EPID-08ISOCITRATE DEHYDROGENASE (IDH) MUTATION AND METHYL-GUANINE METHYL TRANSFERASE (MGMT) PROMOTER METHYLATION STATUS IN GLIOBLASTOMA: RESULTS OF A PROSPECTIVE MOLECULAR GLIOBLASTOMA REGISTRY

Abstract

BACKGROUND: The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood. METHODS: We investigated the association between methMGMT and mIDH with progression free survival (PFS) and overall survival (OS) in a prospectively collected molecular registry of 274 glioblastoma patients. RESULTS: For glioblastoma patients who underwent concurrent Temozolomide and Radiation Therapy (TMZ + RT), OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS (mOS): 35.8 mo, median PFS (mPFS):27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo,mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ + RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo; PFS: 9.9 mo v 6.5 mo). While TMZ + RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ + RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3-10 fold increase in TMZ resistance after long-term passage. CONCLUSION: Our study demonstrates that IDH and MGMT promoter methylation status independently associate with favorable outcome in TMZ + RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.