MGMT Methylation a Survival Biomarker in High-Risk Low-Grade Gliomas?

A DNA-level biomarker may be helpful in predicting survival outcomes in patients with high-risk, low-grade gliomas, a new study suggests. The NRG Oncology/ Radiation Therapy Oncology Group (RTOG) collaborative clinical trials group reports that MGMT promoter methylation has the potential to be used as an independent prognostic biomarker in World Health Organization–designated grade II gliomas. The findings suggest that it could be beneficial to incorporate this biomarker into future clinical trial designs.

The study, by Arnab Chakravarti, MD, and colleagues, was published in JAMA Oncology. It showed patients with MGMT methylated tumors were more than twice as likely to survive after combination treatment with temozolomide and radiotherapy (RT) than patients with unmethylated tumors. Previously reported findings from the NRG Oncology/RTOG 0424 clinical trial report a 3-year overall survival (OS) benefit for certain brain tumor patients who receive the drug temozolomide in addition to RT, compared with the standard of care. Data regarding the significance of MGMT promoter methylation status, however, were not examined.

Chakravarti, chair of radiation oncology at The Ohio State University Comprehensive Cancer Center (OSUCCC), Columbus, said there is a wide range of outcomes for patients with these tumor types. He noted that some patients succumb to their glioma within months, while others live years beyond their diagnosis. It is critical to identify biomarkers that are prognostic in this patient population, he emphasized.

The researchers conducted a retrospective analysis of 129 glioma patients (median age, 48 years) who participated in the NRG Oncology/RTOG 0424 clinical trial. In this group, 75 patients had tissue samples available that could be analyzed for MGMT promoter methylation status. They found 57 of 75 patients (76%) had MGMT promoter methylation and the remainder had unmethylated status. Univariate analyses showed that an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52) and progression-free survival (PFS; HR, 3.06).

First study author Erica Bell, PHS, who is also with the OSUCCC, said these are the first data to highlight the test’s potential prognostic value beyond a standard molecular test (IDH1/2 mutation status) that is currently used to help predict glioma patient survival outcomes. The study showed that MGMT promoter methylation was significantly correlated with PFS and OS on univariate and multivariate analyses, both with and without adjusting for IDH1/2 status (wild-type vs mutant).

These new data represent the first clinical trial–based evidence of the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide, according to the authors. Previously published data support the use of MGMT promoter methylation as a biomarker of survival in patients with glioblastoma.