BRAF in Lung Cancers: Analysis of Patient Cases Reveals Recurrent BRAF Mutations, Fusions, Kinase Duplications, and Concurrent Alterations

Abstract

Purpose Dabrafenib and trametinib are approved for the management of advanced non–small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B RAF alterations in lung cancer. Patients and Methods A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements. Results Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations ( P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated. Conclusion This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR AF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations

“…We confirmed that TP53, EGFR, KRAS, and NF1 were among the most often comutated genes in BRAF-mutant and BRAF-focally amplified tumors, consistent with previous reports. 36 In addition, we found that KRAS mutations were enriched in cases having class 3 BRAF mutations, which is also consistent with previous reports, 13,37 and preclinical data highlighting that these kinase-impaired alterations require additional RAS activation (e.g., KRAS mutations) or receptor tyrosine kinase activation (e.g., EGFR mutations) to promote cell growth and survival. 19,20 We also found that there was a significant association between NF1 mutations and class 2 BRAF mutations compared with class 1 (p ¼ 0.05).…”

Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors

“…[23][24][25] Of the nine unique partners identified among 10 cases with BRAF fusions in this report, aspartylglucosaminidase (AGA)-BRAF and Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 3 (AGAP3)-BRAF fusions have been reported in NSCLC, whereas KIAA1549-BRAF was identified in other tumors. Among the recently reported 21 distinct BRAF partners in NSCLC 25 , SALL2-BRAF is a novel fusion not reported previously. SALL2 contains four separate zinc finger domains which can bind to DNA and function as a transcription repressor as well as interact with SV40 large T antigen.…”

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers

“…FGFR fusions were identified in approximately 0.2% of NSCLC cases from a large series of 26,054 patients and included one patient that had clinical benefit to an investigational FGFR inhibitor [90]. Similarly, low frequencies have been identified for BRAF fusions (0.2-2.8%) [91,92], MET fusions (0.04%) [93], and EGFR fusions (0.08%) [94]. Owing to the rarity of these fusion drivers and the limited epidemiological and clinical characterization of these cohorts, our understanding of the incidence of BM and intracranial efficacy of targeted therapies is limited.…”