Recurrence patterns across medulloblastoma subgroups

An integrated clinical and molecular analysis

Vijay Ramaswamy, Marc Remke, Eric Bouffet, Claudia C. Faria, Sebastien Perreault, Yoon-Jae Cho, David J. Shih, Betty Luu, Adrian M. Dubuc, Paul A. Northcott, Ulrich Schüller, Sridharan Gururangan, Roger McLendon, Darell Bigner, Maryam Fouladi, Keith L. Ligon, Scott L. Pomeroy, Sandra Dunn, Joanna Triscott, Nada Jabado & 24 others Adam Fontebasso, David T.W. Jones, Marcel Kool, Matthias A. Karajannis, Sharon L. Gardner, David Zagzag, Sofia Nunes, José Pimentel, Jaume Mora, Eric Lipp, Andrew W. Walter, Marina Ryzhova, Olga Zheludkova, Ella Kumirova, Jad Alshami, Sidney E. Croul, James T. Rutka, Cynthia Hawkins, Uri Tabori, Kari Elise T. Codispoti, Roger J. Packer, Stefan M. Pfister, Andrey Korshunov, Michael D. Taylor

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

Original languageEnglish (US)
Pages (from-to)1200-1207
Number of pages8
JournalThe Lancet Oncology
Volume14
Issue number12
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

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Medulloblastoma
Recurrence
Neoplasms
Therapeutics
Craniospinal Irradiation
Neoplasm Metastasis
Moscow
Survival
Russia
National Institutes of Health (U.S.)

ASJC Scopus subject areas

  • Oncology

Cite this

Ramaswamy, V., Remke, M., Bouffet, E., Faria, C. C., Perreault, S., Cho, Y-J., ... Taylor, M. D. (2013). Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis. The Lancet Oncology, 14(12), 1200-1207. https://doi.org/10.1016/S1470-2045(13)70449-2

Recurrence patterns across medulloblastoma subgroups : An integrated clinical and molecular analysis. / Ramaswamy, Vijay; Remke, Marc; Bouffet, Eric; Faria, Claudia C.; Perreault, Sebastien; Cho, Yoon-Jae; Shih, David J.; Luu, Betty; Dubuc, Adrian M.; Northcott, Paul A.; Schüller, Ulrich; Gururangan, Sridharan; McLendon, Roger; Bigner, Darell; Fouladi, Maryam; Ligon, Keith L.; Pomeroy, Scott L.; Dunn, Sandra; Triscott, Joanna; Jabado, Nada; Fontebasso, Adam; Jones, David T.W.; Kool, Marcel; Karajannis, Matthias A.; Gardner, Sharon L.; Zagzag, David; Nunes, Sofia; Pimentel, José; Mora, Jaume; Lipp, Eric; Walter, Andrew W.; Ryzhova, Marina; Zheludkova, Olga; Kumirova, Ella; Alshami, Jad; Croul, Sidney E.; Rutka, James T.; Hawkins, Cynthia; Tabori, Uri; Codispoti, Kari Elise T.; Packer, Roger J.; Pfister, Stefan M.; Korshunov, Andrey; Taylor, Michael D.

In: The Lancet Oncology, Vol. 14, No. 12, 01.11.2013, p. 1200-1207.

Research output: Contribution to journalArticle

Ramaswamy, V, Remke, M, Bouffet, E, Faria, CC, Perreault, S, Cho, Y-J, Shih, DJ, Luu, B, Dubuc, AM, Northcott, PA, Schüller, U, Gururangan, S, McLendon, R, Bigner, D, Fouladi, M, Ligon, KL, Pomeroy, SL, Dunn, S, Triscott, J, Jabado, N, Fontebasso, A, Jones, DTW, Kool, M, Karajannis, MA, Gardner, SL, Zagzag, D, Nunes, S, Pimentel, J, Mora, J, Lipp, E, Walter, AW, Ryzhova, M, Zheludkova, O, Kumirova, E, Alshami, J, Croul, SE, Rutka, JT, Hawkins, C, Tabori, U, Codispoti, KET, Packer, RJ, Pfister, SM, Korshunov, A & Taylor, MD 2013, 'Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis', The Lancet Oncology, vol. 14, no. 12, pp. 1200-1207. https://doi.org/10.1016/S1470-2045(13)70449-2
Ramaswamy, Vijay ; Remke, Marc ; Bouffet, Eric ; Faria, Claudia C. ; Perreault, Sebastien ; Cho, Yoon-Jae ; Shih, David J. ; Luu, Betty ; Dubuc, Adrian M. ; Northcott, Paul A. ; Schüller, Ulrich ; Gururangan, Sridharan ; McLendon, Roger ; Bigner, Darell ; Fouladi, Maryam ; Ligon, Keith L. ; Pomeroy, Scott L. ; Dunn, Sandra ; Triscott, Joanna ; Jabado, Nada ; Fontebasso, Adam ; Jones, David T.W. ; Kool, Marcel ; Karajannis, Matthias A. ; Gardner, Sharon L. ; Zagzag, David ; Nunes, Sofia ; Pimentel, José ; Mora, Jaume ; Lipp, Eric ; Walter, Andrew W. ; Ryzhova, Marina ; Zheludkova, Olga ; Kumirova, Ella ; Alshami, Jad ; Croul, Sidney E. ; Rutka, James T. ; Hawkins, Cynthia ; Tabori, Uri ; Codispoti, Kari Elise T. ; Packer, Roger J. ; Pfister, Stefan M. ; Korshunov, Andrey ; Taylor, Michael D. / Recurrence patterns across medulloblastoma subgroups : An integrated clinical and molecular analysis. In: The Lancet Oncology. 2013 ; Vol. 14, No. 12. pp. 1200-1207.
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abstract = "Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89{\%}]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85{\%}] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.",
author = "Vijay Ramaswamy and Marc Remke and Eric Bouffet and Faria, {Claudia C.} and Sebastien Perreault and Yoon-Jae Cho and Shih, {David J.} and Betty Luu and Dubuc, {Adrian M.} and Northcott, {Paul A.} and Ulrich Sch{\"u}ller and Sridharan Gururangan and Roger McLendon and Darell Bigner and Maryam Fouladi and Ligon, {Keith L.} and Pomeroy, {Scott L.} and Sandra Dunn and Joanna Triscott and Nada Jabado and Adam Fontebasso and Jones, {David T.W.} and Marcel Kool and Karajannis, {Matthias A.} and Gardner, {Sharon L.} and David Zagzag and Sofia Nunes and Jos{\'e} Pimentel and Jaume Mora and Eric Lipp and Walter, {Andrew W.} and Marina Ryzhova and Olga Zheludkova and Ella Kumirova and Jad Alshami and Croul, {Sidney E.} and Rutka, {James T.} and Cynthia Hawkins and Uri Tabori and Codispoti, {Kari Elise T.} and Packer, {Roger J.} and Pfister, {Stefan M.} and Andrey Korshunov and Taylor, {Michael D.}",
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TY - JOUR

T1 - Recurrence patterns across medulloblastoma subgroups

T2 - An integrated clinical and molecular analysis

AU - Ramaswamy, Vijay

AU - Remke, Marc

AU - Bouffet, Eric

AU - Faria, Claudia C.

AU - Perreault, Sebastien

AU - Cho, Yoon-Jae

AU - Shih, David J.

AU - Luu, Betty

AU - Dubuc, Adrian M.

AU - Northcott, Paul A.

AU - Schüller, Ulrich

AU - Gururangan, Sridharan

AU - McLendon, Roger

AU - Bigner, Darell

AU - Fouladi, Maryam

AU - Ligon, Keith L.

AU - Pomeroy, Scott L.

AU - Dunn, Sandra

AU - Triscott, Joanna

AU - Jabado, Nada

AU - Fontebasso, Adam

AU - Jones, David T.W.

AU - Kool, Marcel

AU - Karajannis, Matthias A.

AU - Gardner, Sharon L.

AU - Zagzag, David

AU - Nunes, Sofia

AU - Pimentel, José

AU - Mora, Jaume

AU - Lipp, Eric

AU - Walter, Andrew W.

AU - Ryzhova, Marina

AU - Zheludkova, Olga

AU - Kumirova, Ella

AU - Alshami, Jad

AU - Croul, Sidney E.

AU - Rutka, James T.

AU - Hawkins, Cynthia

AU - Tabori, Uri

AU - Codispoti, Kari Elise T.

AU - Packer, Roger J.

AU - Pfister, Stefan M.

AU - Korshunov, Andrey

AU - Taylor, Michael D.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

AB - Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

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