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 language | English (US) |
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Pages (from-to) | 1809-1816 |
Number of pages | 8 |
Journal | Clinical Cancer Research |
Volume | 25 |
Issue number | 6 |
DOIs | |
State | Published - 2019 |
Funding
O.L. Chinot reports receiving commercial research grants from Roche and speakers bureau honoraria from Celdex and Immatics, and is a consultant/ advisory board member for Abbvie. L.B. Nabors is a consultant/advisory board member for Abbvie. W. van Criekinge is an employee of MDxHealth. No potential conflicts of interest were disclosed by the other authors. Written on behalf of the European Organisation for Treatment and Research of Cancer (EORTC) Brain Tumor Group and the AVAGlio, CENTRIC, CORE, and RTOG 0825 Clinical Trial Groups. E. Genbrugge's fellowship at EORTC (Brussels, Belgium) was supported by a grant from the EORTC Brain Tumor Group.
ASJC Scopus subject areas
- General Medicine