Abstract
Background MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival.MethodsWe included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy.ResultsThere were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46–0.79, P = 0.005) and low (HR 0.67, 95% CI 0.50–0.89, P < 0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P = 0.097; high methylation P = 0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P < 0.001).ConclusionsQuantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.
Highlights
O-6 methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is an important biomarker in glioblastoma management
Key points Quantitative MGMT promoter methylation may provide additional prognostic value The extent of MGMT promoter methylation modified the effect of temozolomide on survival in those receiving not completing the temozolomide regimen Patients completing the temozolomide regimen had more favorable outcome regardless of MGMT promoter methylation ipt Importance of study r O-6 methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is associated with better survival in patients with glioblastoma
This dichotomy may mask additional prognostic values associated with extent of r MGMT methylation. sc Some studies have reported a positive association between extent of MGMT methylation and u survival,6–9 but their smaller cohorts precluded analyses adjusting for confounders
Summary
Quantitative MGMT methylation may provide additional prognostic value. This d is important when assessing clinical and research therapies. Key points Quantitative MGMT promoter methylation may provide additional prognostic value The extent of MGMT promoter methylation modified the effect of temozolomide on survival in those receiving not completing the temozolomide regimen Patients completing the temozolomide regimen had more favorable outcome regardless of MGMT promoter methylation ipt Importance of study r O-6 methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is associated with better survival in patients with glioblastoma. Our findings did not a demonstrate an interaction between MGMT methylation and completed temozolomide regimen, which suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. Quantitative MGMT methylation may provide Accepted additional prognostic information in clinical and therapeutic studies
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