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MGMT Promoter Methylation Predicts Survival of Glioma Patients Following Combination Treatment

NEW YORK (GenomeWeb) – MGMT promoter methylation could serve as a prognostic biomarker of survival for patients with high-risk, low-grade gliomas undergoing a combination treatment, according to a new study.

In a previous study, a team from the NRG Oncology/Radiation Therapy Oncology Group found that most patients with high-risk, low-grade gliomas who were treated with temozolomide in combination with radiation therapy had an increased overall survival of three years, as compared to the standard of care. Low-grade gliomas vary clinically, and median survival times can range from a few months to more than a decade. The high-risk patients in this study had multiple risk factors for recurrence.

But that study didn't examine patients' MGMT promoter methylation status. Methylation at that site silences MGMT gene and protein expression and increases temozolomide sensitivity.

In a study appearing in JAMA Oncology today, researchers led by Ohio State University's Arnab Chakravarti went back to the tumor samples collected during that clinical trial to examine MGMT promoter methylation status. Patients with MGMT promoter-methylated tumors were more than twice as likely as those with MGMT promoter-unmethylated tumors to survive after combination treatment, they reported.

"Identifying biomarkers — prognostic and predictive markers — is critical for personalizing care and giving patients the best quality of life and chances of longer survival," Chakravarti said in a statement. "Some patients succumb to the disease within months, others live years beyond their diagnosis. We need better methods of determining which patients are likely to have more aggressive tumors."

The initial study included 129 patients, for 75 of whom the researchers could determine MGMT promoter methylation status using Illumina HumanMethylation 450 BeadChip data. The patients whose methylation status could be determined had similar pre-treatment characteristics as those whose status could not be ascertained.

Of those 75 patients, 57 had methylated MGMT promoters and 18 did not. As the researchers expected, most patients with unmethylated MGMT promoters had astrocytoma.

Unmethylated MGMT promoter status significantly associated with both worse overall survival and progression-free survival after combination therapy. The researchers reported hazard ratios of 3.52 and 3.06, respectively.

They also took patients' IDH1/2 mutation status into account, as IDH1/2 mutations are associated with the hypermutation phenotype in gliomas and with MGMT promoter methylation. However, even with folding IDH1/2 mutation status into a multivariable analysis, MGMT promoter status was still significantly associated with overall and progression-free survival.

The authors noted, however, that their study has a number of limitations, including its small sample size and lack of molecular data from historical controls.

Still, they said their findings show that MGMT methylation could be a prognostic biomarker. "The results are critical, demonstrating that MGMT methylation may be a prognostic biomarker and may represent a class of patients who have better prognoses," Chakravarti and his colleagues wrote.