Multicenter Study

. 2023 Dec 8;25(12):2273-2286.

doi: 10.1093/neuonc/noad114.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

Anna S Kolodziejczak^{1

2

3}, Lea Guerrini-Rousseau^{4

5}, Julien Masliah Planchon⁶, Jonas Ecker^{1

2

3

7}, Florian Selt^{1

2

3

7}, Martin Mynarek^{8

9}, Denise Obrecht⁸, Martin Sill^{1

10}, Robert J Autry^{1

10}, Eric Stutheit-Zhao^{1

10

11}, Steffen Hirsch^{1

3

10}, Elsa Amouyal¹², Christelle Dufour^{4

5}, Olivier Ayrault¹³, Jacob Torrejon¹³, Sebastian M Waszak^{14

15}, Vijay Ramaswamy^{16

17}, Virve Pentikainen¹⁸, Haci Ahmet Demir¹⁹, Steven C Clifford²⁰, Ed C Schwalbe^{20

21}, Luca Massimi²², Matija Snuderl²³, Kristyn Galbraith²³, Matthias A Karajannis²⁴, Katherine Hill²⁴, Bryan K Li²⁴, Mike Walsh²⁴, Christine L White^{25

26

27}, Shelagh Redmond²⁸, Loizou Loizos²⁹, Marcus Jakob³⁰, Uwe R Kordes⁸, Irene Schmid³¹, Julia Hauer³², Claudia Blattmann³³, Maria Filippidou³⁴, Gianluca Piccolo³⁵, Wolfram Scheurlen³⁶, Ahmed Farrag^{37

38}, Kerstin Grund³⁹, Christian Sutter³⁹, Torsten Pietsch⁴⁰, Stephan Frank⁴¹, Denis M Schewe⁴², David Malkin⁴³, Myriam Ben-Arush⁴⁴, Astrid Sehested⁴⁵, Tai-Tong Wong⁴⁶, Kuo-Sheng Wu⁴⁷, Yen-Lin Liu⁴⁸, Fernando Carceller⁴⁹, Sabine Mueller⁵⁰, Schuyler Stoller⁵¹, Michael D Taylor¹⁶, Uri Tabori¹⁷, Eric Bouffet^{17

52}, Marcel Kool^{1

10

53}, Felix Sahm^{1

54}, Andreas von Deimling⁵⁴, Andrey Korshunov⁵⁴, Katja von Hoff^{55

56}, Christian P Kratz⁵⁷, Dominik Sturm^{1

7

58}, David T W Jones^{1

58}, Stefan Rutkowski⁸, Cornelis M van Tilburg^{1

2

3

7}, Olaf Witt^{1

2

3

7}, Gaëlle Bougeard⁵⁹, Kristian W Pajtler^{1

3

7

10}, Stefan M Pfister^{1

3

7

10}, Franck Bourdeaut¹², Till Milde^{1

2

3

7}

Affiliations

¹ Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
² CCU Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
³ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁴ Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.
⁵ Molecular Predictors and New Targets in Oncology, Inserm U981 Team "Genomics and Oncogenesis of pediatric Brain Tumors," Gustave Roussy, Université Paris-Saclay, Villejuif, France.
⁶ Department of Diagnostic and Theranostic Medicine, Somatic Genetics Unit, Institut Curie, Paris-Science Lettres University, Paris, France.
⁷ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹ Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
¹¹ Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
¹² SIREDO Pediatric Oncology Center, Institut Curie, Paris-Science Lettres University, Paris, France.
¹³ Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
¹⁴ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
¹⁵ Department of Neurology, University of California, San Francisco, CA, USA.
¹⁶ Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁸ Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
¹⁹ Department of Pediatric Hematology-Oncology, Private Memorial Ankara Hospital, Ankara, Turkey.
²⁰ Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom.
²¹ Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.
²² Pediatric Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy.
²³ Department of Pathology, New York University Langone Health, New York City, NY, USA.
²⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
²⁵ Victorian Clinical Genetics Services, Parkville, Australia.
²⁶ Hudson Institute of Medical Research, Clayton, Australia.
²⁷ Department of Molecular and Translational Science, Monash University, Clayton, Australia.
²⁸ Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
²⁹ Pediatric Oncology/Hematology/Immunology at the Medical School of the University of Nicosia, Nicosia, Cyprus.
³⁰ Department of Paediatric Haematology, Oncology and Stem-Cell Transplantation, University Hospital Regensburg, Regensburg, Germany.
³¹ Paediatric Haematology and Oncology, Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
³² Pediatric Haematology and Oncology, University Hospital Carl Gustav Carus, Dresden, Germany.
³³ Paediatric Haematology, Oncology and Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.
³⁴ Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece.
³⁵ Neuro-Oncology Unit, IRCCS Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
³⁶ Paediatric Haematology and Oncology, Cnopfsche Paediatric Clinic, Nurnberg, Germany.
³⁷ Department of Paediatric Haematology, Oncology and Stem-Cell Transplantation, Paediatric Clinic, University Hospital Aachen, Aachen, Germany.
³⁸ Department of Pediatric Oncology, South Egypt Cancer Institute, Assiut University, Egypt.
³⁹ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
⁴⁰ Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany.
⁴¹ Division of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.
⁴² Department of Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
⁴³ Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
⁴⁴ Pediatric Hematology Oncology, Rambam Medical Center, Haifa, Israel.
⁴⁵ Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Copenhagen University Hospital, Copenhagen, Denmark.
⁴⁶ Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
⁴⁷ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴⁸ Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴⁹ Paediatric and Adolescent Oncology Drug Development Team, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, United Kingdom.
⁵⁰ Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, USA.
⁵¹ Department of Neurology, University of California, San Francisco, USA.
⁵² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology/ Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵³ Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
⁵⁴ Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, and CCU Neuropathology, German Cancer Institute (DKF), Heidelberg, Germany.
⁵⁵ Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁵⁶ Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
⁵⁷ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
⁵⁸ Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
⁵⁹ Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, F-76000 Rouen, France.

PMID: 37379234
PMCID: PMC10708940
DOI: 10.1093/neuonc/noad114

Multicenter Study

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

Anna S Kolodziejczak et al. Neuro Oncol. 2023.

. 2023 Dec 8;25(12):2273-2286.

doi: 10.1093/neuonc/noad114.

Authors

Affiliations

¹ Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
² CCU Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
³ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁴ Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.
⁵ Molecular Predictors and New Targets in Oncology, Inserm U981 Team "Genomics and Oncogenesis of pediatric Brain Tumors," Gustave Roussy, Université Paris-Saclay, Villejuif, France.
⁶ Department of Diagnostic and Theranostic Medicine, Somatic Genetics Unit, Institut Curie, Paris-Science Lettres University, Paris, France.
⁷ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹ Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
¹¹ Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
¹² SIREDO Pediatric Oncology Center, Institut Curie, Paris-Science Lettres University, Paris, France.
¹³ Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
¹⁴ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
¹⁵ Department of Neurology, University of California, San Francisco, CA, USA.
¹⁶ Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁸ Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
¹⁹ Department of Pediatric Hematology-Oncology, Private Memorial Ankara Hospital, Ankara, Turkey.
²⁰ Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom.
²¹ Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.
²² Pediatric Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy.
²³ Department of Pathology, New York University Langone Health, New York City, NY, USA.
²⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
²⁵ Victorian Clinical Genetics Services, Parkville, Australia.
²⁶ Hudson Institute of Medical Research, Clayton, Australia.
²⁷ Department of Molecular and Translational Science, Monash University, Clayton, Australia.
²⁸ Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
²⁹ Pediatric Oncology/Hematology/Immunology at the Medical School of the University of Nicosia, Nicosia, Cyprus.
³⁰ Department of Paediatric Haematology, Oncology and Stem-Cell Transplantation, University Hospital Regensburg, Regensburg, Germany.
³¹ Paediatric Haematology and Oncology, Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
³² Pediatric Haematology and Oncology, University Hospital Carl Gustav Carus, Dresden, Germany.
³³ Paediatric Haematology, Oncology and Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.
³⁴ Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece.
³⁵ Neuro-Oncology Unit, IRCCS Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
³⁶ Paediatric Haematology and Oncology, Cnopfsche Paediatric Clinic, Nurnberg, Germany.
³⁷ Department of Paediatric Haematology, Oncology and Stem-Cell Transplantation, Paediatric Clinic, University Hospital Aachen, Aachen, Germany.
³⁸ Department of Pediatric Oncology, South Egypt Cancer Institute, Assiut University, Egypt.
³⁹ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
⁴⁰ Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany.
⁴¹ Division of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.
⁴² Department of Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
⁴³ Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
⁴⁴ Pediatric Hematology Oncology, Rambam Medical Center, Haifa, Israel.
⁴⁵ Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Copenhagen University Hospital, Copenhagen, Denmark.
⁴⁶ Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
⁴⁷ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴⁸ Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴⁹ Paediatric and Adolescent Oncology Drug Development Team, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, United Kingdom.
⁵⁰ Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, USA.
⁵¹ Department of Neurology, University of California, San Francisco, USA.
⁵² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology/ Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵³ Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
⁵⁴ Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, and CCU Neuropathology, German Cancer Institute (DKF), Heidelberg, Germany.
⁵⁵ Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁵⁶ Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
⁵⁷ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
⁵⁸ Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
⁵⁹ Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, F-76000 Rouen, France.

PMID: 37379234
PMCID: PMC10708940
DOI: 10.1093/neuonc/noad114

Abstract

Background: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.

Methods: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated.

Results: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively).

Conclusions: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Keywords: Li–Fraumeni syndrome; TP53; medulloblastoma; survival.

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Conflict of interest statement

O.W. and T.M. received research funding from Biomed Valley and Day One Therapeutics. C.M.v.T. participated in advisory boards for Novartis, Alexion and Bayer. U. K. participated in advisory board for Novartis and GBT. S.R. participated in advisory boards for Bayer, BMS, Novartis, and Roche, and in a DMSC for Cellgene. M.A.K. received research funding from Y-mAbs Therapeutics. M.S. is scientific advisor and shareholder of C2i Genomics and Halo Dx and received research funding from Lilly USA.

Figures

**Figure 1:**
Characteristics of the Li–Fraumeni syndrome (LFS) medulloblastoma (MB) patient cohort. (A) Age distribution at MB diagnosis; (B) *TP53* constitutional variants in LFS MB patients; (C) *TP53* variant pathogenicity; (D) Somatic *TP53* mutational status in LFS-associated MB (LOH—loss of heterozygosity); (E) Origin of constitutional *TP53* variants in LFS MB patients; (F) t-SNE clustering of DNA methylation profiles of LFS MBs with a reference SHH-MB cohort; (G) LFS-associated MB subgroups classified based on DNA methylation profile.

**Figure 2:**
Survival of Li–Fraumeni syndrome (LFS) medulloblastoma (MB) patients: (A) Progression-free (PFS), event-free (EFS) and overall survival (OS) for LFS MB patients; (B) Impact of tumor resection radicality on survival of LFS MB patients (GTR—gross-total resection, STR—subtotal resection); (C) Impact of M-status on survival in LFS MB patients.

**Figure 3:**
Impact of treatment modalities on survival of Li-Fraumeni syndrome (LFS) medulloblastoma (MB) patients: (A) Impact of relative chemotherapy (CT) and radiotherapy (RT) timepoints on survival of LFS MB patients; (B) Impact of overall chemotherapy intensity on survival of LFS MB patients (HI—high-intensity, SI—standard-intensity); (C) Impact of overall chemotherapy intensity on survival of LFS MB patients with distinguished PNET HR+ protocol.

**Figure 4:**
Medulloblastoma (MB) recurrence pattern in Li-Fraumeni syndrome (LFS) patients: (A) Recurrence frequency; (B) Impact of metastasis (M)-status on recurrence frequency; (C) Recurrence pattern according to M-status; (D) Impact of radiation treatment (RT) on recurrence frequency; (E) Recurrence location in relation to the RT field; F: Impact of resection staging on recurrence frequency (GTR—gross-total resection, STR—subtotal resection).

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Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

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Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

Authors

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Abstract

Conflict of interest statement

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