Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

• Type of Material: Article
• Authors: Liana Nobre, Hospital for Sick Children University of Toronto; Michal Zapotocky, Fakultní Nemocnice v Motole; Sara Khan, Monash University; Kohei Fukuoka, Saitama Children's Medical Center; Adriana Fonseca, Hospital for Sick Children University of Toronto; Tara McKeown, Hospital for Sick Children University of Toronto; David Sumerauer, Fakultní Nemocnice v Motole; Ales Vicha, Fakultní Nemocnice v Motole; Wieslawa A. Grajkowska, Instytut "Pomnik - Centrum Zdrowia Dziecka"; Joanna Trubicka, Instytut "Pomnik - Centrum Zdrowia Dziecka"; Kay Ka Wai Li, Chinese University of Hong Kong; Ho-Keung Ng, Chinese University of Hong Kong; Luca Massimi, Università Cattolica del Sacro Cuore, Facoltà di Medicina e Chirurgia; Ji Yeoun Lee, Seoul National University Children's Hospital; Seung-Ki Kim, Seoul National University Children's Hospital; Shayna Zelcer, The University of Western Ontario; Alexandra Vasiljevic, McMaster University; Cecile Faure-Conter, Institut d'Hémato-Oncologie Pédiatrique; Peter Hauser, Semmelweis Egyetem; Boleslaw Lach, McMaster University; Marie-Lise van Veelen-Vincent, Erasmus Medical Center; Pim J. French, Erasmus Medical Center; Erwin Van Meir, Emory University; William A. Weiss, University of California, San Francisco; Nalin Gupta, University of California, San Francisco; Ian f. Pollack, University of Pittsburgh School of Medicine; Ronald L. Hamilton, University of Pittsburgh School of Medicine; Amulya Nageswara Rao, Mayo Clinic; Caterina Giannini, Mayo Clinic; Joshua b. Rubin, Washington University School of Medicine in St. Louis; Andrew S. Moore, Children’s Health Queensland; Lola B. Chambless, Vanderbilt University Medical Center; Rajeev Vibhakar, University of Colorado Anschutz Medical Campus; Young Shin Ra, University of Ulsan; Maura Massimino, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; Roger E. McLendon, Duke University; Helen Wheeler, Kolling Institute of Medical Research; Massimo Zollo, Università degli Studi di Napoli Federico II; Veronica Ferruci, Università degli Studi di Napoli Federico II; Toshihiro Kumabe, Kitasato University School of Medicine; Claudia C. Faria, Santa Maria Hospital, Lisbon; Jaroslav Sterba, Masarykova Univerzita; Shin Jung, Chonnam National University Hwasun Hospital; Enrique López-Aguilar, Instituto Mexicano del Seguro Social; Jaume Mora, Hospital Sant Joan de Déu Barcelona; Carlos G. Carlotti, Universidade de São Paulo; James M. Olson, Fred Hutchinson Cancer Research Center; Sarah Leary, Seattle Children's Hospital; Jason Cain, Monash University; Lenka Krskova, Fakultní Nemocnice v Motole; Josef Zamecnik, Fakultní Nemocnice v Motole; Cynthia Hawkins, Hospital for Sick Children University of Toronto; Uri Tabori, Hospital for Sick Children University of Toronto; Annie Huang, Hospital for Sick Children University of Toronto; Ute Bartels, Hospital for Sick Children University of Toronto; Paul A. Northcott, St. Jude Children's Research Hospital; Michael D. Taylor, Hospital for Sick Children University of Toronto; Stephen Yip, The University of British Columbia; Jordan R. Hansford, Monash University; Eric Bouffet, Hospital for Sick Children University of Toronto; Vijay Ramaswamy, Hospital for Sick Children University of Toronto
• Language: English
• Date: 2020-06-23
• Publisher: Cell Press
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.xcrm.2020.100038
• Title of Journal or Parent Work: Cell Reports Medicine
• Volume: 1
• Issue: 3
• Grant/Funding Information: This study was partially funded with support provided by the Government of Ontario Ministry of Research, Innovation and Science and the Princess Margaret Cancer Foundation.; M.M. is supported by Associazione Con Lorenzo per Mano, Como, Italy. Tumor samples and coded data were supplied by the Children’s Cancer Centre Tissue Bank at the Murdoch Children’s Research Institute and The Royal Children’s Hospital. Establishment and running of the Children’s Cancer Centre Tissue Bank is made possible through generous support from Cancer In Kids @ RCH (http://cika.org.au/), The Royal Children's Hospital Foundation, and the Murdoch Children's Research Institute.; V.R. is supported by operating funds from the Canadian Institutes of Health Research, the Brain Tumour Foundation of Canada, the American Brain Tumor Association, the C.R. Younger Foundation, Nelina’s Hope, Meagan’s Walk, the Garron Family Cancer Center, and b.r.a.i.n.child. V.R. and M.D.T. are supported by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team translational research grant (SU2C-AACR-DT1113).; E.B. is supported by the Garron Family Chair in Childhood Cancer Research of the Hospital for Sick Children and University of Toronto. M. Zapotocky is supported by the Charles University Grant Agency (PRIMUS/19/MED/06) and MH CZ – DRO, University Hospital Motol, Prague, Czech Republic 00064203.; M. Zollo is supported by the Italian Association for Cancer Research (AIRC 2019–2024) grant IG #2219. E.G.V.M. is supported by NIH grants R01NS096236 and R01CA235162 and the CURE Childhood Cancer Foundation.; L.N. was supported by a Meagan’s Walk fellowship in pediatric neuro-oncology and the Hospital for Sick Children Clinician Scientist Training Program.; M.D.T. is supported by operating funds from the National Institutes of Health (5R01CA159859-08 and R01NS106155-01) and the Pediatric Brain Tumor Foundation.
• Keywords: Relapse; Oncology; Medulloblastoma; Children; WNT-activated; Treatment Outcome; Pediatrics; Haematology
• Research Categories: Health Sciences, Human Development; Health Sciences, Oncology; Health Sciences, Pathology; Biology, Cell

Abstract

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.