title: Validation of companion diagnostic for detection of mutations in codons 12 and 13 of the KRAS gene in patients with metastatic colorectal cancer: analysis of the NCIC CTG CO.17 trial.
abstract: BACKGROUND
  The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab.
  
  
  OBJECTIVE
  To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy.
  
  
  METHODS
  Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes. Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P = .002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P = .55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing.
  
  
  CONCLUSIONS
  These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy.
authors.affiliation: Bristol-Myers Squibb, Rte 206 and Province Line Rd, Princeton, NJ 08543, USA. christopher.harbison@bms.com
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Harbison
authors.forename: Christine E
authors.initials: CE
authors.lastname: Horak
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Ledeine
authors.forename: Pralay
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Malone
authors.forename: Chris
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.forename: Christos S
authors.initials: CS
authors.lastname: Karapetis
authors.forename: Shirin
authors.initials: S
authors.lastname: Khambata-Ford
authors.forename: Nancy
authors.initials: N
authors.lastname: Gustafson
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Trifan
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Chang
authors.forename: Paul
authors.initials: P
authors.lastname: Ravetto
authors.forename: George A Green
authors.initials: GA
authors.lastname: Iv
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D003062:Codon / Q000235:genetics*; D018389:Codon, Nonsense; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003062:Codon; D018389:Codon, Nonsense; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab