title: Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy.
abstract: OBJECTIVE
  The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.
  
  
  METHODS
  Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAF(V600E) (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.
  
  
  RESULTS
  dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAF(V600E) or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (P(interaction) = .009) and lymph node category (N1 v N2; P(interaction) = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAF(V600E) (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (P(interaction) = .037).
  
  
  CONCLUSIONS
  The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.
authors.affiliation: Frank A. Sinicrope, Michelle R. Mahoney, Thomas C. Smyrk, Stephen N. Thibodeau, Garth D. Nelson, Daniel J. Sargent, and Steven R. Alberts, Mayo Clinic, Mayo Cancer Center and the North Central Cancer Treatment Group, Rochester, MN; Robert S. Warren, University of California San Francisco, San Francisco, CA; Monica M. Bertagnolli, Brigham and Women's Hospital, Boston, MA; and Richard M. Goldberg, The Ohio State University Comprehensive Cancer Center, Columbus, OH.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Robert S
authors.initials: RS
authors.lastname: Warren
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.forename: Garth D
authors.initials: GD
authors.lastname: Nelson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D053843:DNA Mismatch Repair; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: 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; D002955:Leucovorin; D005472:Fluorouracil
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