P12.41.B MGMT PROMOTER METHYLATION STATUS FOR GLIOBLASTOMA: DETERMINATION OF THE CLINICALLY RELEVANT CUT-OFF VALUE FOR TREATMENT PREDICTION

Abstract

Abstract BACKGROUND Methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is a predictive factor for glioblastoma (GBM) treated with alkylating agents, such as Temozolomide (TMZ). It correlates with increased survival in GBM patients with MGMT promoter methylated tumours. For methylation specific PCR, used in several trials, the clinically relevant cut-off has previously been defined. However, to date there is no consensus regarding the optimal analytical method for the clinic or relevant cut-off value for the chosen method. MATERIAL AND METHODS Glioma patients from five university hospitals in Sweden with MGMT test results using the same pyrosequencing kit analysing four CpGs (Qiagen) were identified. From this cohort patients diagnosed with GBM and reported to have received concomitant chemo-radiotherapy with TMZ (CCRT) were selected from the Swedish quality registry for primary brain tumours (SQR) together with prognostic factors. Quantitative MGMT methylation status in percent was obtained from the departments of pathology, as the mean of the four CpGs clinically used, and the results from each separate CpG will be provided. Both the mean and separate CpGs will be linked to survival and prognostic factors. The clinically relevant cut-off will be calculated at a 50% probability to be unmethylated. ROC analysis will be performed for an optimal cut-off supervised by overall survival (OS). RESULTS MGMT results from 2133 patients were identified. Among these, 510 patients were reported to have received CCRT with TMZ. They had available data regarding obtained treatment including received dose of radiotherapy (RT) and had been diagnosed as GBM, all but 22 molecularly confirmed. Of these, 121 patients had received 40Gy hypofractionated RT, 379 patients ≥50Gy, of which 368 patients had received 60Gy. Ten patients who received <40Gy are excluded from further analysis. Hence, a total of 500 patients are included in the final analysis. An optimal cut-off for unmethylated MGMT using multiple discriminant analysis will be proposed after receiving data regarding prognostic factors: age, performance status, type of surgery and MGMT promoter methylation status of the individual CpGs. A grey zone will also be defined. An updated analysis will be presented. CONCLUSION In this study we will define the clinically relevant cut-off, and grey zone, when using the pyrosequencing kit analysing four CpGs to determine the MGMT methylation status. Hence, enabling a better treatment prediction for alkylating agents, mainly TMZ, in GBM patients, enhancing individualized treatment. It also enables inclusion of patients in future first line clinical trials omitting TMZ for patients with truly unmethylated MGMT. Support: The Medical Research Council of Southeast Sweden (FORSS) and a grant from Region Kalmar Län

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