Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis - 30/10/13

Doi : 10.1016/S1470-2045(13)70449-2

Vijay Ramaswamy, MD ^a,^c,^d, Marc Remke, MD ^a,^c,^d, Eric Bouffet, ProfMD ^b,^c, Claudia C Faria, MD ^a,^c,^e, Sebastien Perreault, MD ^g, Yoon-Jae Cho, MD ^g, David J Shih, MSc ^a,^c,^d, Betty Luu, BSc ^c, Adrian M Dubuc, PhD ^a,^c,^d, Paul A Northcott, PhD ^h, Ulrich Schüller, MD ^j, Sridharan Gururangan, ProfMD ^k, Roger McLendon, ProfMD ^k, Darell Bigner, ProfMD ^k, Maryam Fouladi, ProfMD ^l, Keith L Ligon, MD ^m,^o,^p, Scott L Pomeroy, ProfMD ^n,^q, Sandra Dunn, PhD ^r, Joanna Triscott, BSc ^r, Nada Jabado, MD ^s, Adam Fontebasso, BSc ^s, David T W Jones, PhD ^h, Marcel Kool, PhD ^h, Matthias A Karajannis, MD ^t, Sharon L Gardner, MD ^t, David Zagzag, ProfMD ^u,^v, Sofia Nunes, MD ^w, José Pimentel, MD ^f, Jaume Mora, MD ^x, Eric Lipp, MD ^k, Andrew W Walter, MD ^y, Marina Ryzhova, MD ^z, Olga Zheludkova, MD ^aa, Ella Kumirova, MD ^aa, Jad Alshami, BSc ^s, Sidney E Croul, ProfMD ^c, James T Rutka, ProfMD ^a,^c,^d, Cynthia Hawkins, ProfMD ^a,^c, Uri Tabori, MD ^b,^c, Kari-Elise T Codispoti, MD ^ab, Roger J Packer, ProfMD ^ab, Stefan M Pfister, ProfMD ^h,^ac, Andrey Korshunov, ProfMD ^i,^ad, Michael D Taylor, ProfMD ^a,^c,^d,^⁎

^a Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada

^b Division of Pediatric Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada

^c Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada

^d Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

^e Division of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal

^f Laboratory of Neuropathology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal

^g Department of Neurology, Stanford University, Palo Alto, CA, USA

^h Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

ⁱ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

^j Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany

^k The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

^l Division of Hematology/Oncology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

^m Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

ⁿ Department of Neurology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

^o Boston Children’s Hospital, Boston, MA, USA

^p Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

^q Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA

^r Division of Hematology/Oncology, British Columbia Children’s Hospital, Vancouver, BC, Canada

^s Division of Pediatric Hematology/Oncology, Montreal Children’s Hospital, Montreal, PQ, Canada

^t Division of Pediatric Hematology/Oncology, NYU Langone Medical Center, New York, NY, USA

^u Department of Pathology, NYU Langone Medical Center, New York, NY, USA

^v Department of Neurosurgery, NYU Langone Medical Center, New York, NY, USA

^w Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal

^x Department of Oncology, Hospital Sant Joan de Deu de Barcelona, Barcelona, Spain

^y A I duPont Hospital for Children, Wilmington, DE, USA

^z Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia

^aa Department of Pediatric Neurooncology, Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

^ab Center for Neuroscience and Behavioral Medicine, Children’s National Medical Center, Washington, DC, USA

^ac Heidelberg University Hospital, Department of Pediatric Hematology and Oncology, Heidelberg, Germany

^ad Department of Neuropathology, University of Heidelberg, Heidelberg, Germany

^* Correspondence to: Prof Michael D Taylor, Hospital for Sick Children, Toronto, ON, Canada

Summary

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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Vol 14 - N° 12

P. 1200-1207 - novembre 2013 Retour au numéro

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Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis - 30/10/13

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