. 2020 Jun 23;1(3):100038.

doi: 10.1016/j.xcrm.2020.100038.

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Liana Nobre^{1

2

3}, Michal Zapotocky^{4

3}, Sara Khan^{5

6}, Kohei Fukuoka⁷, Adriana Fonseca¹, Tara McKeown¹, David Sumerauer⁴, Ales Vicha⁴, Wieslawa A Grajkowska⁸, Joanna Trubicka⁸, Kay Ka Wai Li⁹, Ho-Keung Ng⁹, Luca Massimi¹⁰, Ji Yeoun Lee¹¹, Seung-Ki Kim¹¹, Shayna Zelcer¹², Alexandre Vasiljevic¹³, Cécile Faure-Conter¹⁴, Peter Hauser¹⁵, Boleslaw Lach¹⁶, Marie-Lise van Veelen-Vincent¹⁷, Pim J French¹⁸, Erwin G Van Meir¹⁹, William A Weiss^{20

21}, Nalin Gupta²⁰, Ian F Pollack²², Ronald L Hamilton²³, Amulya A Nageswara Rao²⁴, Caterina Giannini²⁵, Joshua B Rubin²⁶, Andrew S Moore^{27

28}, Lola B Chambless²⁹, Rajeev Vibhakar³⁰, Young Shin Ra³¹, Maura Massimino³², Roger E McLendon³³, Helen Wheeler³⁴, Massimo Zollo³⁵, Veronica Ferruci³⁵, Toshihiro Kumabe³⁶, Claudia C Faria³⁷, Jaroslav Sterba³⁸, Shin Jung³⁹, Enrique López-Aguilar⁴⁰, Jaume Mora⁴¹, Carlos G Carlotti⁴², James M Olson⁴³, Sarah Leary⁴⁴, Jason Cain⁵, Lenka Krskova⁴⁵, Josef Zamecnik⁴⁵, Cynthia E Hawkins^{46

47}, Uri Tabori^{1

47

2

48}, Annie Huang^{1

47

48}, Ute Bartels¹, Paul A Northcott⁴⁹, Michael D Taylor^{47

50

48}, Stephen Yip⁵¹, Jordan R Hansford^{5

6}, Eric Bouffet¹, Vijay Ramaswamy^{1

47

50

48

52}

Affiliations

¹ Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
² Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
³ These authors contributed equally.
⁴ Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
⁵ Monash Children's Cancer Centre, Monash University, Melbourne, VIC, Australia.
⁶ Children's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁷ Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
⁸ Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
⁹ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
¹⁰ Fondazione Policlinico A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy.
¹¹ Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea.
¹² Division of Pediatric Hematology/Oncology, Western University, London, ON, Canada.
¹³ Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada.
¹⁴ Department of Pediatrics, Institut d'Hemato-Oncologie Pediatrique, Lyon, France.
¹⁵ Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
¹⁶ 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.
¹⁷ Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁸ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁹ Departments of Neurosurgery, Hematology, and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, USA.
²⁰ Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
²¹ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
²² Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²³ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²⁴ Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.
²⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁶ Departments of Pediatrics, Anatomy, and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA.
²⁷ Queensland Children's Medical Research Institute, Children's Health Queensland, Brisbane, QLD, Australia.
²⁸ Division of Oncology, Children's Health Queensland, Brisbane, QLD, Australia.
²⁹ Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA.
³⁰ Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.
³¹ Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, South Korea.
³² Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
³³ Department of Pathology, Duke University, Durham, NC, USA.
³⁴ Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia.
³⁵ Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Naples, Italy.
³⁶ Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
³⁷ Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal.
³⁸ Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno, Czech Republic.
³⁹ Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea.
⁴⁰ Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico.
⁴¹ Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.
⁴² Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil.
⁴³ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁴ Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA, USA.
⁴⁵ Department of Pathology and Molecular Medicine, University Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴⁶ Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴⁷ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁴⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴⁹ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁵⁰ Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
⁵¹ Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵² Lead Contact.

PMID: 32743560
PMCID: PMC7394286
DOI: 10.1016/j.xcrm.2020.100038

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Liana Nobre et al. Cell Rep Med. 2020.

. 2020 Jun 23;1(3):100038.

doi: 10.1016/j.xcrm.2020.100038.

Authors

Affiliations

¹ Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
² Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
³ These authors contributed equally.
⁴ Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
⁵ Monash Children's Cancer Centre, Monash University, Melbourne, VIC, Australia.
⁶ Children's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁷ Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
⁸ Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
⁹ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
¹⁰ Fondazione Policlinico A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy.
¹¹ Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea.
¹² Division of Pediatric Hematology/Oncology, Western University, London, ON, Canada.
¹³ Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada.
¹⁴ Department of Pediatrics, Institut d'Hemato-Oncologie Pediatrique, Lyon, France.
¹⁵ Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
¹⁶ 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.
¹⁷ Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁸ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁹ Departments of Neurosurgery, Hematology, and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, USA.
²⁰ Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
²¹ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
²² Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²³ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²⁴ Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.
²⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁶ Departments of Pediatrics, Anatomy, and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA.
²⁷ Queensland Children's Medical Research Institute, Children's Health Queensland, Brisbane, QLD, Australia.
²⁸ Division of Oncology, Children's Health Queensland, Brisbane, QLD, Australia.
²⁹ Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA.
³⁰ Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.
³¹ Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, South Korea.
³² Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
³³ Department of Pathology, Duke University, Durham, NC, USA.
³⁴ Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia.
³⁵ Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Naples, Italy.
³⁶ Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
³⁷ Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal.
³⁸ Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno, Czech Republic.
³⁹ Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea.
⁴⁰ Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico.
⁴¹ Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.
⁴² Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil.
⁴³ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁴ Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA, USA.
⁴⁵ Department of Pathology and Molecular Medicine, University Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴⁶ Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴⁷ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁴⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴⁹ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁵⁰ Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
⁵¹ Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵² Lead Contact.

PMID: 32743560
PMCID: PMC7394286
DOI: 10.1016/j.xcrm.2020.100038

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.

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Conflict of interest statement

DECLARATION OF INTERESTS The authors declare no competing interests.

Figures

**Figure 1**
Predictors of Relapse in WNT MB (A and B) Progression-free (A) and overall (B) survival of WNT MB. Light blue shading represents 95% CIs. (C) t-SNE visualization of 401 primary MB samples profiled by genome-wide methylation profiling. WNT cases are divided into those with no relapse, relapse, and no clinical information. (D) Copy number plot of a late relapse after 16 years, confirming monosomy 6 (WNT subgroup) at diagnosis and relapse. One late death was not confirmed to be a relapse and was attributed to chronic respiratory failure secondary to long-standing neurological dysfunction and possible tracheostomy failure.

**Figure 2**
Effect of Maintenance Chemotherapy on Survival in WNT MB Treated with Modern Protocols (A and B) Progression-free survival (A) and overall survival (B) of WNT MB stratified by individuals receiving no cyclophosphamide or high-dose cyclophosphamide/ifosfamide-based maintenance chemotherapy regimens. The p values were determined using a log rank test. Lighter shading around the survival curve represents 95% CIs

See this image and copyright information in PMC

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Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Affiliations

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous