MGMT Promoter Methylation Predicts Survival in 1p19q-Codeleted Gliomas after Chemotherapy

Abstract

MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy in glioblastomas and used to guide treatment decisions. However, the role of MGMT promoter status in low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large datasets. We recently found that MGMT promoter methylation predicts progression-free survival in 1p19q-codeleted gliomas after alkylating chemotherapy in a meta-analysis of three prospective cohorts. There were not enough deaths to determine the effect on overall survival. Here, we query a large national database to determine the association between MGMT promoter methylation and overall survival in patients with 1p19q-codeleted gliomas. We identified all patients with newly diagnosed gliomas in the National Cancer Database (NCDB) from 2010-2016 with 1p19q-codeletion and information on MGMT promoter methylation status. The cohort was stratified based on receipt of chemotherapy. Multivariable Cox proportional hazards regression modeling was used to assess the effect of MGMT promoter methylation status on overall survival after adjusting for age, sex, race, co-morbidity, grade, extent of resection, chemotherapy, and radiotherapy. We identified 530 eligible patients, 373 (70.4%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 400 (75.5%) patients. For all patients, unmethylated MGMT (uMGMT) was associated with poorer survival compared to mMGMT (75% survival time [75%ST] 45 months vs. not reached, P = .003, adjusted hazard ratio [aHR] 2.36 [95% confidence interval (95% CI) 1.53-3.62]). uMGMT was associated with poorer survival in patients who received chemotherapy (75%ST 22 vs. 66 months, P<.001, aHR 2.55 [95% CI 1.60-4.06]) but not in patients who did not receive chemotherapy (75%ST 110 months vs. not reached, P = 0.7, HR 1.24 [95% CI 0.40-3.81]). To our knowledge, this is the first study to demonstrate an association between overall survival and MGMT promoter status in 1p19q-codeleted gliomas. MGMT promoter status should be used as a stratification factor in future clinical trials of 1p19q-codeleted gliomas that use overall survival as an endpoint.