Abstract
Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n=387). 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; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent 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. Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.
Highlights
Medulloblastoma (MB), the most common malignant paediatric brain tumour, accounts for around 10% of childhood cancer deaths
Key medulloblastoma features were differentially distributed between Infant medulloblastomas (iMB) (
Within iMB, survival was equivalent between consensus molecular subgroups (5yr overall survival (OS); iMBSHH 66% vs. iMBGrp3 50% vs. iMBGrp4 61%, log rank P = 0.397) (5yr progression-free survival (PFS); iMBSHH 53% vs. iMBGrp3 50% vs. iMBGrp4 65%) (Figure 1b, Table S5)
Summary
Medulloblastoma (MB), the most common malignant paediatric brain tumour, accounts for around 10% of childhood cancer deaths. Five-year overall survival (OS) rates of approximately 70% are currently achieved in non-infants (children aged over either 3 or 5 years at diagnosis, depending on national treatment philosophies) using contemporary multimodal therapies (maximal surgical resection, cranio-spinal irradiation (CSI) and adjuvant combination chemotherapy)[1]. Current iMB protocols aim to minimize the permanently disabling late effects associated with irradiation of the developing brain by avoidance/delay of CSI [2]. This must be balanced with morbidity and mortality, and any potential for salvage using CSI at a later stage [3]. Desmoplastic nodular/medulloblastoma with extensive nodularity (DN/MBEN) pathology [4] (~40% of iMB; favourable risk) is the only clinically adopted prognostic risk factor and is used as a basis for de-escalation of treatment [5]; no molecular biomarkers are in current clinical use
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