Lung adenocarcinoma is a heterogeneous tumor with multiple phenotypes that have been associated with prognosis. Recently, we reported that in surgically resected adenocarcinomas, the presence of a solid histologic pattern is associated with poor prognosis. To characterize molecular targets and identify novel prognostic markers in lung adenocarcinoma, we examined by immunohistochemistry (IHC) and tissue microarrays (TMAs) the expression of 75 proteins in archival tumor tissues obtained from 204 surgically resected tumors. We selected two top markers, EZH2 (enhancer of zeste homolog 2) and TTF-1 (thyroid transcription factor-1) that had significant correlation with solid and bronchioloalveolar patterns, respectively, for more detailed clinico-pathologic analyses, including patients’ outcome. EZH2 is part of a protein complex that promotes cancer development by epigenetically silencing tumor suppressor genes. TTF-1 is a transcription factor considered a potential lineage-survival oncogene in lung cancer. For EZH2 and TTF-1 IHC expression analysis, we examined 320 surgically resected lung adenocarcinomas, stages I-III, with median follow-up of 6.7 years. EGFR and KRAS mutation data were available in most cases. High nuclear EZH2 expression in tumor cells correlated with younger patient age (P<0.0001), smoking history (P<0.0001), higher TNM stage (P=0.02), and lack of EGFR mutation (P=0.001). High nuclear TTF-1 expression correlated with female sex (P=0.002), smaller tumor size (P=0.001), lower TNM stage (P=0.02), and EGFR mutation (P=0.007). EZH2 and TTF-1 expression did not correlate with KRAS mutation status; however, we found that their expression levels were significantly higher (P=0.022 and P=0.005, respectively) in tumors with KRAS CYS substitution compared with other amino acid changes. Univariate and multivariate (adjusting by other clinical prognostic factors) analyses were used to correlate EZH2 and TTF-1 expression with recurrence-free survival (RFS) and overall survival (OS). In the multivariate analysis, high EZH2 expression (≥42, median score) was associated with worse RFS (P=0.028 HR 1.53) and OS (P=0.0002; HR 1.94), and high TTF-1 expression (>120 score) correlated with better OS (P=0.004; HR 0.62). We identified a subset (32%) of tumors with low-EZH2/high-TTF-1 that demonstrated better outcome in multivariate analysis, compared with other tumors, including RFS (P=0.004; HR 0.51) and OS (P=0.0007; HR 0.49). These tumors were more frequent in patients with female sex (P=0.003), never-smoking history (P=0.004), smaller tumor size (P=0.018), lower TNM stage (P=0.024), and EGFR mutation (P=0.0001). Our findings indicate that the combined analysis of the EZH2 and TTF-1 expression identifies a subset of lung adenocarcinoma patients with better outcome after surgical resection with curative intent. Supported by DoD grant W81XWH-07-1-0306

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3685. doi:1538-7445.AM2012-3685