Introduction: 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.
Conclusions: 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.
Patient Care: Understanding the need to personalize temozolomide use based on the molecular profile of glioblastomas
Learning Objectives: 1) Understanding the prognostic value of isocitrate dehydrogenase (IDH1) mutations and Methyl-Guanine Methyl Transferase (MGMT) promoter methylation
2) Understanding the influence of IDH1 mutation and MGMT promoter methylation on temozolomide response
3) Understanding the therapeutic strategies against IDH1 mutated glioblastomas
References: 1. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10): 997-1003.
2. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360(8): 765-73.
3. Li J, Taich ZJ, Goyal A, et al. Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas. Oncotarget 2014; 5(17): 7342-56.