title: Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.
abstract: BACKGROUND
  Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance.
  
  
  METHODS
  Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit.
  
  
  RESULTS
  Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05).
  
  
  CONCLUSIONS
  Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide. Electronic address: michael.sorich@flinders.edu.au.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sorich
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide.
authors.forename: M D
authors.initials: MD
authors.lastname: Wiese
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide.
authors.forename: A
authors.initials: A
authors.lastname: Rowland
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Kichenadasse
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 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, Australia.
authors.forename: C S
authors.initials: CS
authors.lastname: Karapetis
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
keywords: RAS mutation; cetuximab; meta-analysis; panitumumab; pharmacogenomics; predictive biomarker