General Hospital Cancer Center, Boston, MA; Mayo Clinic, Rochester, MN; Angeles Clinic and Research Institute, Los Angeles, CA; Inova Fairfax Hospital, Falls Church, VA; University of Vermont, Burlington, VT; Institut Jules Bordet, Brussels, Belgium; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; National Cancer Institute of Canada, Clinical Trials Group, Kingston, Ontario, Canada; Toronto Sunnybrook Odette Cancer Centre, University of Toronto, Ontario, Canada; University of Washington, Seattle, WA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore; Cancer Therapy Evaluation Program, Clinical Investigations Branch, National Cancer Institute, Rockville, MD; Memorial Sloan-Kettering Cancer Center, New York, NY; Mayo Clinic, Jacksonville, FL; and Edinburgh Breast Unit, Western General Hospital, Edinburgh, Scotland

Corresponding author: Paul Goss, MD, PhD, Massachusetts General Hospital Cancer Center, 55 Fruit St, Lawrence House, LRH-302, Boston, MA 02114; e-mail: pgoss{at}partners.org

Purpose The National Cancer Institute of Canada Clinical Trials Group MA.17 trial examined the efficacy of letrozole (LET) started within 3 months of 5 years of adjuvant tamoxifen in postmenopausal hormone receptor–positive early-stage breast cancer. When the trial was unblinded, patients who received placebo (PLAC) were offered LET.

Patients and Methods This cohort analysis describes the outcomes of women assigned PLAC at the initial random assignment after unblinding. Efficacy outcomes of women who chose LET (PLAC-LET group) were compared with those who did not (PLAC-PLAC group) by the hazard ratios and by P values calculated from Cox models that adjusted for imbalances between the groups. Toxicity analyses included only events that occurred after unblinding.

Results There were 1,579 women in the PLAC-LET group (median time from tamoxifen, 2.8 years) and 804 in the PLAC-PLAC group. Patients in the PLAC-LET group were younger; had a better performance status; and were more likely to have had node-positive disease, axillary dissection, and adjuvant chemotherapy than those in the PLAC-PLAC group. At a median follow-up of 5.3 years, disease-free survival (DFS; adjusted hazard ratio [HR], 0.37; 95% CI, 0.23 to 0.61; P < .0001) and distant DFS (HR, 0.39; 95% CI, 0.20 to 0.74; P = .004) were superior in the PLAC-LET group. More self-reported new diagnoses of osteoporosis and significantly more clinical fractures occurred in the women who took LET (5.2% v 3.1%, P = .02).

Conclusion Interpretation of this cohort analysis suggests that LET improves DFS and distant DFS even when there has been a substantial period of time since the discontinuation of prior adjuvant tamoxifen.

published online ahead of print at www.jco.org on March 10, 2008.

Supported by the Canadian Cancer Society Grant No. 10362 from the National Cancer Institute of Canada; by Grants No. CA31946, CA21115, CA25224, CA38926, and CA32102 from the National Cancer Institute; the Pharmacia Corp, a Pfizer Company, New York, NY; and Novartis Pharmaceutials (support and provision of study medication).

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

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