Estrogen-Regulated Genes Predict Survival in Hormone Receptor–Positive Breast Cancers

Abstract

The prognosis of a patient with estrogen receptor (ER) and/or progesterone receptor (PR) –positive breast cancer can be highly variable. Therefore, we developed a gene expression–based outcome predictor for ER+ and/or PR+ (ie, luminal) breast cancer patients using biologic differences among these tumors. The ER+ MCF-7 breast cancer cell line was treated with 17β-estradiol to identify estrogen-regulated genes. These genes were used to develop an outcome predictor on a training set of 65 luminal epithelial primary breast carcinomas. The outcome predictor was then validated on three independent published data sets. The estrogen-induced gene set identified in MCF-7 cells was used to hierarchically cluster a 65 tumor training set into two groups, which showed significant differences in survival (P = .0004). Supervised analyses identified 822 genes that optimally defined these two groups, with the poor-prognosis group IIE showing high expression of cell proliferation and antiapoptosis genes. The good prognosis group IE showed high expression of estrogen- and GATA3-regulated genes. Mean expression profiles (ie, centroids) created for each group were applied to ER+ and/or PR+ tumors from three published data sets. For all data sets, Kaplan-Meier survival analyses showed significant differences in relapse-free and overall survival between group IE and IIE tumors. Multivariate Cox analysis of the largest test data set showed that this predictor added significant prognostic information independent of standard clinical predictors and other gene expression–based predictors. This study provides new biologic information concerning differences within hormone receptor–positive breast cancers and a means of predicting long-term outcomes in tamoxifen-treated patients.