Background: BRAF V600E (class I) mutant non-small cell lung cancer (NSCLC) is well characterized. However, less is known about other classes of BRAF mutations or BRAF fusions in this population. Previous studies have suggested that different classes of BRAF mutations may have varied clinical implications, motivating further study to guide therapeutic options in clinical practice. In this work, we set out to characterize the class of BRAF and co-occurring mutations as well as BRAF fusions in a real-world NSCLC cohort using comprehensive genomic profiling (CGP).

Methods: We retrospectively analyzed de-identified records from 6,511 patients with NSCLC that underwent CGP with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, and full transcriptome RNA-seq for a subset of patients). BRAF mutations were classified based on published literature (PMID: 33019809).

Results: We identified 322/6,511 (4.9%) patients with pathogenic BRAF alterations. The cohort of 322 BRAF-mutant patients consisted of 87 class I patients (27.0%), 82 class II patients (25.5%), 83 class III patients (25.8%), and 70 other/unclassified (21.7%). Genomic analysis identified several significant differences in the co-mutational landscape of distinct BRAF classes including EGFR, KRAS, and NF1 (q<0.05). Pathogenic EGFR mutations were more prevalent in class I (20%) vs class II (6.1%) and class III (7.2%). By contrast, KRAS mutations were more prevalent in class II (13%) and class III (19%) compared to class I (3.4%). Similarly, NF1 mutations were more prevalent in class II (9.8%) and class III (12%) vs class I (2.3%). Notably, DNA and RNA gene fusion analysis identified 13 patients with reported pathogenic BRAF fusions; of these, 11/13 were only identified via RNA-seq.

Conclusions: DNA and RNA-seq analysis showed that BRAF Class II and Class III mutations are associated with distinct genomic characteristics as compared to Class I, such as more frequent concurrent RAS and NF1 mutations. BRAF fusions were also detected, predominantly via RNA sequencing.

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