Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts

Abstract

<p><em>BRAF</em>-V600E mutation (mt) is a strong negative prognostic and predictive biom<em>arker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (a</em>BRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of a<em>BRAF</em>mt was studied. The study included 1449 mCRC patients with 51 (3%) a<em>BRAF</em>mt, 182 (13%) <em>BRAF</em>-V600Emt, 456 (31%) <em>RAS</em>&<em>BRAF</em> wild-type (wt) and 760 (52%) <em>RAS</em>mt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different a<em>BRAF</em>mt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with <em>BRAF</em>-V600Emt. a<em>B</em>RAFmt and <em>BRAF</em>-V600Emt had poorer performance status and received fewer treatment lines than <em>RAS</em>&<em>BRAF</em>wt and <em>RAS</em>mt. OS among a<em>BRAF</em>mt (median 14.4 months) was longer than for <em>BRAF</em>-V600Emt (11.2 months), but shorter than for <em>RAS</em>&<em>BRAF</em>wt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the a<em>BRAF</em>mt. Nine patients with a<em>BRAFm</em>t received cetuximab/panitumumab without response. a<em>BRAF</em>mt represents a distinct subgroup differing from other <em>RAS/BRAF</em> groups, with serrated adenocarcinoma in only half. OS for patients with a<em>BRAF</em>mt tumours was slightly better than for <em>BRAF</em>-V600Emt, but worse than for <em>RAS</em>mt and <em>RAS</em>&<em>BRAF</em>wt. a<em>BRAF</em>mt should not be a contraindication for metastasectomy.</p>