Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy.Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR.Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P ؍ 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P ؍ 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P ؍ 0.017; Cox regression).Conclusions: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.
The methylation status of the O
6
-methylguanine-DNA methyltransferase (
MGMT
) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for
MGMT
methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate
MGMT
classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM
-
450K) BeadChip interrogating 176 CpGs annotated for the
MGMT
gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank
p
< 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom
MGMT
methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (
n
= 50; kappa = 0.88; outcome, log-rank
p
< 0.001). Lower prevalence of
MGMT
methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas
MGMT
was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM
-
450K or HM-27K BeadChip to explore effects of distinct epigenetic context of
MGMT
methylation suspected to modulate treatment resistance in different tumor types.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-012-1016-2) contains supplementary material, which is available to authorized users.
Picard, M; Weller, M (2010). Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.
Patients and MethodsPatients (≥18 to ≤70 years) were treated with cilengitide (500 mg) administered twice weekly i.v. in addition to standard radiotherapy with comcomitant and adjuvant temozolomide. Treatment was continued until disease progression or for a maximum of 35 weeks. The primary endpoint was progression-free survival (PFS) at 6 months.
ResultsFifty-two patients (median age 57 years; 62% male) were included. Six-and 12-month PFS rates were 69% (95% confidence interval [CI], 54-80%) and 33% (95% CI, 21-46%). Median PFS was 8 months (95% CI, 6.0-10.7). Twelve-and 24-month overall survival (OS) rates were 68% (95% CI, 53-79%) and 35% (95% CI, 22-48%). Median
ConclusionCompared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiation demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.5
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