Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation: A Portuguese multicentre study

Abstract

Abstract. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology. The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker, but some controversial data have precluded its clinical use. We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals, uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide (Stupp protocol). The Kaplan-Meier method was used to construct survival curves, and the log-rank test and a Coxregression model were used to analyze patient survival. The methylation status of MGMT was successfully determined in 89% (80/90) of the tumors. The frequency of tumoral MGMT promoter methylation was 47.5%. The median overall survivals (OSs) were 16 months (95% CI 12.2-19.8) and 13 months (95% CI 13.3-18.7) for patients whose tumors had a methylated or unmethylated MGMT, respectively. Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS (P=0.583 by the log-rank test; P=0.617 by the Cox-regression test) or progression-free survival (P=0.775 by the log-rank test; P=0.691 by the Cox-regression test). None of the patient clinical features were significantly correlated with survival. This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients. Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide. Additional robust prospective studies are warranted to clarify whether the MGMT status should be used in clinical decisions.

Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis

“…Twenty studies met the inclusion criteria for this metaanalysis, including a total of 2,018 patients (Table 1) [7,17,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Two of these studies also reported subgroup analyses.…”

“…If the 95% CI interval was not reported, it was calculated from the HR and associated P value [16]. For one study the authors sent us their raw data, and granted us permission to generate the HR and 95% CI [17].…”

The Impact of IDH1 Mutation and MGMT Promoter Methylation on Recurrence-Free Interval in Glioblastoma Patients Treated With Radiotherapy and Chemotherapeutic Agents

“…In contrast, other studies revealed that MGMT promoter methylation was not associated with better OS and progression-free survival; both endpoints were comparable in patients with expressed MGMT and those with MGMT silencing. The studies by Costa et al and Park et al on glioblastoma patients treated with TMZ-based chemoradiation revealed that MGMT promoter methylation was not associated with improved outcome [ 12 , 13 ]. Our study found that MGMT promoter methylation was not associated with a significant change in patient outcome.…”

“…The relationship of MGMT promoter methylation with IDH1 mutation, treatment modalities and survival rates showed controversial results. Some studies revealed that glioblastomas with methylated MGMT promoter were more sensitive to chemotherapeutic agent (TMZ) resulting in a better survival rate [9][10][11], while other studies revealed that MGMT promoter methylation was not associated with better overall survival (OS) [12,13]. Combs et al also found a none-favourable OS in a group of 160 patients with glioblastoma treated with radiotherapy and TMZ.…”

Prognostic and Predictive Biomarkers in Gliomas

“…Not only MGMT is a positive predictive factor for TMZ therapy (see Table 1 ), but also MGMT is a positive prognostic marker. Many studies have reported that MGMT methylation predicts longer OS [ 33 , 81 , 151 , 152 , 153 ]. Zhang et al conducted a meta-analysis of 15 studies reporting the effect of MGMT promoter methylation on OS by univariate analysis and 14 studies by multivariate analysis.…”