Estrogen receptor β expression is associated with tamoxifen response in ERα-negative breast carcinoma

Purpose: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ER alpha) -positive breast carcinoma but are not indicated for persons with ER alpha-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ER alpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ER beta, in patients treated with adjuvant tamoxifen. Experimental Design: We investigated ER beta 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: ER beta was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ER alpha-negative patients (P = 0.003; P = 0.04), but not in the ER alpha-positive subgroup (P = 0.49; P = 0.88). Lack of ER beta conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ER alpha-negative subgroup even after adjustment for other markers. ER alpha was an independent marker only within the ER beta-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ER beta gene expression profile was identified and was markedly different from the ER alpha signature. Conclusion: Expression of ER beta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ER alpha-negative breast cancer patients and involves a gene expression program distinct from ER alpha. These results may be highly clinically significant, because in the United States alone, similar to 10,000 women are diagnosed annually with ER alpha-negative/ER beta-positive breast carcinoma and may benefit from adjuvant tamoxifen.