title: Meta-analysis of the predictive value of KRAS mutations in treatment response using cetuximab in colorectal cancer.
abstract: OBJECTIVE
  The monoclonal antibody cetuximab that targets epidermal growth factor receptor (EGFR) has been found effective in the treatment of colorectal cancer. However, mutations in exons 12 and 13 of KRAS oncogene have been reported as negative predictive factors for the treatment response using cetuximab. The purpose of this study was to conduct a meta-analysis of the published studies investigating the predictive value of KRAS mutations in the efficacy of cetuximab in patients suffering from colorectal cancer.
  
  
  METHODS
  A systematic search of the literature was performed in PubMed, Medline, and Cochrane databases. Sensitivities, specificities and predictive values (negative and positive) of KRAS mutations as regards treatment response were calculated.
  
  
  RESULTS
  Twenty-six studies were initially found during the literature search. After thorough evaluation, 13 papers were excluded for various reasons. Therefore, 13 studies were included in the present meta-analysis. In these studies, specificities were found much higher than sensitivities. Combining the data from the 13 studies, it was found that KRAS mutations comprise a negative predictive biomarker for response to cetuximab with very high specificity (0.96; 95% CI 0.84-0.99), and low sensitivity (0.47; 95% CI 0.43-0.50). Finally, the publication bias was found statistically significant.
  
  
  CONCLUSIONS
  The results of the present meta-analysis suggest that cetuximab should be administered only to patients with colorectal cancer who have the wild type (KRASw) oncogene. Mutations in the KRAS gene are a negative predictive factor for response to cetuximab with very high specificity and low sensitivity. The latter may very well be attributed to additional mechanisms of resistance to anti-EGFR therapies such as mutations in BRAF.
authors.affiliation: Department of Medical Oncology, 401 General Army Hospital, Athens, Greece. tsoukn@yahoo.gr
authors.forename: N
authors.initials: N
authors.lastname: Tsoukalas
authors.forename: A A
authors.initials: AA
authors.lastname: Tzovaras
authors.forename: M
authors.initials: M
authors.lastname: Tolia
authors.forename: I D
authors.initials: ID
authors.lastname: Kostakis
authors.forename: A
authors.initials: A
authors.lastname: Papakostidi
authors.forename: N
authors.initials: N
authors.lastname: Pistamaltzian
authors.forename: A
authors.initials: A
authors.lastname: Ardavanis
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D009154:Mutation; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D017594:Publication Bias; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab