title: Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset.
abstract: BACKGROUND
  The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.
  
  
  METHODS
  We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model.
  
  
  RESULTS
  KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051).
  
  
  CONCLUSIONS
  KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.
  
  
  BACKGROUND
  This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
authors.affiliation: UMR-S1147, INSERM, Paris; Paris Descartes University, Paris; APHP Department of Biology, Georges Pompidou Hospital, Paris.
authors.forename: H
authors.initials: H
authors.lastname: Blons
authors.affiliation: Department of Pathology, APHP Ambroise Paré Hospital, Boulogne-Billancourt; Paris-Ouest University, Versailles Saint-Quentin.
authors.forename: J F
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon.
authors.forename: K
authors.initials: K
authors.lastname: Le Malicot
authors.affiliation: Department of Pathology, APHP Ambroise Paré Hospital, Boulogne-Billancourt.
authors.forename: C
authors.initials: C
authors.lastname: Julié
authors.affiliation: APHP Department of Hepatogastroenterology and GI Oncology, Georges Pompidou Hospital, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Zaanan
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mini
authors.affiliation: 1st Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Folprecht
authors.affiliation: Deptartment of Gastroenterology, Erasme University Hospital, Brussels, Belgium.
authors.forename: J L
authors.initials: JL
authors.lastname: Van Laethem
authors.affiliation: Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Thaler
authors.affiliation: UCL Cancer Institute, University College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: Department of Oncology, Rigshospitalet, København, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Nørgård-Petersen
authors.affiliation: Department of Digestive Oncology, University Hospitals and KULeuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Department of Hepato-Gastroenterology, Dijon University Hospital and INSERM U 866, Dijon.
authors.forename: C
authors.initials: C
authors.lastname: Lepage
authors.affiliation: GI Oncology, Les Oudairies Hospital, La Roche sur Yon, France.
authors.forename: M A
authors.initials: MA
authors.lastname: Zawadi
authors.affiliation: Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Salazar
authors.affiliation: UMR-S1147, INSERM, Paris; Paris Descartes University, Paris; APHP Department of Biology, Georges Pompidou Hospital, Paris.
authors.forename: P
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: APHP Department of Hepatogastroenterology and GI Oncology, Georges Pompidou Hospital, Paris, France; Paris Descartes University, Paris. Electronic address: julien.taieb@egp.aphp.fr.
authors.forename: J
authors.initials: J
authors.lastname: Taieb
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D005091:Exons; D005260:Female; D005472:Fluorouracil; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil
keywords: KRAS mutation; cetuximab; colorectal cancer; distal colon; prognosis; proximal colon