title: Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.
abstract: Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy.
  
  
  
  We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed.
  
  
  
  We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months).
  
  
  
  Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
authors.forename: M
authors.initials: M
authors.lastname: Del Rio
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
authors.forename: C
authors.initials: C
authors.lastname: Mollevi
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
authors.forename: F
authors.initials: F
authors.lastname: Bibeau
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
authors.forename: N
authors.initials: N
authors.lastname: Vie
authors.affiliation: Centre Hospitalier Universitaire de Toulouse, F-31300, France; Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche 1037 INSERM - Université Toulouse III, France.
authors.forename: J
authors.initials: J
authors.lastname: Selves
authors.affiliation: Université de Versailles, Boulogne, France; Hôpital Ambroise Paré, Boulogne, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Université de Montpellier, Montpellier, F-34090, France; Service d'Anatomie et Cytologie Pathologiques, CHU Nîmes, Place du Professeur Debré, 30029, Nîmes, France.
authors.forename: P
authors.initials: P
authors.lastname: Roger
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
authors.forename: C
authors.initials: C
authors.lastname: Gongora
authors.affiliation: INSERM U916, Institut Bergonié, Université de Bordeaux, France.
authors.forename: J
authors.initials: J
authors.lastname: Robert
authors.affiliation: Service d'oncologie médicale, CHU Dupuytren, avenue Luther-King, 87000, Limoges, France.
authors.forename: N
authors.initials: N
authors.lastname: Tubiana-Mathieu
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France.
authors.forename: M
authors.initials: M
authors.lastname: Ychou
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut régional du Cancer de Montpellier, Montpellier, F-34298, France. Electronic address: pierre.martineau@inserm.fr.
authors.forename: P
authors.initials: P
authors.lastname: Martineau
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011379:Prognosis; D015996:Survival Rate; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Bevacizumab; Cetuximab; Colorectal neoplasms; FOLFIRI protocol; Folfox protocol; Gene expression profiling