Cell Reports Medicine (Jun 2020)
Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
- Liana Nobre,
- Michal Zapotocky,
- Sara Khan,
- Kohei Fukuoka,
- Adriana Fonseca,
- Tara McKeown,
- David Sumerauer,
- Ales Vicha,
- Wieslawa A. Grajkowska,
- Joanna Trubicka,
- Kay Ka Wai Li,
- Ho-Keung Ng,
- Luca Massimi,
- Ji Yeoun Lee,
- Seung-Ki Kim,
- Shayna Zelcer,
- Alexandre Vasiljevic,
- Cécile Faure-Conter,
- Peter Hauser,
- Boleslaw Lach,
- Marie-Lise van Veelen-Vincent,
- Pim J. French,
- Erwin G. Van Meir,
- William A. Weiss,
- Nalin Gupta,
- Ian F. Pollack,
- Ronald L. Hamilton,
- Amulya A. Nageswara Rao,
- Caterina Giannini,
- Joshua B. Rubin,
- Andrew S. Moore,
- Lola B. Chambless,
- Rajeev Vibhakar,
- Young Shin Ra,
- Maura Massimino,
- Roger E. McLendon,
- Helen Wheeler,
- Massimo Zollo,
- Veronica Ferruci,
- Toshihiro Kumabe,
- Claudia C. Faria,
- Jaroslav Sterba,
- Shin Jung,
- Enrique López-Aguilar,
- Jaume Mora,
- Carlos G. Carlotti,
- James M. Olson,
- Sarah Leary,
- Jason Cain,
- Lenka Krskova,
- Josef Zamecnik,
- Cynthia E. Hawkins,
- Uri Tabori,
- Annie Huang,
- Ute Bartels,
- Paul A. Northcott,
- Michael D. Taylor,
- Stephen Yip,
- Jordan R. Hansford,
- Eric Bouffet,
- Vijay Ramaswamy
Affiliations
- Liana Nobre
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Michal Zapotocky
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
- Sara Khan
- Monash Children's Cancer Centre, Monash University, Melbourne, VIC, Australia; Children’s Cancer Centre, Royal Children’s Hospital, Murdoch Children’s Research Institute, Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia
- Kohei Fukuoka
- Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan
- Adriana Fonseca
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
- Tara McKeown
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
- David Sumerauer
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
- Ales Vicha
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
- Wieslawa A. Grajkowska
- Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
- Joanna Trubicka
- Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
- Kay Ka Wai Li
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- Ho-Keung Ng
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- Luca Massimi
- Fondazione Policlinico A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy
- Ji Yeoun Lee
- Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
- Seung-Ki Kim
- Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
- Shayna Zelcer
- Division of Pediatric Hematology/Oncology, Western University, London, ON, Canada
- Alexandre Vasiljevic
- Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada
- Cécile Faure-Conter
- Department of Pediatrics, Institut d’Hemato-Oncologie Pediatrique, Lyon, France
- Peter Hauser
- Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
- Boleslaw Lach
- 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
- Marie-Lise van Veelen-Vincent
- Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, the Netherlands
- Pim J. French
- Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands
- Erwin G. Van Meir
- Departments of Neurosurgery, Hematology, and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, USA
- William A. Weiss
- Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Nalin Gupta
- Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, San Francisco, CA, USA
- Ian F. Pollack
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Ronald L. Hamilton
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Amulya A. Nageswara Rao
- Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA
- Caterina Giannini
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
- Joshua B. Rubin
- Departments of Pediatrics, Anatomy, and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA
- Andrew S. Moore
- Queensland Children’s Medical Research Institute, Children’s Health Queensland, Brisbane, QLD, Australia; Division of Oncology, Children’s Health Queensland, Brisbane, QLD, Australia
- Lola B. Chambless
- Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA
- Rajeev Vibhakar
- Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
- Young Shin Ra
- Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, South Korea
- Maura Massimino
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Roger E. McLendon
- Department of Pathology, Duke University, Durham, NC, USA
- Helen Wheeler
- Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia
- Massimo Zollo
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Naples, Italy
- Veronica Ferruci
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Naples, Italy
- Toshihiro Kumabe
- Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
- Claudia C. Faria
- Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
- Jaroslav Sterba
- Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno, Czech Republic
- Shin Jung
- Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea
- Enrique López-Aguilar
- Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico
- Jaume Mora
- Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
- Carlos G. Carlotti
- Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
- James M. Olson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Sarah Leary
- Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, USA
- Jason Cain
- Monash Children's Cancer Centre, Monash University, Melbourne, VIC, Australia
- Lenka Krskova
- Department of Pathology and Molecular Medicine, University Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic
- Josef Zamecnik
- Department of Pathology and Molecular Medicine, University Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic
- Cynthia E. Hawkins
- Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
- Uri Tabori
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Annie Huang
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Ute Bartels
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
- Paul A. Northcott
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Michael D. Taylor
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Stephen Yip
- Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Jordan R. Hansford
- Monash Children's Cancer Centre, Monash University, Melbourne, VIC, Australia; Children’s Cancer Centre, Royal Children’s Hospital, Murdoch Children’s Research Institute, Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia
- Eric Bouffet
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
- Vijay Ramaswamy
- Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Corresponding author
- Journal volume & issue
-
Vol. 1,
no. 3
p. 100038
Abstract
Summary: 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.
