title: Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.
abstract: OBJECTIVE
  To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF(MT)) status in metastatic colorectal cancer (mCRC).
  
  
  METHODS
  A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data.
  
  
  RESULTS
  The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAF(MT). BRAF(MT) was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P < 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors [HR, 1.33; 95% confidence interval (CI), 1.12-1.57 and HR, 1.35; 95% CI, 1.13-1.61, respectively), and for patients with BRAF(MT) compared with BRAF wild-type (BRAF(WT)) tumors (HR, 1.34; 95% CI, 1.17-1.54 and HR, 1.91; 95% CI, 1.66-2.19, respectively). PFS and OS were significantly decreased for patients with BRAF(MT) within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAF(WT) or BRAF(MT).
  
  
  CONCLUSIONS
  Prevalence of dMMR and BRAF(MT) in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAF(MT) status.
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands. Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Venderbosch
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.affiliation: Department of Oncology, Gray Institute for Radiation Oncology, Biology University of Oxford, Oxford, United Kingdom.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Maughan
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Smith
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
authors.affiliation: MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.affiliation: MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.affiliation: Department of Pathology, Anatomy and Tumor Biology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Quirke
authors.affiliation: Department of Medical Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Seymour
authors.affiliation: Department of Pathology, Anatomy and Tumor Biology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Richman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Danielle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anton F J
authors.initials: AF
authors.lastname: de Haan
authors.affiliation: Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. M.Koopman-6@umcutrecht.nl.
authors.forename: Miriam
authors.initials: M
authors.lastname: Koopman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016022:Case-Control Studies; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D006801:Humans; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1