title: Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients.
abstract: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer.
  
  
  
  Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested.
  
  
  
  Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations.
  
  
  
  Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting.
  
  
  
  This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
authors.affiliation: Paris Descartes University, Paris Sorbonne cité, Department of Digestive Oncology, HEGP, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Taieb
authors.affiliation: Biology, Université Paris Descartes, Sorbonne Paris Cité; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, INSERM UMR-S1147, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Balogoun
authors.affiliation: Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France.
authors.forename: K
authors.initials: K
authors.lastname: Le Malicot
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Universitat Autònoma de Barcelona, Spanish Gastrointestinal Tumours TTD Group, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mini
authors.affiliation: Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Folprecht
authors.affiliation: Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium.
authors.forename: J-L
authors.initials: JL
authors.lastname: Van Laethem
authors.affiliation: Pathology Department, Ambroise Paré Hospital, Boulogne, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, CRB EPIGENETEC, INSERM UMR-S1147, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Mulot
authors.affiliation: Department of Gastroenterology, Centre Hospitalier de Belfort-Montbeliard, Belfort, France.
authors.forename: S
authors.initials: S
authors.lastname: Fratté
authors.affiliation: Department of Radiotherapy and Medical Oncology, Polyclinique Francheville, Périgueux, France.
authors.forename: C-B
authors.initials: CB
authors.lastname: Levaché
authors.affiliation: Department of medical Oncology, Institut de Cancerologie de la Loire, Saint-Priest-En-Jarez, France.
authors.forename: L
authors.initials: L
authors.lastname: Saban-Roche
authors.affiliation: Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Thaler
authors.affiliation: Department of Oncology, Rigshospitalet, København, Denmark.
authors.forename: L N
authors.initials: LN
authors.lastname: Petersen
authors.affiliation: UCL Cancer Institute, University College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: Biology, Université Paris Descartes, Sorbonne Paris Cité; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, INSERM UMR-S1147, Paris, France.|Université Sorbonne Paris Cité, INSERM UMR-S1147, CNRS SNC 5014, Centre Universitaire des Saints-Pères, Equipe labélisée LIGUE Contre le Cancer, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Perkins
authors.affiliation: Hepato-Gastroenterology Department, Dijon University Hospital and INSERM U 866, Dijon, France.
authors.forename: C
authors.initials: C
authors.lastname: Lepage
authors.affiliation: Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Biology, Université Paris Descartes, Sorbonne Paris Cité; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, INSERM UMR-S1147, Paris, France.|Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Zaanan
authors.affiliation: Biology, Université Paris Descartes, Sorbonne Paris Cité; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, INSERM UMR-S1147, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D009944:Organoplatinum Compounds; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil
keywords: BRAF mutations; FOLFOX; RAS mutations; adjuvant; cetuximab; phase III; prognosis; stage III colon cancer