BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis

Background: While the negative prognostic role of BRAF V600E mutation in metastatic colorectal cancer (mCRC) is well established, the impact of BRAF codons 594 and 596 mutations, occurring in <1% of CRCs, is completely unknown. The present work aims to describe clinical, pathological and molecular features and prognosis of BRAF codons 594 and 596 mutant mCRCs, compared with BRAF V600E mutant and wild-type ones. Patients and methods: Patients treated for mCRC at three Italian Institutions between October 2006 and October 2014, with available KRAS and NRAS codon 12, 13, 59, 61, 117 and 146 and BRAF codon 594, 596 and 600 mutational status, as detected by means of direct sequencing or matrix assisted laser desorption ionization time-of-flight MassArray, were included. Results: Ten patients bearing BRAF codons 594 or 596 mutated tumors were identified and compared with 77 and 542 patients bearing BRAF V600E mutated and BRAF wild-type tumors, respectively. While BRAF V600E mutated tumors were more frequently right-sided, mucinous and with peritoneal spread, BRAF 594 or 596 mutated were more frequently rectal, nonmucinous and with no peritoneal spread. All BRAF 594 or 596 mutated tumors were microsatellite stable. Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival (OS) when compared with BRAF V600E mutated [median OS: 62.0 versus 12.6 months; hazard ratio: 0.36 (95% confidence interval 0.20-0.64), P = 0.002], both at univariate and multivariate analyses. Conclusions: BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features, pathological characteristics and clinical outcome. This is consistent with preclinical evidences of a kinase inactivating effect of these mutations. The role of CRAF in transducing the intracellular signal downstream BRAF 594 or 596 mutated proteins opens the way to further preclinical investigation.