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.
| Original language | English (US) |
|---|---|
| Article number | 100038 |
| Journal | Cell Reports Medicine |
| Volume | 1 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jun 23 2020 |
Keywords
- WNT
- chemotherapy
- expression
- medulloblastoma
- methylation
- radiation
- recurrence
- subgroup
- survival
- wingless
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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In: Cell Reports Medicine, Vol. 1, No. 3, 100038, 23.06.2020.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
AU - Nobre, Liana
AU - Zapotocky, Michal
AU - Khan, Sara
AU - Fukuoka, Kohei
AU - Fonseca, Adriana
AU - McKeown, Tara
AU - Sumerauer, David
AU - Vicha, Ales
AU - Grajkowska, Wieslawa A.
AU - Trubicka, Joanna
AU - Li, Kay Ka Wai
AU - Ng, Ho Keung
AU - Massimi, Luca
AU - Lee, Ji Yeoun
AU - Kim, Seung Ki
AU - Zelcer, Shayna
AU - Vasiljevic, Alexandre
AU - Faure-Conter, Cécile
AU - Hauser, Peter
AU - Lach, Boleslaw
AU - van Veelen-Vincent, Marie Lise
AU - French, Pim J.
AU - Van Meir, Erwin G.
AU - Weiss, William A.
AU - Gupta, Nalin
AU - Pollack, Ian F.
AU - Hamilton, Ronald L.
AU - Nageswara Rao, Amulya A.
AU - Giannini, Caterina
AU - Rubin, Joshua B.
AU - Moore, Andrew S.
AU - Chambless, Lola B.
AU - Vibhakar, Rajeev
AU - Ra, Young Shin
AU - Massimino, Maura
AU - McLendon, Roger E.
AU - Wheeler, Helen
AU - Zollo, Massimo
AU - Ferruci, Veronica
AU - Kumabe, Toshihiro
AU - Faria, Claudia C.
AU - Sterba, Jaroslav
AU - Jung, Shin
AU - López-Aguilar, Enrique
AU - Mora, Jaume
AU - Carlotti, Carlos G.
AU - Olson, James M.
AU - Leary, Sarah
AU - Cain, Jason
AU - Krskova, Lenka
AU - Zamecnik, Josef
AU - Hawkins, Cynthia E.
AU - Tabori, Uri
AU - Huang, Annie
AU - Bartels, Ute
AU - Northcott, Paul A.
AU - Taylor, Michael D.
AU - Yip, Stephen
AU - Hansford, Jordan R.
AU - Bouffet, Eric
AU - Ramaswamy, Vijay
N1 - Funding Information: L.N. was supported by a Meagan’s Walk fellowship in pediatric neuro-oncology and the Hospital for Sick Children Clinician Scientist Training Program . 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 ). 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 . 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 . 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 . 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 . Funding Information: L.N. was supported by a Meagan's Walk fellowship in pediatric neuro-oncology and the Hospital for Sick Children Clinician Scientist Training Program. 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). 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. 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. 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. 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. Conceptualization, L.N. E.B. and V.R.; Methodology, L.N. M.Z. (Michal Zapotocky), and V.R.; Investigation, L.N. and V.R.; Data Curation, M.Z. (Michal Zapotocky), S.K. D.S. A.V. W.A.G. J.T. K.K.W.L. H.-K.N. L.M. J.Y.L. S.-K.K. S.Z. A.V. C.F.-C. P.H. B.L. M.-L.v.V.-V. P.J.F. E.G.V.M. W.A.W. N.G. I.F.P. R.L.H. A.A.N.R. C.G. J.B.R. A.S.M. L.B.C. R.V. Y.S.R. M.M. R.E.M. H.W. M.Z. (Massimo Zollo), V.F. T.K. C.C.F. J.S. S.J. E.L.-A. J.M. C.G.C. J.M.O. S.L. J.C. L.K. J.Z. C.E.H. U.T. A.H. U.B. M.D.T. J.R.H. and V.R.; Formal Analysis, L.N. M.Z.(Michal Zapotocky), K.F. A.F. and V.R.; Writing ? Review & Editing, L.N. E.B. and V.R.; Resources, M.Z. (Michal Zapotocky), S.K. D.S. A.V. T.M. W.A.G. J.T. K.K.W.L. H.-K.N. L.M. J.Y.L. S.-K.K. S.Z. A.V. C.F.-C. P.H. B.L. M.L.v.V.-V. P.J.F. E.G.V.M. W.A.W. N.G. I.F.P. R.L.H. A.A.N.R. C.G. J.B.R. A.S.M. L.B.C. R.V. Y.S.R. M.M. R.E.M. H.W. M.Z. (Massimo Zollo), V.F. T.K. C.C.F. J.S. S.J. E.L.-A. J.M. C.G.C. J.M.O. S.L. J.C. L.K. J.Z. C.E.H. U.T. A.H. U.B. M.D.T. S.Y. J.R.H. and V.R. Project Administration, E.B. and V.R.; Supervision, V.R.; Funding Acquisition, M.Z. (Michal Zapotocky), J.C. M.D.T. and VR. The authors declare no competing interests. Publisher Copyright: © 2020 The Author(s)
PY - 2020/6/23
Y1 - 2020/6/23
N2 - 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.
AB - 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.
KW - WNT
KW - chemotherapy
KW - expression
KW - medulloblastoma
KW - methylation
KW - radiation
KW - recurrence
KW - subgroup
KW - survival
KW - wingless
UR - http://www.scopus.com/inward/record.url?scp=85095781132&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095781132&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2020.100038
DO - 10.1016/j.xcrm.2020.100038
M3 - Article
C2 - 32743560
AN - SCOPUS:85095781132
SN - 2666-3791
VL - 1
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 3
M1 - 100038
ER -