The mutational landscape of older patients with IDH wild-type glioblastoma (GBM).

Abstract

e14033 Background: Advanced age is associated with poorer outcomes in GBM and current NCCN guidelines distinguish older GBM patients (≥70 years, oGBM) from their younger counterparts ( < 70 years, yGBM). We aim to characterize age-related comprehensive mutational profiles with the long-term goal of improving treatment strategies, outcomes, and rational clinical trial design. Specifically, we focused on IDH-wildtype (WT) oGBM, investigated if oGBM are more likely to acquire temozolomide-induced hypermutations, and finally, compared the frequency of high-tumor mutational burden (TMB) between oGBM vs. yGBM. Methods: Comprehensive molecular profiles of 1,657 adult IDH-WT GBM tumors tested at Caris Life Sciences (Phoenix, AZ) were queried. Tests included NGS of DNA (NextSeq, 592 Genes and NovaSEQ, WES) and RNA (NovaSeq) sequencing. SBS11 gene signature (i.e temozolomide-induced hypermutational profile) was queried using SigProfiler (Alexandrov 2020, Nature). Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons ( q) was < 0.05. Results: We identified 1,657 patients (range 21-89 years old, median 61 years) with IDH-wildtype GBM, 22% (360) of whom were ≥ 70 years. There was a slight male predominance (60%) for all ages. The most prevalent alterations in oGBM were TERT promoter mutation (105/131,80%), MGMT promoter methylation (pMe) (175/346, 51%), and PTEN mutation (129/349, 37%). EGFR amplification was seen in 35% (125/356) and EGFRvIII in 23% (81/360); Overall, fusions were seen in 12% (44 of 360) oGBM; events > 1% included MET (3.6%), FGFR3 (3.1%), EGFR (2.6%) and ROS1 (1.4%). 17% (56/349) of oGBM had positive PD-L1 by IHC. High TMB ( > 10mt/Mb) tumors were rare (3.1%) and MSI-high tumors even rarer (0.8%) in oGBM. When compared to yGBM, MGMT pMe was more prevalent (51% vs 38%, risk ratio (RR) 1.35 [1.19-1.52], q < 0.05) and NF1 mutations were less frequent in oGBM (21% v 34%, RR 0.62 [0.50-0.77], q < 0.05). No significant differences were seen in other key markers examined. The prevalence of SBS11 gene signature across all ages (data available for 1,141 patients) was 1.2% and was comparable across the age spectrum; no significant difference seen in the MGMT pMe group when oGBM was compared to yGBM (3.9% vs. 1.8 %, p= 0.3). Conclusions: This study represents the largest comprehensive molecular characterization of older IDH-WT GBM patients. We show that molecular profiles of IDH-WT GBM are remarkably similar across the age spectrum, including immunotherapy-associated markers, gene fusion landscape, EGFR amplification, and TMB. The significantly higher prevalence of MGMT pMe and lower NF-1 mutation rate in the older population bear significant prognostic and therapeutic implications.