Elevated MGMT Gene Expression is Independently Associated with Worse Overall Survival in NRG Oncology/RTOG 9813: A Phase III Study of Radiation Therapy (RT) and Temozolomide (TMZ) Versus RT and Nitrosourea (NU) in Anaplastic Grade III Glioma

Abstract

This study sought to determine the prognostic significance of MGMT gene expression in NRG Oncology/RTOG 9813. Gene expression data were generated using a transcriptome array on 76 patients from NRG Oncology/RTOG 9813. The MGMT-STP27 prediction model was used to calculate MGMT promoter methylation status from methylation probe data. Univariate (UVAs) and multivariate analyses (MVAs) were conducted using the Cox proportional hazards model and the log-rank test, to determine the effect of MGMT expression as a continuous variable on progression-free survival (PFS) and overall survival (OS). Patient pre-treatment characteristics and treatment assignment were taken into consideration as covariates for the MVAs. Upon UVAs, elevated MGMT gene expression was significantly associated with worse OS (HR = 1.56; 95% CI (1.17-2.08); p = 0.003) and PFS (HR = 1.39; 95% CI (1.06-1.82); p = 0.019). Models with time-varying effects were used for MVAs due to concerns over the proportional hazards assumption and included the following variables: MGMT gene expression, MGMT promoter methylation, age, IDH mutation, surgery, and KPS. Elevated MGMT gene expression was significantly associated with worse OS (HR = 1.74 95% CI (1.02-2.97); p = 0.043) for its long-term effect. Similarly for PFS, including MGMT promoter methylation, age and IDH mutation, elevated MGMT gene expression was significantly associated with worse PFS (HR = 2.34 for long-term effect; 95% CI (1.22-4.49); p = 0.01). This effect was also similar when MGMT promoter methylation was not included in the MVAs. Elevated MGMT gene expression was found to be an independent prognostic biomarker in anaplastic astrocytomas treated with RT plus TMZ or RT plus NU independent of MGMT methylation status. This is the first study, to our knowledge, to identify the significance of MGMT gene expression on OS, independent of MGMT promoter methylation, in a phase III study of anaplastic glioma patients using rigorous MVAs. Validation of the prognostic significance of MGMT gene expression is ongoing as well as our efforts to increase sample size.