MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide. A Pooled Analysis of Four Clinical Trials
| Autor: | L. Burt Nabors, Thierry Gorlia, J. Straub, Olivier Chinot, Els Genbrugge, Monika E. Hegi, Mark R. Gilbert, Greg Jones, Wim Van Criekinge, Roger Stupp, Michael Weller |
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| Přispěvatelé: | University of Zurich, Hegi, Monika E |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Bevacizumab 610 Medicine & health Article law.invention 03 medical and health sciences 0302 clinical medicine Randomized controlled trial law Internal medicine medicine Cutoff 1306 Cancer Research Temozolomide Receiver operating characteristic business.industry Standard treatment 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 10040 Clinic for Neurology Clinical trial 030220 oncology & carcinogenesis DNA methylation 2730 Oncology business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Clin Cancer Res Clinical cancer research, vol. 25, no. 6, pp. 1809-1816 |
| Popis: | Purpose: The methylation status of the O6-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 (log2[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 (R2 = 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. |
| Databáze: | OpenAIRE |
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