MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Mar 11, 2005The New England journal of medicine

How MGMT gene silencing relates to temozolomide benefit in brain cancer

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Abstract

The MGMT promoter was methylated in 45 percent of 206 assessable glioblastoma cases.

MGMT promoter methylation is linked to improved survival in glioblastoma patients receiving treatment.
A significant survival advantage was observed in patients with methylated MGMT promoters treated with temozolomide and radiotherapy, with a median survival of 21.7 months compared to 15.3 months for those receiving only radiotherapy.
In patients without MGMT promoter methylation, there was no significant survival difference between the two treatment groups.
MGMT promoter methylation may serve as an independent favorable prognostic factor for glioblastoma patients (P<0.001).

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BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.

METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis.

RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups.

CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

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MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

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