Path-12. contemporary molecular landscape, survival, and prognostic factors in over 4,000 gliomas

Abstract INTRODUCTION Molecular glioma classification and advances in treatment modalities have expanded therapeutic options for patients. We sought to capture the genomic landscape, prognostic features, and contemporary outcomes of gliomas. METHODS We assembled patients from TCGA (n=770) and multi-institutional datasets (n=3,546) with somatic mutations and copy number/structural variants. All gliomas were classified using molecular definitions (WHO 2021/cIMPACT-NOW). We identified correlations between genes through permutations testing and prognostic features through multivariate cox models with backwards elimination. RESULTS We analyzed 4,316 patients (median age 52yrs, 41% female), including 2,155 glioblastoma, 1,199 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, and 343 other IDH1/2-wiltype gliomas. Molecular classification shifted 27.2% of gliomas from their original histopathologic designation. Canonical alterations categorized glioma subtypes, showing unique correlations with clinical features and mutual exclusivity of alterations in tumorigenic pathways. 2,433 patients had clinical outcomes: 1,296 glioblastomas, 584 IDH1/2-mutant astrocytoma, and 327 oligodendrogliomas. Patients from contemporary institutional cohorts had improved overall survival compared to TCGA patients: glioblastoma (non-TCGA:17.9mo,TCGA:15.0mo,p< 0.0001), IDH1/2-mutant astrocytoma (non-TCGA:180mo,TCGA: 87.9mo,p=0.0002), and oligodendroglioma (non-TCGA: not reached,TCGA:135mo,p< 0.0001). In contemporary cohorts, median survival in grade 2-3 IDH1/2-mutant astrocytoma (180.3mo) was double that of grade 4 (75.4mo, p< 0.0001). In GBM and oligodendrogliomas, patients >65yrs had worse outcomes than patients 20-64yrs (p< 0.001). In glioblastoma, age (HR:1.03), CDKN2A/B homozygous deletion (HR:1.22), and NF1 alterations (HR:1.31) were negatively prognostic. Chemotherapy (HR:0.64), MGMT-methylation (HR:0.44), 19q-gain (HR:0.70), and non-TCGA cohort (HR:0.54,HR:0.34) were positively prognostic. In IDH1/2-mutant astrocytoma, CDKN2A/B homozygous deletion (HR:2.75), CCND2 alteration (HR:2.89), EGFR amplification (HR:2.93), PDGFRA alteration (HR:2.87), 9p-loss (HR:3.09), and 10q-loss (HR:1.99) were negatively prognostic; white race was the only prognostically positive feature (HR:0.35). CONCLUSIONS Overall survival in gliomas has improved over time. We corroborated canonical features and identified new prognostic features that are subtype-specific. The unique molecular profiles across glioma subtypes provide insight into biological drivers that influence heterogenous clinical outcomes.