Characteristics Of Genetic Classification In Lung Adenocarcinomas And It’s Relation With Morphologic Classification

Lung cancer is still the leading cause of cancer-related mortality worldwide. As a common malignancy, the 5-year survival rate of advanced non-small cell lung cancer(NSCLC) remains poor, about 15%. NSCLC comprises three different subtypes: squamous-cell carcinoma, large-cell carcinoma and adenocarcinoma. The squamous-cell carcinoma accounts for 60% of all cases of lung cancer.Lung adenocarcinomas have diverse genetic and morphological backgrounds, and are usually classified according to their distinct oncogenic mutations (or so-called driver mutations) and histological subtypes (the de novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS]). Although both these classifications are essential for personalized treatment, their integrated clinical effect remains unclear. Therefore, we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis. Analysis for oncogenic mutations included the direct sequencing of EGFR, KRAS, HER2, BRAF, PIK3CA, ALK, and RET for oncogenic mutations/rearrangements, and a re-review of the IASLC/ATS/ERS classification was undertaken. Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ,20 minimally invasive adenocarcinomas,901 invasive adenocarcinomas,44 invasive mucinous adenocarcinomas (IMA), and 3 other variants. IMA had lower prevalence of EGFR mutations but higher prevalence of KRAS, ALK, and HER2 mutations than invasive adenocarcinomas. Smoking, a solid predominant pattern, and a mucinous component were independently associated with less EGFR mutations. ALK rearrangements were more frequently observed in tumors with a minor mucinous component, while KRAS mutations were more prevalent in smokers. A total of 503 patients with stage I-IIIA tumors were analyzed for overall survival (OS) and relapse-free survival (RFS). The stage and histological pattern were independent predictors of RFS, and the pathological stage was the only independent predictor for OS. Although patients with EGFR mutations had better OS than those without mutations, no oncogenic mutation was an independent predictor of survival. Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification, which facilitates a morphology-based mutational analysis strategy. The combination of these 2 classifications might not increase the prognostic ability, but it provides essential information for personalized treatment.