TY - JOUR
T1 - MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide
T2 - A pooled analysis of four clinical trials
AU - Hegi, Monika E.
AU - Genbrugge, Els
AU - Gorlia, Thierry
AU - Stupp, Roger
AU - Gilbert, Mark R.
AU - Chinot, Olivier L.
AU - Burt Nabors, L.
AU - Jones, Greg
AU - Van Criekinge, Wim
AU - Straub, Josef
AU - Weller, Michael
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-3181
DO - 10.1158/1078-0432.CCR-18-3181
M3 - Article
C2 - 30514777
AN - SCOPUS:85063011133
SN - 1078-0432
VL - 25
SP - 1809
EP - 1816
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -
