PATH-55. Prognostic Significance of DNA Methylation-Defined Molecular Subtypes in Posterior Fossa Ependymomas

INTRODUCTION Ependymomas are a heterogenous group of central nervous system tumors, with significant variability in clinical outcomes influenced by molecular subtype, location, and extent of resection. Posterior fossa (PF) ependymomas represent a distinct clinical challenge due to variable prognosis and treatment response. The objective of this study was to determine whether recent advances in DNA methylation profiling which have enabled more precise molecular classification, will guide prognosis and therapy in posterior fossa ependymomas. METHODS We retrospectively analyzed 18 patients with ependymomas who underwent DNA methylation testing at our institution. The mean age was 37.9 years (17 months to 78 years). Tumor locations included the posterior fossa (n=11), spine (n=4), and supratentorial region (n=3). Tumor grading revealed WHO I (n=1), WHO II (n=7), WHO III (n=9), and one unassigned. Molecular subtypes identified were PF-EPN-A (n=3), PF-EPN-B (n=4), PF-SE (n=4), SP-MPE (n=2), SP-EPN (n=2), ST-EPN-RELA (n=3), and one unclassifiable case. RESULTS PF-EPN-A subtypes were associated with a higher recurrence rate (2 of 3), and poorer progression-free survival, even with adjuvant radiation, while PF-EPN-B showed no recurrence following gross total resection (GTR). This aligns with prior reports estimating 5-years progression-free survival rates ranging from 26.1% to 56.8% for PF-EPN-A and exceeding 70% for PF-EPN-B with complete resection. PF-EPN-B and PF-SE subtypes achieved better outcomes with GTR alone, whereas PF-EPN-A demonstrated limited responsiveness. CONCLUSION These findings align with previous studies supporting the integration of DNA methylation profiling into routine evaluation for ependymoma management. For posterior fossa tumors, both molecular subtype and extent of resection should guide postoperative management, emphasizing the need for subtype-specific therapeutic approaches, particularly for high-risk PF-EPN-A cases.