1053 Genomic Alterations Predictive of Rapid Early Tumor Progression in IDH-Wild Type GBM

INTRODUCTION: Glioblastoma IDH-WT (IDH-WT GBM) may experience rapid early tumor progression (REP). REP may occur in up to 50% GMB cases. Genetic characteristics predictive of REP in GBM have not been previously described. METHODS: We identified 282 patients from our institutional database, all diagnosed with IDH-wild type (IDH-WT) GBM. Patients underwent Next-Generation sequencing targeting 315 tumor-associated genes. We included patients who had an MRI 48 hours following surgery and a second MRI before starting chemoradiotherapy. REP was characterized as progression per RANO criteria before the initiation of adjuvant chemoradiotherapy. The study focused on outcomes such as progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-five IDH-WT GBM patients were included for the statistical analysis. From these, 14 patients were found to have REP and 31 did not meet REP criteria. The Non-REP group was found to have a PFS of 8 months (95%CI=6.190-9.810) while REP was associated with a PFS of 1 month (95%CI=0.398-1.602). Log-rank p=<0.001. Univariate and multivariate analyses on PFS revealed six mutations associated high risk of progression: CDK6 HR=8.929 (CI= 1.054-75.638) p=0.045, CDKN2A/B HR=0.373 (CI= 0.164-0.848) p=0.019, CREBBP HR=8.929 (CI= 1.054-75.638) p=0.045, FANCA HR=8.929 (CI= 1.054-75.638) p=0.45, MAGI2 HR=8.929 (CI= 1.054-75.638) p=0.045 and MYCN HR=8.929 (CI= 1.054-75.638) p=0.045. CONCLUSIONS: This pilot study provides novel insights into the genetic underpinnings of REP in IDH-WT glioblastoma (GBM). Specific gene mutations, including CDK6, CDKN2A/B, FANCA, CREBBP, MYCN, and MAGI2, were found to be associated with a heightened risk of reduced PFS in REP. These identified mutations hold promise as potential prognostic markers or therapeutic targets for addressing the aggressive nature of this form of GBM.