Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild-Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study

SIMPLE SUMMARY: O(6)-methylguanine (O(6)-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy and glioblastoma patients, and its prognostic role is still unclear. The quantitative pyrosequencing (PSQ) approach has proven to be feasible for MGMT promoter methylation testing. We report the data of a large study analyzing MGMT promoter methylation status by pyrosequencing and its association with overall survival. We enrolled a large cohort of newly diagnosed Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients, all with rather homogeneous clinical characteristics, from nine neuro-oncology centers. Our data showed better survival when MGMT > 15% but also suggested a more complex (i.e., non-linear) relationship between survival and MGMT, resulting in an increase in the negative prognostic effect of a decrease in methylation of the MGMT promoter. ABSTRACT: Background. O(6)-methylguanine (O(6)-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild-type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤2, and radio-chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time-dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut-off of 15% for MGMT methylation. The 2-year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p < 0.00001). However, we also found a non-linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0–4%, 18.9 months for MGMT in 4–40%, and 29.9 months for MGMT in 40–100%. Conclusions. Our findings suggested a non-linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild-type glioblastoma patients treated with chemoradiotherapy.