title: Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.
abstract: OBJECTIVE
  Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting.
  
  
  METHODS
  Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models.
  
  
  RESULTS
  KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003).
  
  
  CONCLUSIONS
  In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.
authors.affiliation: Oncosurgery, Geneva UniversityHospital, Geneva, Switzerland. arnaud.roth@sim.hcuge.ch
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Roth
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Pu
authors.initials: P
authors.lastname: Yan
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiocca
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.forename: Daniel
authors.initials: D
authors.lastname: Dietrich
authors.forename: Bart
authors.initials: B
authors.lastname: Biesmans
authors.forename: György
authors.initials: G
authors.lastname: Bodoky
authors.forename: Carlo
authors.initials: C
authors.lastname: Barone
authors.forename: Enrique
authors.initials: E
authors.lastname: Aranda
authors.forename: Bernard
authors.initials: B
authors.lastname: Nordlinger
authors.forename: Laura
authors.initials: L
authors.lastname: Cisar
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Fred
authors.initials: F
authors.lastname: Bosman
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D000090063:Proto-Oncogene Mas; 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: C117307:KRAS protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins