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BRAF‐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. [ABSTRACT FROM AUTHOR]

Anti-EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti-EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti-EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses. EGFR GCN was analysed by EGFR immunohistochemistry guided automated silver in situ hybridisation. Increased EGFR GCN (≥4.0) predicted a better response and prolonged progression free survival in anti-EGFR treated RAS/BRAF/PIK3CA wild type patients (Log-rank test, p = 0.0004). In contrast, survival of RAS/BRAF/PIK3CA wild type, EGFR GCN below 4.0 patients did not differ from patients with mutant RAS, BRAF or PIK3CA. Our study indicates that EGFR GCN predicts anti-EGFR treatment efficacy in patients with RAS/BRAF/PIK3CA wt metastatic CRC. Tumours with EGFR GCN below 4.0 appear to be as refractory to anti-EGFR treatment as tumours with mutation in any of the RAS/RAF/PIK3CA pathway genes. [ABSTRACT FROM AUTHOR]