title: Molecular-Based Recursive Partitioning Analysis Model for Glioblastoma in the Temozolomide Era: A Correlative Analysis Based on NRG Oncology RTOG 0525.
abstract: OBJECTIVE
  There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era.
  
  
  OBJECTIVE
  To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables.
  
  
  METHODS
  NRG Oncology RTOG 0525 specimens (n = 452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model consisting of the same clinical variables (age, Karnofsky Performance Status, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent data set (n = 176).
  
  
  METHODS
  Overall survival (OS).
  
  
  RESULTS
  In 452 specimens, MGMT (hazard ratio [HR], 1.81; 95% CI, 1.37-2.39; P < .001), survivin (HR, 1.36; 95% CI, 1.04-1.76; P = .02), c-Met (HR, 1.53; 95% CI, 1.06-2.23; P = .02), pmTOR (HR, 0.76; 95% CI, 0.60-0.97; P = .03), and Ki-67 (HR, 1.40; 95% CI, 1.10-1.78; P = .007) protein levels were found to be significant on single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, Karnofsky Performance Status, extent of resection, and neurological function) were incorporated into a new model. Of 166 patients used for the new NRG-GBM-RPA model, 97 (58.4%) were male (mean [SD] age, 55.7 [12.0] years). Higher MGMT protein level was significantly associated with decreased MGMT promoter methylation and vice versa (1425.1 for methylated vs 1828.0 for unmethylated; P < .001). Furthermore, MGMT protein expression (HR, 1.84; 95% CI, 1.38-2.43; P < .001) had greater prognostic value for OS compared with MGMT promoter methylation (HR, 1.77; 95% CI, 1.28-2.44; P < .001). The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared with the existing clinically based RPA model and MGMT promoter methylation in NRG Oncology RTOG 0525. The prognostic significance of the NRG-GBM-RPA was subsequently confirmed in an independent data set (n = 176).
  
  
  CONCLUSIONS
  This new NRG-GBM-RPA model improves outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for patients with GBM treated with radiation and temozolomide and was biologically validated in an independent data set. The revised RPA has the potential to contribute to improving the accurate assessment of prognostic groups in patients with GBM treated with radiation and temozolomide and to influence clinical decision making.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00304031.
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, Ohio.
authors.forename: Erica Hlavin
authors.initials: EH
authors.lastname: Bell
authors.affiliation: NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Pugh
authors.affiliation: The Ohio State University Center for Biostatistics, Columbus, Ohio.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McElroy
authors.affiliation: National Institutes of Health, Bethesda, Maryland.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: University of Maryland Medical Systems, Baltimore, Maryland (during trial)6now with Miami Cancer Institute, Coral Gables, Florida.
authors.forename: Minesh
authors.initials: M
authors.lastname: Mehta
authors.affiliation: University of Calgary, Calgary, Alberta, Canada.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Klimowicz
authors.affiliation: Moffitt Cancer Center, Tampa, Florida.
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
authors.affiliation: University of Alabama, Birmingham, Alabama.
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.affiliation: Utrecht Cancer Center, Utrecht, Netherlands.
authors.forename: Pierre
authors.initials: P
authors.lastname: Robe
authors.affiliation: University of Freiburg, Freiburg, Germany.
authors.forename: Anca-L
authors.initials: AL
authors.lastname: Grosu
authors.affiliation: University Hospital Zurich, Zürich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Emory University, Atlanta, Georgia.
authors.forename: Walter
authors.initials: W
authors.lastname: Curran
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, Ohio.
authors.forename: Aline P
authors.initials: AP
authors.lastname: Becker
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, Ohio.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Salavaggione
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Blumenthal
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brown
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
authors.forename: Jon
authors.initials: J
authors.lastname: Glass
authors.affiliation: McGill University Health Centre, Montreal, Québec, Canada.
authors.forename: Luis
authors.initials: L
authors.lastname: Souhami
authors.affiliation: Intermountain Medical Center, Murray, Utah.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Arizona Oncology Services Foundation, Tucson, Arizona.
authors.forename: David
authors.initials: D
authors.lastname: Brachman
authors.affiliation: UPMC-Shadyside Hospital, Pittsburgh, Pennsylvania.
authors.forename: John
authors.initials: J
authors.lastname: Flickinger
authors.affiliation: NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: Minhee
authors.initials: M
authors.lastname: Won
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, Ohio.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D003131:Combined Modality Therapy / Q000379:methods / Q000401:mortality; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004812:Epidemiologic Methods; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D045643:DNA Repair Enzymes; D000077204:Temozolomide