Abstract 3667: ERβ and PR expression show opposite effects on survival in NSCLC with no sex differences

Abstract

Abstract Sex steroids may be targets for lung cancer intervention. Estrogen has been shown to stimulate, while progesterone has been shown to inhibit, lung cancer growth. Cross-talk between the estrogen and the epidermal growth factor (EGF) signaling pathways in lung cancer has been reported. To further clarify the roles of estrogen, progesterone and EGF receptors, we analyzed primary lung tumors and normal lung tissue from 183 patients (primarily non-small cell lung cancer histologies) for expression and localization of estrogen receptor α (ERα), estrogen receptor β (ERβ), aromatase, progesterone receptor (PR), and EGF receptor (EGFR) using immunohistochemistry. No differences were observed in any marker expression analyzed by sex or histology. ERα expression was positive only when using an antibody that also detects ERα deletion variants, consistent with mRNA profiles of lung tumor cell lines showing multiple ERα variants with no full-length mRNA. ERα expression showed no effect on survival. Tumor tissues were found to express significantly higher levels (p<.001) of ERβ (both nuclear and cytoplasmic) and variant ERα compared to matched normal lung tissues, suggesting up-regulation of these proteins in lung cancer. Conversely, PR was expressed at significantly higher levels (p=.007) in normal tissue compared to tumor. Positive correlations were observed between ER subtypes and the other markers, suggesting hormonal pathways are often expressed together. Cytoplasmic ERβ expression was identified as a negative prognostic predictor of overall survival in all patients, males and females (p=.021). However, elevated ERβ cytoplasmic expression was predictive of survival in stage III/IV patients (p=.012) but not in stage I/II patients (p=.353), suggesting ERβ signaling is a more important survival determinant in advanced disease. Patients with high PR expression had longer time to progression (TTP) than patients with low PR expression; this was significant in stage I/II patients (p=0.008) but not in stage III/IV patients (p=.834). PR signaling may protect against recurrence in early stage patients. Survival advantage in all patients was more pronounced when degree of EGFR staining was combined with PR staining (p=0.004). When degree of ERβ was included, patients with low ERβ, low EGFR and high PR had longer TTP than the opposite (p=0.021) suggesting that these signaling pathways interact and cooperate within the tumor to affect prognosis. Low aromatase was protective only when considering other markers. Patients with high ERβ expression and advanced disease may be good candidates for anti-estrogen therapy while patients with low PR expression and early stage disease may be candidates for progesterone supplementation. Phenotyping all interacting targets may select patients for combining hormonal modulation with anti-EGFR therapy. Supported by NCI P50 CA090440 (JMS) and Flight Attendant Medical Research Institute (LPS). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3667.