title: Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group.
abstract: BACKGROUND
  The added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study.
  
  
  METHODS
  Of the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status.
  
  
  RESULTS
  Mutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) <2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557-558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176).
  
  
  CONCLUSIONS
  In GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS.
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Patrikidou
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Domont
authors.affiliation: Biostatistics Department, Centre Léon Bérard, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.affiliation: Biostatistics Department, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Binh
authors.initials: B
authors.lastname: Bui-Nguyen
authors.affiliation: Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
authors.affiliation: Department of Medical Oncology, Centre Alexis Vautrin, Nancy, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Rios
authors.affiliation: Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Medicine, Hopital La Timone, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.affiliation: Department of Medicine, Institut Claudius Regaud, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.affiliation: Department of Medical Oncology, Institut du Cancer du Montpellier, Montpellier, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Cupissol
authors.affiliation: Biostatistics Department, Centre Léon Bérard, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Pérol
authors.affiliation: Université de Versailles and Hôpital Ambroise Paré, Boulogne, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: CRCL INSERM U1052 & Université Claude Bernard Lyon 1 & Centre Léon Bérard, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Villejuif, France. Electronic address: Axel.LECESNE@gustaveroussy.fr.
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D005602:France; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
keywords: GIST; imatinib mesylate; mutational status; outcome analysis; prognostic factors