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Donald A. Berry, PhD; Constance Cirrincione, MS; I. Craig Henderson, MD; Marc L. Citron, MD; Daniel R. Budman, MD; Lori J. Goldstein, MD; Silvana Martino, DO; Edith A. Perez, MD; Hyman B. Muss, MD; Larry Norton, MD; Clifford Hudis, MD; Eric P. Winer, MD

JAMA. 2006;295:1658-1667.

Context  Breast cancer estrogen-receptor (ER) status is useful in predicting benefit from endocrine therapy. It may also help predict which patients benefit from advances in adjuvant chemotherapy.

Objective  To compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative vs ER-positive tumors.

Design, Setting, and Patients  Trial data from the Cancer and Leukemia Group B and US Breast Cancer Intergroup analyzed; patient outcomes by ER status compared using hazards over time and multivariate models. Randomized trials comparing (1): 3 regimens of cyclophosphamide, doxorubicin, and fluorouracil (January 1985 to April 1991); (2) 3 doses of doxorubicin concurrent with cyclophosphamide, with or without subsequent paclitaxel (May 1994 to April 1997); (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also 3-week vs 2-week cycles (September 1997 to March 1999). A total of 6644 node-positive breast cancer patients received adjuvant treatment.

Main Outcome Measures  Disease-free and overall survival.

Results  For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21%, 25%, and 23% in the 3 studies, respectively, and 55% comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9%, 12%, and 8% in the 3 studies, and 26% overall. The overall mortality rate reductions associated with chemotherapy improvements were 55% and 23% among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%.

Conclusion  Among patients with node-positive tumors, ER-negative breast cancer, biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50% in comparison with low-dose cyclophosphamide, doxorubicin, and fluorouracil as used in the first study.

Author Affiliations: University of Texas M. D. Anderson Cancer Center, Houston (Dr Berry); Cancer and Leukemia Group B Statistical Center, Durham, NC (Ms Cirrincione); University of California at San Francisco (Dr Henderson); Albert Einstein College of Medicine, Lake Success, NY (Dr Citron); North Shore University Hospital, Manhasset, NY (Dr Budman); Fox Chase Cancer Center, Philadelphia, Pa (Dr Goldstein); Angeles Clinic and Research Institute, Santa Monica, Calif (Dr Martino); Mayo Clinic and Mayo Foundation, Jacksonville, Fla (Dr Perez); Vermont Cancer Center, Burlington (Dr Muss); Memorial Sloan-Kettering Cancer Center, New York, NY (Drs Norton and Hudis); and the Dana-Farber Cancer Institute, Boston, Mass (Dr Winer).

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