Predictive Biomarkers and Personalized Medicine Prognostic and Therapeutic Implications of Aromatase Expression in Lung Adenocarcinomas with EGFR Mutations

Purpose: Lung adenocarcinomas amongnever-smokers aremore common in females than inmales. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFRmutations and postsurgical prognosis. Experimental Design: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFRmutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib. Results:Aromatase gene expressionwas not correlatedwith patients’ clinicopathologic factors, including EGFRmutation status. High aromatase expression was associated with poor prognosis for both recurrencefree survival (P 1⁄4 0.004) and overall survival (P 1⁄4 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFRmutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib. Conclusions: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFRmutations, and may also be a beneficial therapeutic target in those patients. Clin Cancer Res; 20(13); 1–10. 2014 AACR.