Abstract
Abstract PURPOSE To study disease characteristics, prognostic markers and outcome in patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma by CNS WHO grade. EXPERIMENTAL DESIGN We determined molecular biomarkers and assembled clinical and outcome data in a cohort of 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) confirmed by central pathology review. RESULTS The median age for astrocytoma, IDH mutant, CNS WHO grade 4, was 37 (range: 23-79 years) and similar to patients with CNS WHO grade 2 or 3 tumors. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p< 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was 22.2 years (95% n.a.) for grade 2, 8.1 years (95% 5.4-10.8) for grade 3 and 4.7 years (95% 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% 4.3-6.7) without (n=58) versus 1.8 years (95% 0-4.1) with (n=12) homozygous CDKN2A homozygous deletion. Reduced global DNA methylation as indicated by LINE-1 methylation levels was strongly associated with CNS WHO grade 4 (p< 0.001) and poor outcome among IDH-mutant astrocytoma patients. MGMT promoter methylation status was not prognostic for overall survival. CONCLUSIONS The CNS WHO grade is prognostic in patients with IDH-mutant astrocytoma. CDKN2A homozygous deletion and reduced LINE-1 methylation levels are linked to CNS WHO grade 4 and associate with shorter survival. These data serve to inform on clinical trial designs, e.g., using IDH inhibitors, in this patient population.
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