Expression of both Estrogen Receptor-beta 1 (ER-β1) and its co-regulator Steroid Receptor RNA Activator Protein (SRAP) are predictive for benefit from tamoxifen therapy in patients with Estrogen Receptor-alpha (ER-α)-Negative Early Breast Cancer (EBC)

Roles of Estrogen Receptor-beta 1 (ER-beta 1) and its co-regulator Steroid Receptor RNA Activator Protein (SRAP) in breast cancer remain unclear. Previously, ER-beta 1 and SRAP expression were found positively correlated in breast cancer and, therefore, expression of these two molecules could characterize cancers with a distinct clinical outcome. ER-beta 1 and SRAP expression was determined by immunohistochemistry (IHC) in tissue microarrays from a randomized, placebo-controlled trial (NCIC-CTG-MA12), designed to determine the benefit of tamoxifen following chemotherapy in premenopausal early breast cancer (EBC). Expression was dichotomized into low and high using median IHC scores. Relationships with survival used Cox modeling. In the whole cohort, ER-beta 1 and SRAP were not prognostic. However, high ER-beta 1 and SRAP significantly predicted tamoxifen responsiveness [overall survival, interaction test, P = 0.03; relapse-free survival (RFS), interaction test, P = 0.01]. Stratification by ER-alpha-status found predictive benefit only in ER-alpha-negative cases. The difference in RFS between tamoxifen and placebo was greater in patients whose tumors expressed both high SRAP and ER-beta 1[hazard ratio = 0.07; 95% confidence interval (CI) 0.01-0.41; P = 0.003] versus those with low SRAP or ER-beta 1 (interaction test, P = 0.02). The interaction test was not significant in ER-alpha-positive cohorts. This study provides evidence that both ER-beta 1 and SRAP could be predictive biomarkers of tamoxifen benefit in ER-alpha-negative premenopausal EBC.