title: Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951.
abstract: OBJECTIVE
  Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples.
  
  
  METHODS
  Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively.
  
  
  RESULTS
  All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50).
  
  
  CONCLUSIONS
  Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.
authors.affiliation: Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Lale
authors.initials: L
authors.lastname: Erdem-Eraslan
authors.forename: Lonneke A
authors.initials: LA
authors.lastname: Gravendeel
authors.forename: Johan
authors.initials: J
authors.lastname: de Rooi
authors.forename: Paul H C
authors.initials: PH
authors.lastname: Eilers
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.forename: Wim G M
authors.initials: WG
authors.lastname: Spliet
authors.forename: Wilfred F A
authors.initials: WF
authors.lastname: den Dunnen
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Teepen
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Peter A E
authors.initials: PA
authors.lastname: Sillevis Smitt
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008130:Lomustine / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011344:Procarbazine / Q000008:administration & dosage; D011379:Prognosis; D059467:Transcriptome; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine