BRAF mutation classes and co-occurring mutations in NSCLC.

Abstract

9083 Background: Targeted therapy against unique molecular drivers has revolutionized non-small cell lung cancer (NSCLC) treatment. BRAF mutations, present in 2%-5%, have emerged as therapeutic targets, and can be divided into three classes: kinase-activating monomers (class I, V600) or dimers (class II), or kinase-inactivating dimers (class III). Most studies have focused on BRAF V600E NSCLC. Limited clinical data suggest classes II and III may not respond well to chemo- or targeted therapy and tend to have a poorer prognosis. Little is known about co-occurring mutations. This study examines BRAF classes and co-occurring mutations in NSCLC. Methods: Between October 2018 and October 2021, data from 3009 NSCLC Oncotype MAP test results were analyzed. This test utilizes tumor DNA to identify single nucleotide variants, indels, copy number alterations, and select structural variants/fusions by next generation sequencing with a 257 gene panel. Tumor mutational burden and microsatellite instability are also assessed. Pathogenic/likely pathogenic mutations were identified, BRAF mutations assigned to 3 different classes based on current understanding, and associations of other mutated genes with BRAF class examined. Results: Among samples, 133 (4.4%) had BRAF mutations: 30 class I (1%); 42 class II (1.4%); 36 class III (1.2%); and 25 unclassified (0.8%) (Table). Two genes showed associations with BRAF class: STK11 was significantly overrepresented in class II and III, and SETD2 in class I (p<0.05 for both). BRAF class II mutations were further divided into subclasses, IIa (n= 5) and IIb (n= 35); two could not be assigned. The lack of a positive association between KRAS (and NF1) and BRAF class III was unexpected since class III is RAS-dependent while class I and II are RAS-independent. The overrepresentation of STK11 in classes II (with 11/12 events in IIb) and III might explain, at least in part, the poor prognosis relative to class I. By contrast, SETD2 is overrepresented in class I, which might help explain its better response to immunotherapy. Conclusions: For the first time we report the incidence of BRAF mutation classes and associated co-mutations in NSCLC. These associations may help to explain therapeutic outcomes. The impact of coexisting STK11 mutations in class II subclasses warrants further investigation.[Table: see text]