SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: a multi-cohort analysis.

KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from (c) the MSK-IMPACT (MSK-IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e-04 for disease-free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS-TP53 comutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P = 0.0091) in the MSK-IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.

A Population-Based Study of Outcomes in Surgically Resected T3N0 Non-Small Cell Lung Cancer in The Netherlands, Defined Using TNM-7 and TNM-8; Justification of Changes and an Argument to Incorporate Histology in the Staging Algorithm.

OBJECTIVE: The objective was to study outcomes in patients in a population registry who were surgically staged as having pT3N0 NSCLC according to the seventh and eighth editions of the TNM staging classification. METHODS: Details of patients who underwent surgery for NSCLC staged as pT3N0M0 from 2010 to 2013 on the basis of the seventh edition of the TNM classification were retrieved from the Netherlands Comprehensive Cancer Organization. These data were next matched with corresponding pathology data from a nationwide registry. Patients were categorized into four major pT3 subgroups as follows: those with a tumor diameter more than 7 cm, those with separate tumor nodules in the same lobe (two or more nodules), those with parietal pleural invasion, and a mixed group (consisting mainly of those with a tumor diameter larger than 7 cm combined with parietal pleural invasion). RESULTS: A total of 683 patients were eligible for analysis. The 3- and 5-year overall survival (OS) rates for the subtype tumor diameter larger than 7 cm were 59.9% and 47.2%, respectively, and were comparable to the rates for the subtype with pleural invasion (50.4% and 45.3%), respectively. The mixed group had worse 3- and 5-year OS rates (37.5% and 28.7%, respectively), which were comparable to the outcomes for TNM eighth edition-staged IIIB and pT4 cases in the International Association for the Study of Lung Cancer database. For the subtype two or more nodules, the 3- and 5-year OS rates were 70.6% and 62.8%, respectively, with patients with adenocarcinoma showing a significantly better OS than did patients with squamous cell carcinoma: a 5-year OS rate of 65.1% versus 47.2%, respectively (p < 0.001), suggesting that the prognosis for the adenocarcinoma subgroup may be comparable to that for the pT2 category, whereas squamous cell carcinoma nodules can remain pT3. CONCLUSION: This population analysis of overall survival rate by pT3N0 subcategory for NSCLC suggests that histologic type is a relevant descriptor in the category two or more nodules. The findings do not support migration of the group with a tumor diameter larger than 7 cm to the category pT4in the eighth edition of the TNM classification, and they suggest that a combination of two pT3 descriptors (the mixed group) merits migration to pT4.