PATH-25. EXPLORING THE PROGNOSTIC IMPLICATIONS OF MOLECULAR ALTERATIONS IN ASTROCYTOMAS USING COMPREHENSIVE GENOMIC PROFILING (CGP)

Abstract

Abstract BACKGROUND Astrocytomas display molecular heterogeneity with prognostic implications for genomic alterations, including IDH, EGFR, TERT promoter and CDKN2A/B. Increasing access to comprehensive genomic profiling (CGP) provides an opportunity to characterize the genomic landscape of these tumors and their clinical implications. METHODS Patients with astrocytomas undergoing CGP through the Australian Molecular Screening and Therapeutics (MoST) precision oncology program between March 2017 and January 2022 were identified; the frequencies of genomic alterations were assessed. Associations between overall survival (OS) and alterations in EGFR, TERT promoter and/or CDKN2A/B were estimated using Kaplan-Meier methods. RESULTS 214 patients with astrocytomas were included. Median age was 49 years; majority were ECOG performance status 0-1 at screening (N=200/214, 93%) and histologically grade 4 (N=184/214, 86%). The median OS (mOS) for the cohort was 26.2mo (95%CI 24.0-31.5). For histologically grade 2/3 IDH-mutant tumors, mOS was 31.3mo (N=1) and 122.6mo (N=11, 95%CI 110-NA) for those with or without alterations in EGFR, TERT promoter and/or CDKN2A/B, respectively. For histologically grade 2/3 IDH-wildtype tumors, mOS was 19.9mo (N=7, 95%CI 15.8-NA) and 118.5mo (N=10, 95%CI 77.3-NA), respectively. For histologically grade 4 IDH-mutant tumors, mOS was 81.3mo (N=4, 95%CI 32.7-NA) and 82.8mo (N=15, 95%CI 71.0-NA), respectively. For histologically grade 4 IDH-wildtype tumors, mOS was 19.6mo (N=120 [56% TERT promoter, 42% EGFR, 14% CDKN2A/B], 95%CI 18.0-24.8) compared to 32.1mo (N=45, 95%CI 22.0-58.6; logrank P=0.0015), respectively. In grade 4 IDH-wildtype tumors additional co-occurring alterations involved PTEN (39%), TP53 (33%), NF1 (21%), RB1 (13%), CDK4 (13%) and PIK3CA (5%) genes. For the overall cohort, potentially actionable variants were seen in BRAF (5%), KIT (5%), MSH2 (2%), FGFR1 (1%) and FGFR3 (4%). Tumor mutational burden was ≥5 mutations/ megabase in 14%, without significant OS impact. CONCLUSION CGP provides additional prognostic information that complements histological grading. This demonstrates an emerging role in understanding the molecular heterogeneity of astrocytomas.