PATH-04. Yield of integrated Multi-omic Diagnostics of Pediatric CNS Tumors the Máxima(l) Way: Evaluation of the Dutch National Pediatric Oncology Center.

Introduction Pediatric neuro-oncological care in the Netherlands is centralized at the Princess Máxima Center, standardizing diagnostics and treatment. Since 2020, routine workups for pediatric CNS tumors entail integrated histological and molecular analyses including DNA-methylation, whole-RNA-­sequencing, and whole-exome-sequencing. This study highlights the benefits of multi-omic diagnostics for pediatric CNS tumors. Methods Diagnostic data was retrospectively collected from patients (ages 0–18) undergoing surgery between June 2020 and January 2025. With 96% providing informed consent, data from complete molecular workups was analyzed for 531 CNS tumor samples (474 primary, 57 recurrences). Tumors included gliomas (low-grade (LGGs): 217, high-grade (HGGs): 79, ependymomas: 46), embryonal tumors (97), high-grade neuro-epithelial tumors (HGNET: 8), adamantinomatous craniopharyngiomas (38), germ cell tumors (21), and others (25). Results Using integrated histological-molecular analysis, 95% of cases could be classified according to the CNS WHO 2021, enabling tailored therapy. Only 26 cases were designated “not elsewhere classified,” (8 HGNETs, 3 HGGs, 12 LGGs, 3 embryonal tumors). Within LGGs, molecular drivers were identified in 99% of cases, with 94% being therapeutically targetable. These therapeutics span seven inhibitory classes (e.g., BRAF, FGFR, tyrosine kinases), which are all clinically available. In HGGs, a molecular driver and/or co-alteration was also identified in 99% of cases, with 70% being potentially targetable. However, unlike LGG-therapeutics, these span 12 distinct inhibitory classes (e.g., PTEN, PDGFR, CDKN2A/B), with few clinically available drugs. This is partly because of the rarity of the various HGG subtypes and additional obstacles like the blood-brain barrier. Targetable drivers were limited for ependymomas and medulloblastomas, however, subtype-level classification was achieved in 98% of ependymomas and 93% of embryonal tumors, enabling enrollment in tumor-(sub)type specific clinical trials. Conclusion Centralized diagnostics at the Princess Máxima Center has not only enabled WHO-conform diagnoses in 95% of cases, but also paved the way for personalized therapy, potentially resulting in better outcome.