Immunohistochemical Expression of Estrogen and Progesterone Receptors Identifies a Subset of NSCLCs and Correlates with EGFR Mutation

Purpose: To determine the frequency of estrogen receptor alpha and beta and progesterone receptor protein immunohistochemical expression in a large set of non-small cell lung carcinoma (NSCLC) specimens and to compare our results with those for some of the same antibodies that have provided inconsistent results in previously published reports. Experimental Design: Using multiple antibodies, we investigated the immunohistochemical expression of estrogen receptors alpha and beta and progesterone receptor in 317 NSCLCs placed in tissue microarrays and correlated their expression with patients' clinicopathologic characteristics and in adenocarcinomas with EGFR mutation status. Results: Estrogen receptors alpha and beta were detected in the nucleus and cytoplasm of NSCLC cells; however, the frequency of expression (nucleus, 5-36% for alpha and 42-56% for beta; cytoplasm: <1-42% for alpha and 20-98% for beta) varied among the different antibodies tested. Progesterone receptor was expressed in the nuclei of malignant cells in 63% of the tumors. Estrogen receptor alpha nuclear expression significantly correlated with adenocarcinoma histology, female gender, and history of never smoking (P = 0.0048 to <0.0001). In NSCLC, higher cytoplasmic estrogen receptor alpha expression significantly correlated with worse recurrence-free survival (hazard ratio, 1.77; 95% confidence interval, 1.12, 2.82; P = 0.015) in multivariate analysis. In adenocarcinomas, estrogen receptor alpha expression correlated with EGFR mutation (P = 0.0029 to <0.0001). Estrogen receptor beta and progesterone receptor but not estrogen receptor alpha expressed in the normal epithelium adjacent to lung adenocarcinomas. Conclusions: Estrogen receptor alpha and beta expression distinguishes a subset of NSCLC that has defined clinicopathologic and genetic features. In lung adenocarcinoma, estrogen receptor alpha expression correlates with EGFR mutations. (Clin Cancer Res 2009;15(17): 5359-68)