P11.60.A Quantitative analysis of the MGMT methylation status of glioblastomas in the light of the 2021 WHO classification

Abstract

Abstract Background Glioblastomas with methylation of the promotor region of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene exhibit increased sensitivity to alkylating chemotherapy. Quantitative assessment of the MGMT promotor methylation status might provide additional prognostic information. The aim of our study was to determine a quantitative threshold of MGMT methylation for better survival among patients with isocitrate dehydrogenase (IDH) wildtype glioblastomas. Material and Methods We included consecutive patients treated at our department between 11/2010 and 08/2018. Inclusion criteria were i) diagnosis of glioblastoma, IDH wildtype according to the 2021 WHO classification of tumors of the central nervous system, ii) availability of a quantitative MGMT promotor methylation analysis, iii) absence of an IDH mutation as determined by immunohistochemistry and/or sequencing, and iii) age ≥ 18 years. The primary endpoint was overall survival. To evaluate a threshold for a benefit from temozolomide (TMZ), a secondary analysis included only tumors exposed to TMZ, which were compared to a historical cohort treated by radiotherapy only with a median survival of 13.0 months. Results Between 11/2010 and 08/2018, 321 patients diagnosed with a glioblastoma, IDH wildtype meeting our inclusion criteria were included. Mean age at diagnosis was 64.1 years (± 11.4). Median overall survival was 12.6 months. Kaplan-Meier analysis showed better survival for all groups with ≥ 16% methylation. Similarly, Cox regression analysis confirmed significantly better survival in the groups with 16-30%, 31-60%, and 61-100% methylation. In contrast, survival in the group with 1-15% methylation was similar to that with unmethylated promotor regions. When the percentage of methylation of each patient treated with TMZ was plotted on an ROC curve using survival > 13.0 months as outcome parameter, the Youden index was maximal at ≥ 16% methylation. Conclusion Better survival is seen in patients with glioblastomas with ≥ 16% methylation of the MGMT promotor region than with < 16% methylation. Survival with tumors with 1-15% methylation is similar to with unmethylated tumors. Above 16% methylation, we found no additional benefit with increasing methylation.