MGMT methylation in newly-diagnosed glioblastoma multiforme (GBM): From the S0001 phase III study of radiation therapy (RT) and O6-benzylguanine, (O6BG) plus BCNU versus RT and BCNU alone for newly diagnosed GBM

Abstract

1512 Background: Glioblastoma multiforme (GBM) is a high grade primary brain neoplasm associated with a median survival of less than a year. Historically, one-third of patients seem to benefit from treatment with alkylating chemotherapy. This minority may correspond to a population with decreased levels of active O6-methylguanine- methyltransferase enzyme (MGMT). MGMT repairs tumor DNA damaged by chemotherapy, allowing continued replication after exposure to treatment. Patients with low tumor MGMT activity may be more likely to respond to alkylating treatment. Hypermethylation of the MGMT promoter region leads to decreased transcription of the enzyme and is associated with improved outcome in GBM patients treated with radiation and alkylating chemotherapy. Methods: We studied a patient cohort with newly diagnosed GBM registered on Southwest Oncology Group protocol S0001, a phase III randomized, two arm clinical trial investigating an inhibitor of MGMT (O6-benzylguanine, O6BG). Both groups received standard radiation and BCNU (carmustine). The experimental group additionally received O6BG. We determined polymerase chain reaction (PCR) methylation status of the promoter region of MGMT in 88 patients with adequate tissue samples. In 41 cases, we were able to obtain successful PCR results. Results: 28 of 41 samples (68%) were found to be unmethylated and 13 of 41 (32%, 95% c. i. 18% to 50%) were methylated. Patients with methylated MGMT had a median survival of 12.6 months (95% c.i. of 7.8–15.8 months). Patients with unmethylated MGMT had a median survival of 10.6 months (95% c.i. of 8.7–12.0 months). Median progression-free survivals were 4.5 and 3.1 months respectively, for the methylated and unmethylated groups. Conclusions: This result is consistent with prior studies which showed that approximately two-thirds of patients express MGMT, and accordingly, are resistant to alkylating agents. The subgroup of patients without promoter methylation may be more likely to benefit from treatment with O6BG. Analysis of MGMT promoter methylation status per study treatment group, and correlation with median survival and progression-free survival will be presented. No significant financial relationships to disclose.