BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis
- 1 October 2015
- journal article
- research article
- Published by Elsevier BV in Annals of Oncology
- Vol. 26 (10), 2092-2097
- https://doi.org/10.1093/annonc/mdv290
Abstract
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 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. 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. 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.Funding Information
- ARCO Foundation and Fondazione IRCCS Istituto Nazionale dei Tumori's
- Terapia Molecolare dei Tumori from Fondazione Oncologia Niguarda Ca’ Granda Onlus
- EC 7th Framework Colon Therapy Research COLTHERES
This publication has 22 references indexed in Scilit:
- BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resectionBritish Journal of Cancer, 2015
- Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysisEuropean Journal of Cancer, 2015
- Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS StudiesClinical Cancer Research, 2014
- FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trialThe Lancet Oncology, 2014
- BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancerCancer, 2014
- Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal CancerThe New England Journal of Medicine, 2013
- Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancerCancer, 2011
- Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAFV600E mutationInternational Journal of Cancer, 2011
- KRAS and BRAF Mutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS TrialJournal of Clinical Oncology, 2009
- Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal CancerJournal of Clinical Oncology, 2008