title: The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy.
abstract: Increasingly, biomarkers have been identified that correlate with improved overall and progression-free survival (OS and PFS) in glioblastoma, including MGMT methylation status and mutations in the IDH1 gene. In this study, we investigated the clinical and biological factors associated with long-term survival in glioblastoma patients treated with chemoradiotherapy.
  
  
  
  Demographic and clinical data were collected for all patients with glioblastoma diagnosed between May 2004 and September 2007, treated with chemoradiotherapy and with associated tissue samples available for biomarker analysis. MGMT methylation was determined by pyrosequencing. IDH1 mutation was identified by R132H immunohistochemistry. Univariate Cox regression analysis of factors associated with survival and Kaplan-Meier survival analysis was performed using the SPSS statistics package.
  
  
  
  One hundred patients were included in the study. Median follow-up was 12.2 months (range 1.6-102.4). Median OS was 12.1 months (95 % CI: 10.8-13.3) and median PFS was 8.2 months (95 % CI: 6.8-9.5). The 2-, 3- and 5-year survival was 18, 9 and 6 % respectively. Three patients are still alive at 7.4, 8.3 and 8.5 years after diagnosis. Cox proportional-hazards regression identified independent prognostic factors for OS, female (p = 0.019), MGMT methylation (p < 0.0001) and IDH1 mutation (p = 0.023), and for PFS, MGMT methylation (p = 0.001) and IDH1 mutation (p = 0.018). Kaplan-Meier survival analysis showed that MGMT(methylated)/IDH1(+ve) was associated with a significantly longer OS 66.8 months (95 % CI: 0.0-167.8) and PFS 16.9 months (95 % CI: 11.1-22.7) when compared with MGMT(methylated)/IDH1(-ve) OS 15.5 months (95 % CI: 11.6-19.4) and PFS 9.4 months (95 % CI: 8-10.8) (log-rank, P = 0.000) and MGMT(unmethylated)/IDH1(-ve) OS 11.1 months (95 % CI: 8.5-13.7) and PFS 6.3 months (95 % CI: 4.4-8.3) (log-rank, p = 0.000).
  
  
  
  While the importance of MGMT methylation is well established, we demonstrate that the combination of MGMT(methylated)/IDH1(+ve) is associated with considerably longer OS and PFS in this series of chemoradiotherapy-treated glioblastoma tumours. The long-term cognitive function and quality of life in these long-term survivors warrant investigation.
authors.affiliation: Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK. christopherpaulmillward@gmail.com.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Millward
authors.affiliation: Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Brodbelt
authors.affiliation: Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Haylock
authors.affiliation: Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK.
authors.forename: Rasheed
authors.initials: R
authors.lastname: Zakaria
authors.affiliation: Department of Neuropathology, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK.
authors.forename: Atik
authors.initials: A
authors.lastname: Baborie
authors.affiliation: Department of Neuropathology, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Crooks
authors.affiliation: Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK.
authors.forename: David
authors.initials: D
authors.lastname: Husband
authors.affiliation: Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK.
authors.forename: Aditya
authors.initials: A
authors.lastname: Shenoy
authors.affiliation: Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Wong
authors.affiliation: Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK.|Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jenkinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Glioblastoma; IDH1; MGMT; Methylation; Survival