O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide

Abstract

Background: O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation status was proposed as a prognostic biomarker for patients with glioblastoma. However, the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine-releasing wafers (Gliadel) along with temozolomide (TMZ) is still unknown.

Methods: MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received the Gliadel wafers followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy while they were enrolled in a French multicenter prospective study.

Results: For the whole cohort, the median overall survival (OS) was 17.5 months, and the progression-free survival was 10.3 months. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild-type MGMT (21.7 months vs 15.1 months; P = .025). Similarly, patients who had low MGMT protein expression (≤15%) had a significantly improved OS compared with patients who had high MGMT expression (27.0 months vs 15.1 months; P = .021). The extent of resection was the strongest clinical predictor of outcome. In multivariate Cox models that were adjusted for sex, performance status, and extent of surgery, both MGMT methylation and protein expression were identified as independent prognosticators, and the finding was validated internally using a bootstrap resampling technique. Discrepancies were identified between protein expression and MGMT methylation status, thus suggesting that the 2 assays probably assess different biologic features.

Conclusions: MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol).