• Erica H Bell, Peixin Zhang, Barbara J Fisher, David R Macdonald, Joseph P McElroy, Glenn J Lesser, Jessica Fleming, Arup R Chakraborty, Ziyan Liu, Aline P Becker, Denise Fabian, Kenneth D Aldape, Lynn S Ashby, Maria Werner-Wasik, Eleanor M Walker, Jean-Paul Bahary, Young Kwok, H Michael Yu, Nadia N Laack, Christopher J Schultz, Heidi J Gray, H Ian Robins, Minesh P Mehta, and Arnab Chakravarti.
• Department of Radiation Oncology, The Ohio State University, Columbus.
• JAMA Oncol. 2018 Oct 1; 4 (10): 1405-1409.

ImportanceThe initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported.ObjectiveTo examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes.Design, Setting, And ParticipantsSpecimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses.Main Outcomes And MeasuresProgression-free survival (PFS) and overall survival (OS).ResultsOf all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02).Conclusions And RelevanceIn this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status.Trial RegistrationClinicalTrials.gov Identifier: NCT00114140.

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