title: Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803.
abstract: OBJECTIVE
  Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer.
  
  
  METHODS
  We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status.
  
  
  RESULTS
  Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46).
  
  
  CONCLUSIONS
  BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: McCleary
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.forename: Donna
authors.initials: D
authors.lastname: Hollis
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Paul
authors.initials: P
authors.lastname: Schaefer
authors.forename: Renaud
authors.initials: R
authors.lastname: Whittom
authors.forename: Alexander
authors.initials: A
authors.lastname: Hantel
authors.forename: Al B
authors.initials: AB
authors.lastname: Benson
authors.forename: Donna
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D000077146:Irinotecan; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin