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BACKGROUND Cell-free DNA (cfDNA) profiling has been shown to carry utility as a clinically relevant biomarker in a variety of cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. We hereby evaluated the actionability of profiling cfDNA from cerebrospinal fluid (CSF) based on a multi-institutional cohort of children with medulloblastoma. METHODS 103 children aged ≥ 3 years with medulloblastoma harboring chromosomal aneuploidy enrolled on two prospective therapeutic trials were included. cfDNA was extracted from CSF obtained longitudinally, and profiled by low-coverage whole-genome sequencing (lcWGS) for annotating copy-number variants (CNVs). cfDNA-derived CNVs were compared against patient-matched primary tumor-derived CNVs and correlated with outcome. cfDNA profiles at diagnosis and relapse were compared to evaluate tumor evolution. RESULTS Tumor-derived somatic CNVs were detected in 72% of baseline cfDNA samples, with higher detection rate in samples from patients with metastatic disease than those without (90% versus 50%, chi-square p=0.001). Longitudinal profiling of cfDNA revealed correlation between CNV detectability and clinical course, with detection of tumor-derived CNVs in cfDNA samples predating radiographic progression for ≥ 3 months in 62% of relapsing patients. Presence of cfDNA-derived CNVs in CSF collected during chemotherapy and at the end of therapy was significantly associated with inferior PFS (log-rank p&amp;lt;0.0001 for both time-points). Comparison of CNV profiles from cfDNA at baseline and relapse revealed molecular divergence in a subset of patients. CONCLUSION These results carry major implications and supports the incorporation of cfDNA profiling in upcoming medulloblastoma protocols for more sensitive and accurate disease monitoring and personalization of treatment.

MBRS-20. CSF-DERIVED CIRCULATING TUMOR DNA AS A BIOMARKER FOR DISEASE PROGRESSION AND TUMOR EVOLUTION IN MEDULLOBLASTOMA