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Estrogen Receptor ß Expression Is Associated with Tamoxifen Response in ER-Negative Breast Carcinoma

Authors' Affiliations: Departments of ¹ Oncology and ² Theoretical Physics, Lund University, Lund, Sweden; ³ Institute for Cancer Genetics, Columbia University, New York, New York; ⁴ Institute of Medical Technology, University of Tampere, Tampere, Finland; and ⁵ Department of Pathology, Seinäjoki Central Hospital, Seinäjoki, Finland

Requests for reprints: Sofia K. Gruvberger-Saal, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Irving Cancer Research Center, Suite 406, New York, NY 10032. Phone: 212-851-5263; Fax: 212-851-5267; E-mail: sg2414{at}columbia.edu.

Purpose: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ER)–positive breast carcinoma but are not indicated for persons with ER-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ER-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERß, in patients treated with adjuvant tamoxifen.

Experimental Design: We investigated ERß by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.

Results: ERß was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ER-negative patients (P = 0.003; P = 0.04), but not in the ER-positive subgroup (P = 0.49; P = 0.88). Lack of ERß conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ER-negative subgroup even after adjustment for other markers. ER was an independent marker only within the ERß-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERß gene expression profile was identified and was markedly different from the ER signature.

Conclusion: Expression of ERß is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ER-negative breast cancer patients and involves a gene expression program distinct from ER. These results may be highly clinically significant, because in the United States alone, 10,000 women are diagnosed annually with ER-negative/ERß-positive breast carcinoma and may benefit from adjuvant tamoxifen.

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