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

Abstract

AbstractBRAF‐V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non‐V600Emt, designated atypical BRAFmt (aBRAFmt) 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 aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF‐V600Emt, 456 (31%) RAS&BRAF wild‐type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real‐world and 4% of population‐based cohorts. Twenty‐six different aBRAFmt 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 BRAF‐V600Emt. aBRAFmt and BRAF‐V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF‐V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF‐V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.