Integrated biomarker and treatment correlates of prognosis in infant non-WNT/non-SHH medulloblastoma: a multinational retrospective cohort study

BACKGROUND: Infant medulloblastoma (age <3-5 years at diagnosis) is a major challenge in paediatric oncology. Clinical studies of molecularly defined non-WNT/non-SHH infant medulloblastoma (~60% of cases) have not been done, and this group is currently considered to have uniformly high risk. Understanding the potential for its biological subclassification and clinical stratification is an essential goal towards improved outcomes. This study therefore aimed to directly compare different therapeutic approaches in non-WNT/non-SHH infant medulloblastoma and assess the relationships between outcomes and clinicomolecular features. METHODS: ]; confidence score >0·8) using DNA methylation array-based classification. Patient clinical and molecular data were collected from contributing institutions and centrally reviewed using standardised annotation protocols. A survival cohort was defined by the availability of complete progression-free and overall survival data, and grouped by whether principal upfront therapy included craniospinal irradiation or consisted of chemotherapy only. Chemotherapy was subclassified into high-dose, intraventricular methotrexate-based, and standard-dose regimens. We assessed the relationships between tumour molecular pathology, treatments received, and outcomes (progression-free and overall survival) using Kaplan-Meier plots, univariable log-rank tests, and Cox regression. FINDINGS: subgroup 2 or 3 without MYC amplification who were treated upfront with chemotherapy only (n=10) had 5-year progression-free survival of 30% (12-77) and 5-year overall survival of 58% (34-100). INTERPRETATION: clinical trials. FUNDING: Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero, and Blue Skye Thinking.