title: Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.
abstract: BACKGROUND
  Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.
  
  
  METHODS
  We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC.
  
  
  RESULTS
  Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07).
  
  
  CONCLUSIONS
  This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.
authors.affiliation: 1] Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia [2] Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Rowland
authors.affiliation: 1] Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia [2] School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: M M
authors.initials: MM
authors.lastname: Dias
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Wiese
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Kichenadasse
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: McKinnon
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: C S
authors.initials: CS
authors.lastname: Karapetis
authors.affiliation: 1] Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia [2] Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sorich
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf