title: KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance).
abstract: OBJECTIVE
  We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive.
  
  
  METHODS
  The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models.
  
  
  RESULTS
  KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001).
  
  
  CONCLUSIONS
  KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033-43. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Harry H
authors.initials: HH
authors.lastname: Yoon
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: David
authors.initials: D
authors.lastname: Tougeron
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Garth D
authors.initials: GD
authors.lastname: Nelson
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Suresh G
authors.initials: SG
authors.lastname: Nair
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.affiliation: Authors' Affiliations: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; Lehigh Valley Hospital, Allentown, Pennsylvania; and Ohio State University, Columbus, Ohio sinicrope.frank@mayo.edu.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant; D003062:Codon; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003062:Codon; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil