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Journal Article Ahead of print 1 citation

PubMed: 42150584 DOI: 10.1016/S2352-4642(26)00067-2

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

Lancet Child Adolesc Health

Authors: Stacey Richardson, Debbie Hicks, Melissa Gough, Ellie R Butler, Dean Thompson, Jemma Castle, Stephen Crosier, Miguel Garcia-Ariza, Idoia Martín-Guerrero, Sabine Plasschaert, Franck Bourdeaut, Christelle Dufour, Julien Masliah-Planchon, Francesca Romana Buttarelli, Veronica Biassoni, Maura Massimino, Koichi Ichimura, Yonehiro Kanemura, Vijay Ramaswamy, Amar Gajjar, Martin Mynarek, Stefan Rutkowski, Marcel Kool, Stefan M Pfister, Andrey Korshunov, Edward C Schwalbe, Simon Bailey, Steven C Clifford

Affiliations

  • Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  • Biobizkaia Health Research Institute, Pediatric Hematology and Oncology Unit, Hospital Universitario Cruces, Barakaldo, Spain.
  • Biobizkaia Health Research Institute, Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, Spain.
  • Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • Paris-Cité University & SIREDO Oncology Center (Pediatric, Adolescent and Young Adults Oncology), Institut Curie, Paris, France.
  • Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Paris, France.
  • Unité de Génétique Somatique, Institut Curie, Paris, France.
  • Dipartimento Scienze Oncologiche Radiologiche Anatomo-Patologiche, Sapienza Universita di Roma, Rome, Italy.
  • Dipartimento di Ematologia ed Oncoematologica Pediatrica, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
  • Department of Pathology, Kyorin University Faculty of Medicine, Tokyo, Japan.
  • Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka, Japan; Department of Neurosurgery, NHO Osaka National Hospital, Osaka, Japan.
  • Programme in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Hopp Children's Cancer Center Heidelberg (KiTZ), Division of Pediatric Neuro-Oncology (B062), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Hopp Children's Cancer Center Heidelberg (KiTZ), Division of Pediatric Neuro-Oncology (B062), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Hopp Children's Cancer Center Heidelberg (KiTZ), Division of Pediatric Neuro-Oncology (B062), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; School of Natural Sciences, Northumbria University, Newcastle upon Tyne, UK.
  • Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Abstract

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

We assembled an international cohort of infants with non-WNT/non-SHH medulloblastoma identified from non-trial cohorts in nine countries. Inclusion criteria were age 0-5 years and a principal non-WNT/non-SHH medulloblastoma classification (group 3 [MB Group3] or group 4 [MB Group4]; 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

The total collected cohort (n=375) comprised 262 males and 110 females (three patients had missing sex data), with a median age of 3·0 years (IQR 2·5-4·0). MB Group3 tumours predominated (246 [66%] of 375 patients), among which molecular subgroups 4 (98 [40%]), 2 (75 [30%]), and 3 (46 [19%]) were most common. The remaining 129 (34%) of 375 patients had MB Group4 tumours. 313 patients were included in the survival cohort. Upfront craniospinal irradiation was associated with significantly better 5-year progression-free survival (62% [95% CI 55-70]) than non-craniospinal irradiation approaches (including focal radiotherapy or chemotherapy-only strategies; 33% [23-44]; p<0·0001). When upfront chemotherapy-only approaches were used, high-dose chemotherapy produced better survival rates (5-year overall survival 60% [95% CI 42-87]) than standard-dose chemotherapy (27% [13-57]). Patients with MB Group3 subgroup 4 represented a novel chemosensitive group, with 5-year progression-free survival of 64% (95% CI 44-95) when treated upfront with high-dose chemotherapy only (n=14). Patients with MB Group3 subgroup 2 or 3 with MYC amplification (n=10) had 5-year progression-free and overall survival rates of 0% when treated with chemotherapy only. Patients with MB Group3 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

Non-WNT/non-SHH infant medulloblastoma outcomes are associated with specific biomarkers and type of therapy received. This real-world experience identifies a favourable-risk group (MB Group3 subgroup 4) with good prognosis and a very-high-risk group (MB Group3 subgroup 2 or 3 with MYC amplification) with poor prognosis, providing a foundation for biomarker-driven MB Group3 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.

MeSH

Craniospinal Irradiation, Progression-Free Survival, Cohort Studies, Classification, Medulloblastoma, Drug Therapy, Biomarkers, Therapeutics, Pediatrics, Prognosis, Infant, Survival Rate, Chemotherapy

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