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

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

Clin Cancer Res. 2018 Dec 04;:

Authors: Hegi ME, Genbrugge E, Gorlia T, Stupp R, Gilbert MR, Chinot OL, Nabors LB, Jones G, van Criekinge W, Straub J, Weller M

Abstract
PURPOSE: The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is predictive for benefit from temozolomide in glioblastoma. 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 glioblastoma patients 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. Receiver operating characteristics (ROC) analysis identified an optimal cutoff supervised by overall survival (OS).
RESULTS: For 4041 patients valid MGMT results were obtained, whereof 1725 were randomized. The unsupervised cutoff in the training dataset was 1.27 (log2[1000x(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 "grey zone" patients (>-0.28, ≤1.27), the latter comprising ~10% of cases. In contrast, for MGMT methylated patients (>1.27) more methylation was not related to better outcome. Both methylated and grey zone patients performed significantly better for OS than truly unmethylated patients (HR=0.35, 95% 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 (R2=0.94).
CONCLUSIONS: Low MGMT methylation (grey zone) may confer some sensitivity to temozolomide treatment, hence the lower safety margin should be considered for selecting unmethylated glioblastoma patients into trials omitting temozolomide.

PMID: 30514777 [PubMed - as supplied by publisher]

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