MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide: A Pooled Analysis of Four Clinical Trials.

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Download: Hegi_etal_Suppl_data_CCR_2018.pdf (365.27 [Ko])
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Serval ID
serval:BIB_F20783904E75
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide: A Pooled Analysis of Four Clinical Trials.
Journal
Clinical cancer research
Author(s)
Hegi M.E., Genbrugge E., Gorlia T., Stupp R., Gilbert M.R., Chinot O.L., Nabors L.B., Jones G., Van Criekinge W., Straub J., Weller M.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Publication state
Published
Issued date
15/03/2019
Peer-reviewed
Oui
Volume
25
Number
6
Pages
1809-1816
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The methylation status of the O <sup>6</sup> -methylguanine DNA methyltransferase (MGMT) gene promoter is predictive for benefit from temozolomide in glioblastoma (GBM). A clinically optimized cutoff was sought allowing patient selection for therapy without temozolomide, while avoiding to withhold it from patients who may potentially benefit.Experimental Design: Quantitative MGMT methylation-specific PCR data were obtained for newly diagnosed patients with GBM screened or treated with standard radiotherapy and temozolomide in four randomized trials. The pooled dataset was randomly split into a training and test dataset. The unsupervised cutoff was obtained at a 50% probability to be (un)methylated. ROC analysis identified an optimal cutoff supervised by overall survival (OS).
For 4,041 patients valid MGMT results were obtained, whereof 1,725 were randomized. The unsupervised cutoff in the training dataset was 1.27 (log <sub>2</sub> [1,000 × (MGMT+1)/ACTB]), separating unmethylated and methylated patients. The optimal supervised cutoff for unmethylated patients was -0.28 (AUC = 0.61), classifying "truly unmethylated" (≤-0.28) and "gray zone" patients (>-0.28, ≤1.27), the latter comprising approximately 10% of cases. In contrast, for patients with MGMT methylation (>1.27) more methylation was not related to better outcome. Both methylated and gray zone patients performed significantly better for OS than truly unmethylated patients [HR = 0.35, 95% confidence interval (CI), 0.27-0.45, P < 0.0001; HR = 0.58, 95% CI, 0.43-0.78, P < 0.001], validated in the test dataset. The MGMT assay was highly reproducible upon retesting of 218 paired samples (R <sup>2</sup> = 0.94).
Low MGMT methylation (gray zone) may confer some sensitivity to temozolomide treatment, hence the lower safety margin should be considered for selecting patients with unmethylated GBM into trials omitting temozolomide.
Keywords
Antineoplastic Agents, Alkylating/pharmacology, Antineoplastic Agents, Alkylating/therapeutic use, Brain Neoplasms/drug therapy, Brain Neoplasms/genetics, Clinical Trials as Topic, DNA Methylation, DNA Modification Methylases/genetics, DNA Repair Enzymes/genetics, Datasets as Topic, Drug Resistance, Neoplasm/genetics, Female, Glioblastoma/drug therapy, Glioblastoma/genetics, Humans, Male, Middle Aged, Patient Selection, Promoter Regions, Genetic/genetics, Reference Values, Temozolomide/pharmacology, Temozolomide/therapeutic use, Tumor Suppressor Proteins/genetics
Pubmed
Web of science
Open Access
Yes
Create date
10/12/2018 9:36
Last modification date
26/06/2020 6:21
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