Human Cancer Biology 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 α and β and progesterone receptor protein immunohistochemical expression in a large set of non–small cell lungcarcinoma (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 α and β 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 α and β were detected in the nucleus and cytoplasm of NSCLC cells; however, the frequency of expression (nucleus, 5-36% for α and 42-56% for β; cytoplasm: <1-42% for α and 20-98% for β) varied among the different antibodies tested. Progesterone receptor was expressed in the nuclei of malignant cells in 63% of the tumors. Estrogen receptor α 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 α 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 α expression correlated with EGFR mutation (P = 0.0029 to <0.0001). Estrogen receptor β and progesterone receptor but not estrogen receptor α expressed in the normal epithelium adjacent to lung adenocarcinomas. Conclusions: Estrogen receptor α and β expression distinguishes a subset of NSCLC that has defined clinicopathologic and genetic features. In lung adenocarcinoma, estrogen receptor α expression correlates with EGFR mutations. (Clin Cancer Res 2009;15(17): 5359–68) Lung cancer is the most common cause of cancer mortality worldwide, with >1 million deaths each year (1). Lung cancer includes several histologic types, the most frequently occurring of which are two types of non–small cell lung carcinoma (NSCLC): adenocarcinoma and squamous cell carcinoma (2). During the last two decades, mortality rates associated with cancer have continued to decrease across all major sites in men and women; however, the rates for lung cancer in females have continued to increase (3, 4). Despite global statistics estimating that 15% of lung cancer in men and 53% in women are not attributable to smoking (1), smoking remains the primary risk factor for lung cancer. The higher proportion of lung cancer in females who have never smoked compared with males who have never smoked suggests a possible role for gender-dependent hormones in the development of lung cancer (5). Estrogen receptors α and β are expressed in normal lung tissue and in lung tumors in men and women (6), yet the data are inconsistent about whether estrogen receptor expression is Authors' Affiliations: Departments of Pathology, Thoracic/Head and Neck Medical Oncology, Biostatistics; and Thoracic Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas Received 1/13/09; revised 5/21/09; accepted 6/3/09; published OnlineFirst 8/25/09. Grant support: Grants from the Department of Defense (W81XWH-04-10142 and W81XWH-05-2-0027), the Specialized Program of Research Excellence in Lung Cancer Grant P50CA70907 (I.I. Wistuba), and Cancer Center Support Grant CA-16672 from the National Cancer Institute. The costsof publicationof this articleweredefrayed inpart by thepayment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). M.H. Herynk is a Young Clinical Scientist Award Recipient from the Flight Attendants. Requests for reprints: Ignacio I. Wistuba, Department of Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX 77030-4009. Phone: 713-563-9184; Fax: 713-7920309; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0033 5359 Clin Cancer Res 2009;15(17) September 1, 2009 www.aacrjournals.org Research. on April 13, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-09-0033