title: Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.
abstract: OBJECTIVE
  The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer.
  
  
  METHODS
  Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR).
  
  
  RESULTS
  BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20-1.79; P ≤ 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83-2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33-0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit.
  
  
  CONCLUSIONS
  This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15212, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gavin
authors.forename: Linda H
authors.initials: LH
authors.lastname: Colangelo
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Matthew Y
authors.initials: MY
authors.lastname: Remillard
authors.forename: Greg
authors.initials: G
authors.lastname: Yothers
authors.forename: Chungyeul
authors.initials: C
authors.lastname: Kim
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Seung Il
authors.initials: SI
authors.lastname: Kim
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Choi
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Blackmon
authors.forename: Corey
authors.initials: C
authors.lastname: Lipchik
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Petrelli
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.forename: Kay L
authors.initials: KL
authors.lastname: Pogue-Geile
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D053843:DNA Mismatch Repair; D006801:Humans; D053842:Microsatellite Instability; D009154:Mutation; D059645:Mutation Rate; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D048493:Proto-Oncogene Proteins B-raf