Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

2nd Department of Pediatrics Semmelweis University Budapest Hungary

Cancer and Blood Disorders Center Seattle Children's Hospital Seattle WA USA

Children's Cancer Centre Royal Children's Hospital Murdoch Children's Research Institute Department of Pediatrics University of Melbourne Melbourne VIC Australia

Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA USA

Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong Shatin New Territories Hong Kong

Department of Developmental Neurobiology St Jude Children's Research Hospital Memphis TN USA

Department of Hematology Oncology Saitama Children's Medical Center Saitama Japan

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical Biophysics University of Toronto Toronto ON Canada

Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Neurological Surgery Vanderbilt Medical Center Nashville TN USA

Department of Neurology Erasmus University Medical Center Rotterdam the Netherlands

Department of Neurology University of California San Francisco San Francisco CA USA

Department of Neurosurgery Chonnam National University Research Institute of Medical Sciences Chonnam National University Hwasun Hospital and Medical School Hwasun gun Chonnam South Korea

Department of Neurosurgery Division of Pediatric Neurosurgery Seoul National University Children's Hospital Seoul South Korea

Department of Neurosurgery Erasmus University Medical Center Rotterdam the Netherlands

Department of Neurosurgery Kitasato University School of Medicine Sagamihara Kanagawa Japan

Department of Neurosurgery University of Ulsan Asan Medical Center Seoul South Korea

Department of Pathology and Laboratory Medicine University of British Columbia Vancouver BC Canada

Department of Pathology and Molecular Medicine Division of Anatomical Pathology McMaster University and Department of Pathology and Laboratory Medicine Hamilton General Hospital Hamilton ON Canada

Department of Pathology and Molecular Medicine Division of Anatomical Pathology McMaster University Hamilton ON Canada

Department of Pathology and Molecular Medicine University Hospital Motol 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Pathology Duke University Durham NC USA

Department of Pathology The Children's Memorial Health Institute Warsaw Poland

Department of Pathology University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine University Hospital Motol Charles University Prague Czech Republic

Department of Pediatric Oncology School of Medicine Masaryk University Brno Czech Republic

Department of Pediatrics Institut d'Hemato Oncologie Pediatrique Lyon France

Department of Pediatrics University of Colorado Denver Aurora CO USA

Department of Surgery and Anatomy Faculty of Medicine of Ribeirão Preto University of Sao Paulo São Paulo Brazil

Departments of Neurological Surgery and Pediatrics University of California San Francisco San Francisco CA USA

Departments of Neurosurgery Hematology and Medical Oncology School of Medicine and Winship Cancer Institute Emory University Atlanta GA USA

Departments of Pediatrics Anatomy and Neurobiology Washington University School of Medicine St Louis MO USA

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON Canada

Developmental Tumor Biology Laboratory Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM Università di Napoli Federico 2 Naples Italy

Division of Haematology Oncology Department of Pediatrics The Hospital for Sick Children Toronto ON Canada

Division of Neurosurgery Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon Portugal

Division of Oncology Children's Health Queensland Brisbane QLD Australia

Division of Pathology The Hospital for Sick Children Toronto ON Canada

Division of Pediatric Hematology Oncology Hospital Pediatría Centro Médico Nacional Century XXI Mexico City Mexico

Division of Pediatric Hematology Oncology Mayo Clinic Rochester MN USA

Division of Pediatric Hematology Oncology Western University London ON Canada

Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Fondazione Policlinico A Gemelli IRCCS Catholic University Medical School Rome Italy

Institute of Medical Science University of Toronto Toronto ON Canada

Kolling Institute of Medical Research The University of Sydney Sydney NSW Australia

Lead Contact

Monash Children's Cancer Centre Monash University Melbourne VIC Australia

Queensland Children's Medical Research Institute Children's Health Queensland Brisbane QLD Australia

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON Canada

These authors contributed equally

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