Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide.
OBJECTIVE
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.


METHODS
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.
Hegi
Monika E
ME
Laboratory of Tumor Biology and Genetics of the Neurosurgery Departments of the University Hospitals, Lausanne, Switzerland. monika.hegi@hospvd.ch
Diserens
Annie-Claire
AC
Godard
Sophie
S
Dietrich
Pierre-Yves
PY
Regli
Luca
L
Ostermann
Sandrine
S
Otten
Philippe
P
Van Melle
Guy
G
de Tribolet
Nicolas
N
Stupp
Roger
R
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use* / Q000633:toxicity; D001706:Biopsy; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D003131:Combined Modality Therapy; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D016019:Survival Analysis; D000077204:Temozolomide; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide