MEDB-41. Identifying a subgroup of patients with early childhood sonic hedgehog-activated medulloblastoma with unfavorable prognosis after treatment with radiation-sparing regimens including intraventricular methotrexate

Abstract PURPOSE/METHODS: Clinical and molecular risk factors in 142 patients <5 years with desmoplastic medulloblastoma (DMB) or extensive nodularity (MBEN) were investigated. Patients diagnosed between 1992 2020 treated radiation-sparing approaches, 131 intraventricular methotrexate. 14 metastatic disease received high-dose chemotherapy. DNA methylation profiles of 77 sonic hedgehog (SHH)-activated reclassified according to the Heidelberg Brain Tumor Classifier Version 12.3. RESULTS: While incomplete resection did not impact progression-free survival (PFS) overall (OS), MBEN had superior outcomes DMB (5-year PFS 93% vs 71%, p=0.004; 5-year OS 100% 90%, p=0.026). Older less favorable [>3 years] 47% 85% [<1 year] 84% [1-3 years], p<0.001). No TP53 mutations detected (n=47). classification identified three subgroups: SHH-1v12.3 (n=39), SHH-2v12.3 (n=19), SHH-3v12.3 distinct cytogenetic (chromosome 2 gains SHH-1v12.3, very few alterations SHH-2v12.3, chromosome 9q losses SHH-3v12.3), age (median [years] SHH-1v12.3: 1.7, SHH-2v12.3: 0.9, SHH-3v12.3: 3.0, p<0.001), histological distribution (SHH-2v12.3: 74% MBEN, SHH-1v12.3/SHH-3v12.3: 77%/79% DMB, was more unfavorable SHH-3v12.3-medulloblastoma 53% 86% [SHH-1v12.3] 95% [SHH-2v12.3], p=0.002), which remained only factor on multivariable Cox regression for PFS. comparable 94% [SHH-3v12.3] 97% p=0.6). 8/9 radiotherapy at relapse (6 craniospinal, local [1 Gorlin syndrome, 1 BRCA2 germline mutation], no [Gorlin syndrome]). CONCLUSION: We identify an increased when approaches among children early childhood SHH-medulloblastoma. If these tumors differ from SHH-3-medulloblastoma typically described older remains be verified. Treatment recommendations need consider cancer predisposition syndromes.