Pathologic subtype-defined prognosis is dependent on both tumor stage and status of oncogenic driver mutations in lung adenocarcinoma

Previous studies have shown that the prognosis of lung adenocarcinoma is associated with pathological characterization. In this study, we investigated whether pathology-based prognosis was further influenced by both tumor stage and oncogenic driver mutations. To this end, we recruited a cohort of 465 lung adenocarcinoma patients in China. These patients were classified into 6 pathology-defined subtypes i.e., lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA), and invasive mucinous adenocarcinoma (IMA). Oncogenic mutations in EGFR, KRAS, ALK, RET, and BRAF genes were determined using fluorescent real-time RT-PCR. The associations of pathogenic subtype or oncogenic mutation with clinical characteristics were analyzed using Fisher's exact tests. The interactive effects on overall survival (OS) by pathologic subtype, oncogenic mutations, and tumor stage were also determined. We have found that pathogenic subtype of lung adenocarcinoma correlated with smoking habit and tumor cell differentiation. These pathology-defined subtypes can be regrouped into 3 pathology-based prognostic groups: PPG1 (LPA), PPG2 (IMA+APA+PPA), and PPG3 (MPA+SPA) with a favorable, intermediate, and poor OS, respectively. We further demonstrated that this pathology-determined OS can be affected by both tumor stage and status of oncogenic mutations in EGFR, KRAS, ALK, RET, and BRAF genes. Interestingly, the presence of genetic mutations related to ALK, RET and BRAF had an opposite effect on OS between PPG2 (worsen) and PPG3 (improved) patients, reversing the prognostic favorability for patients within these two groups. In conclusion, prognosis of lung adenocarcinoma was defined interactively by pathologic subtype, tumor stage and oncogenic mutation.