AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalised, risk-adapted therapies.
METHODS: We characterised the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n=387).
RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall-survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard-risk (80% OS) using upfront CSI-based therapies; randomised-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. 75% of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (p<0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk-factors described were reproducible in independent cohorts, strongly supporting their further investigation and development.
CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterisation of molecular heterogeneity within iMB. Novel subtypes are clinically-significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.