P05.06.B CLINICAL USEFULNESS OF MGMT PROMOTER METHYLATION QUANTIFICATION IN GBM PATIENTS TREATED WITH CHEMO-RADIATION THERAPY

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Abstract BACKGROUND In glioblastoma (GBM) patients two factors are relevant for prediction of survival: MGMT promoter hypermethylation, which improves the patient’s response to temozolomide (TMZ), and the extent of resection (EOR), with a better overall survival (OS) described in patients subjected to gross total resection (GTR). The aim of our study is to analyze the level of concordance between the results obtained with the standard non-quantitative MGMT analysis methods compared to the quantitative real-time method EpiDirect® and to verify whether the different levels (frequencies) of MGMT promoter hypermethylation, assessed by EpiDirect®, can better predict the response to GBM treatment. MATERIAL AND METHODS MGMT promoter methylation in GBM IDH1 wt cases diagnosed from 2004 to 2022 in two neurosurgical centers (EOC and Insubria University Hospital, Italy) and treated by temozolomide (TMZ) was evaluated for diagnosis by sodium bisulfite pretreatment and methylation-specific PCR (MSP) and then we tested the samples by the new real-time EpiDirect® (Pentabase ApS, Denmark). Cohen index and Kaplan-Meier curves were evaluated for statistics. RESULTS We enrolled 119 GBM cases treated by standard adjuvant partial brain radiation and TMZ based chemotherapy for which MGMT promoter methylation data by MSP or by PCR-pyrosequencing were available for diagnostic purposes. With the common standard methods 41/119 (34.5%) cases were methylated in the MGMT promoter (M) and 72/119 (60.5%) were unmethylated (UM). In addition, 6/119 cases (5.05%) were not evaluable. By EpiDirect® all the cases provided reproducible results, MGMT M was detected in 45/119 cases (37.8%) and UM in 74/119 (62.2%). Comparing Epidirect® to the commonly used methodologies, nine evaluable cases (5 M and 4 UM cases), corresponding to 8% of the entire cohort, showed discrepant methylation results. Despite this, the level of concordance between methodologies was high (K Cohen index corresponding to 0.829). The comparisons of OS, progression-free survival and time-to-progression in the five categories corresponding to different MGMT promoter methylation levels identified by Epidirect® resulted in not statistical significant results considering the whole cohort and then the different kind of surgery (biopsy, partial resection or GTR) (p›0.05). CONCLUSION EpiDirect® is a robust methodology enabling a faster, more sensible and easier evaluation of cases even in presence of a highly damaged DNA. In addition, it shares a high level of superimposition with the most diffused technologies currently used for assessing the MGMT promoter methylation for diagnostic purposes. The EpiDirect® ability to quantify the percentage of MGMT promoter methylation is another advantage of this methodology however we found that it has not clinical relevance on survival.

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