Abstract
BACKGROUND
Glioblastoma patients showing hypermethylation of the promoter of the O6-methylguanine-methyltransferase (MGMT) gene have significantly improved survival when treated with temozolomide compared to patients with hypomethylated MGMT promoters. However, the prognostic and predictive significance of partial MGMT promoter methylation is unclear.
METHODS
The National Cancer Database was queried for patients newly diagnosed in 2018 with histopathologically-confirmed IDH-wildtype glioblastoma. MGMT promoter methylation status was correlated with overall survival (OS) using multivariable Cox regression with Bonferroni correction for multiple testing (p< 0.008 was significant).
RESULTS
3,663 patients were identified with newly diagnosed, histopathologically-confirmed IDH-wildtype glioblastoma and known MGMT promoter methylation. Of the 2,807 patients who received single agent chemotherapy (i.e. likely temozolomide), the MGMT promoter was unmethylated, partially methylated, hypermethylated, and methylated not otherwise specified (NOS) in 57.9%, 5.0%, 3.1%, and 34.0% of cases, respectively, with the later group likely consisting predominantly of hypermethylated cases. Multivariable analysis demonstrated that among patients receiving temozolomide, those with unmethylated MGMT promoters had significantly worse OS than patients with partially methylated MGMT promoters (hazard ratio (HR) 1.94; 95% confidence interval (CI), 1.54-2.44; p< 0.001). However, the OS of hypermethylated patients (HR 1.02; 95% CI, 0.72-1.46; p=0.9) and methylated NOS patients (HR 0.99; 95% CI, 0.78-1.26; p=0.928) were not statistically different from the OS of partially methylated patients.
CONCLUSIONS
IDH-wildtype glioblastoma patients with partial methylation of the MGMT promoter treated with temozolomide have improved OS compared to their unmethylated counterparts, supporting the use of temozolomide therapy in these patients.