Clinical value of MGMT promoter methylation score in IDHmt low-grade glioma for predicting benefit from TMZ treatment

Background: Diffuse IDH mutant low-grade gliomas (LGG) (WHO grade 2) typically affect young adults. The outcome is variable, ranging from 5 to over 20 years. The timing and choice of initial treatments after surgery remain controversial. In particular, radiotherapy is associated with early and late cognitive toxicity. Over 90% of IDHmt LGG exhibit some degree of promoter methylation of the repair gene O(6)-methylguanine-DNA methytransferase (MGMTp) that when expressed blunts the effect of alkylating agent chemotherapy such as temozolomide (TMZ). However, the clinical value of MGMTp methylation predicting benefit from TMZ in LGG is unclear. Methods: Patients treated in the EORTC-22033 phase III trial comparing TMZ versus radiotherapy served as training set to establish a cutoff based on the MGMT-STP27 methylation score. A validation cohort was established with patients treated in a single center first-line TMZ after surgeri(es). Results: The MGMT-STP27 methylation score was associated with better progression free survival (PFS) in the training cohort treated with TMZ, but not radiotherapy. In the validation cohort an association with PFS after TMZ treatment was observed. A cutoff value was established in the training cohort to guide treatment decisions. Set above the 95% confidence interval of being methylated, it was significantly associated with PFS in the TMZ-treated training cohort, but not in the radiotherapy arm. However, this cutoff could not be confirmed in the test cohort. Conclusions: While the MGMTp methylation score was associated with better outcome in TMZ treated IDHmt LGG, a cutoff could not be established to guide treatment decisions. Bisulphite converted genomic DNA from the 109 Low Grade Glioma samples were hybridised to the Illumina Infinium EPIC Human Methylation Beadchip