MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide: A pooled analysis of four clinical trials

Monika E. Hegi*, Els Genbrugge, Thierry Gorlia, Roger Stupp, Mark R. Gilbert, Olivier L. Chinot, L. Burt Nabors, Greg Jones, Wim Van Criekinge, Josef Straub, Michael Weller

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Purpose: The methylation status of the O 6 -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). Results: 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 2 [1,000 (MGMTþ1)/ACTB]), separating unmethylated and methylated patients. The optimal supervised cutoff for unmethylated patients was 0.28 (AUC ¼ 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 ¼ 0.35, 95% confidence interval (CI), 0.27–0.45, P < 0.0001; HR ¼ 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 2 ¼ 0.94). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1809-1816
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number6
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hegi, M. E., Genbrugge, E., Gorlia, T., Stupp, R., Gilbert, M. R., Chinot, O. L., Burt Nabors, L., Jones, G., Van Criekinge, W., Straub, J., & Weller, M. (2019). MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide: A pooled analysis of four clinical trials. Clinical Cancer Research, 25(6), 1809-1816. https://doi.org/10.1158/1078-0432.CCR-18-3181