Clinicopathologic and mutational landscape of BRAFV600E-mutant non–small cell lung carcinoma.

Abstract

9084 Background: BRAF mutations (mts) occur in 2-5% of non-small cell lung cancers (NSCLC) with approximately 50% being BRAFV600E. Limited data is known regarding the mutational landscape (ML) and prognostic role of co-mutations in BRAFV600E NSCLC. We performed this study to evaluate clinicopathological characteristics and the impact of ML in BRAFV600E NSCLC. Methods: Patients (pts) with BRAFV600Emutant NSCLC were identified using MSK-IMPACT at Memorial Sloan Kettering Cancer Center between January 2014 to October 2021. Baseline clinicopathological characteristics and treatment outcomes were annotated. Due to the enrichment of SETD2 in BRAFV600E NSCLC, we conducted further analyses using cbioportal to identify co-mutations of SETD2 with other actionable mutations in NSCLC. Overall survival (OS) was assessed from the date of metastatic disease until death using the log-rank test. Results: BRAF mutations were detected in 5% of NSCLC samples (512/10220) with 22% (97/435 pts) being BRAFV600E. Of the 97 pts with BRAFV600E NSCLC identified: 57 pts (59%) were females, median age of 68 (range: 38-93 years), 58 pts (60%) were former smokers. All BRAFV600E tumors were adenocarcinoma and the median tumor mutational burden was 5 mt/Mb (range: 0-40). 46 pts (48%) with BRAFV600E NSCLC were diagnosed with de novo metastatic disease. Pts receiving targeted therapy at first, second, and subsequent lines of therapy numbered 17 (29%), 18 (31%), and 10 (17%) respectively. Co-alterations of BRAFV600E with TP53 and SETD2 were found in 45% (44/97) and 42% (41/97), respectively. There is a much lower prevalence of concurrent inactivating SETD2 mutations than with other actionable alterations in NSCLC: ROS1 (9%), ALK (8%), RET (8%), HER2 (6%), MET (5%), KRAS (5%), EGFR (2.9%) and BRAFnon-V600E (2%). Median OS in BRAFV600E+/ TP53+ vs BRAFV600E+/ SETD2+ were 35 vs 36 mos (HR 0.88m 95% CI 0.45-1.75, P= 0.71) and BRAFV600E+/ TP53+/ SETD2+ vs BRAFV600E+/ TP53-/ SETD2- were 19 vs 39 mos (HR 0.37, 95% CI 0.09-1.50, P= 0.06). Conclusions: Among the BRAFV600E lung adenocarcinomas, concurrent TP53 mutation and SETD2 inactivation define a patient subset with significantly shorter overall survival. Further studies are warranted to investigate the role of SETD2 mutations in the context of BRAFV600E in NSCLC pts.