Prognostic and therapeutic implications of aromatase expression in lung adenocarcinomas with EGFR mutations

Purpose: Lung adenocarcinomas among never-smokers are more common in females than in males. 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 EGFR mutations 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 exemes-tane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib. Results: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, 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 EGFR mutations, and may also be a beneficial therapeutic target in those patients.