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

Yu Dong,Jie Zhang,Baohui Han,Bo Jin,Shichun Tu,Jinchen Shao,Hong Peng,Ying Li

doi:10.18632/oncotarget.19284

Abstract

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.

Highlights

Lung cancer is the leading cause of cancer death, with the highest mortality rate among all cancers in China and worldwide [1]
The presence of genetic mutations related to ALK, RET and BRAF had an opposite effect on overall survival (OS) between PPG2 and PPG3 patients, reversing the prognostic favorability for patients within these two groups
The patients of lung adenocarcinoma with EGFR mutations have a better response to EGFR tyrosine kinase inhibitors (TKIs) than those without EGFR mutations, while patients that are ALK-positive show a better response to the TKI crizotinib, suggesting that therapeutic effectiveness can be linked to the presence of specific driver mutations [10,11,12,13]

Summary

Introduction

Lung cancer is the leading cause of cancer death, with the highest mortality rate among all cancers in China and worldwide [1]. Emerging evidence suggests that the characteristics defining these subtypes could be independent prognostic factors [15,16,17,18,19,20]. These studies suggest that LPA is often associated with a good prognosis, APA, PPA, and IMA are associated with an intermediate prognosis, whereas MPA and SPA are associated with the worst prognosis [15,16,17,18,19,20]

Methods

Results

Conclusion