Prevalence and breakdown of non-small cell lung cancer BRAF driver mutations in a large UK cohort.

BRAF inhibitors have been shown in clinical trials to improve patient outcomes in non-small cell lung cancer (NSCLC) patients harbouring selected BRAF driver mutations with a limited side effect profile, and therefore show potential as therapeutics in clinical practice. To utilise BRAF inhibitors effectively, understanding the prevalence of BRAF mutations within the local patient population is crucial, especially since NSCLC driver mutation rates have been observed to vary in different populations around the world. We interrogated a clinical archive of next generation sequencing (NGS) data representative of 7 years of routine UK practice in the National Health Service (NHS) to investigate the frequency of BRAF mutations, the breakdown of mutation classes and co-occurrence of other oncogenic driver mutations. Tissue biopsies from NSCLC cases referred to the Sarah Cannon Molecular Diagnostics Laboratory between January 2015 and February 2022 from multiple centres across UK were included in this study. Somatic mutation hotspots in relevant cancer-associated genes were analysed using amplicon/ion-torrent based NGS assays, and all NSCLC samples which harboured recognised BRAF driver mutations were identified through a combination of automated and manual data retrieval. Data regarding any other detected mutations and basic demographic information were also collected. Over the 7-year period, 5384 NSCLC samples were sequenced, with BRAF mutation identified in 185 (3.44%) of cases. These 185 cases represented a total of 73 Class I BRAF mutations (39.5%), 61 Class II mutations (33.0%) and 51 Class III mutations (27.6%). Of the 73 identified Class I mutations, 69 (69/185, 37.3%) were V600E and four (4/185, 2.16%) were non-V600E mutations. Five V600E cases had co-mutations (5/185, 2.7%). Various other known driver mutations were also identified in these 185 tumour samples, with KRAS (18/185, 9.73%) and PIK3CA (7/185, 3.78%) occurring at the highest frequency. This is the first large cohort-level study in the UK to profile the breakdown of BRAF-positive NSCLC biopsy samples using NGS in routine clinical practice. This study defines the proportion of NSCLC patients that may be expected to benefit from BRAF inhibitors and highlights the utility of using NGS as a diagnostic tool to improve targeted therapy stratification for NSCLC patients.