Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome-Reference-Cited by-全球学者库

Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome

Published:2023-06-28 Issue:12 Volume:25 Page:2273-2286
ISSN:1522-8517
Container-title:Neuro-Oncology
language:en
Short-container-title:

Author:

Kolodziejczak Anna S¹²³^ORCID,Guerrini-Rousseau Lea⁴⁵,Planchon Julien Masliah⁶,Ecker Jonas¹²³⁷,Selt Florian¹²³⁷^ORCID,Mynarek Martin⁸⁹^ORCID,Obrecht Denise⁸,Sill Martin¹¹⁰^ORCID,Autry Robert J¹¹⁰,Stutheit-Zhao Eric¹¹⁰¹¹,Hirsch Steffen¹³¹⁰^ORCID,Amouyal Elsa¹²,Dufour Christelle⁴⁵,Ayrault Olivier¹³,Torrejon Jacob¹³,Waszak Sebastian M¹⁴¹⁵,Ramaswamy Vijay¹⁶¹⁷^ORCID,Pentikainen Virve¹⁸,Demir Haci Ahmet¹⁹,Clifford Steven C²⁰,Schwalbe Ed C²⁰²¹,Massimi Luca²²,Snuderl Matija²³,Galbraith Kristyn²³^ORCID,Karajannis Matthias A²⁴^ORCID,Hill Katherine²⁴,Li Bryan K²⁴,Walsh Mike²⁴,White Christine L²⁵²⁶²⁷,Redmond Shelagh²⁸,Loizos Loizou²⁹,Jakob Marcus³⁰,Kordes Uwe R⁸,Schmid Irene³¹,Hauer Julia³²,Blattmann Claudia³³,Filippidou Maria³⁴,Piccolo Gianluca³⁵,Scheurlen Wolfram³⁶,Farrag Ahmed³⁷³⁸,Grund Kerstin³⁹,Sutter Christian³⁹,Pietsch Torsten⁴⁰,Frank Stephan⁴¹,Schewe Denis M⁴²,Malkin David⁴³,Ben-Arush Myriam⁴⁴,Sehested Astrid⁴⁵,Wong Tai-Tong⁴⁶,Wu Kuo-Sheng⁴⁷,Liu Yen-Lin⁴⁸,Carceller Fernando⁴⁹,Mueller Sabine⁵⁰,Stoller Schuyler⁵¹^ORCID,Taylor Michael D¹⁶,Tabori Uri¹⁷^ORCID,Bouffet Eric¹⁷⁵²^ORCID,Kool Marcel¹¹⁰⁵³,Sahm Felix¹⁵⁴^ORCID,von Deimling Andreas⁵⁴,Korshunov Andrey⁵⁴,von Hoff Katja⁵⁵⁵⁶^ORCID,Kratz Christian P⁵⁷,Sturm Dominik¹⁷⁵⁸,Jones David T W¹⁵⁸,Rutkowski Stefan⁸,van Tilburg Cornelis M¹²³⁷,Witt Olaf¹²³⁷,Bougeard Gaëlle⁵⁹,Pajtler Kristian W¹³⁷¹⁰^ORCID,Pfister Stefan M¹³⁷¹⁰^ORCID,Bourdeaut Franck¹²^ORCID,Milde Till¹²³⁷^ORCID

Affiliation:

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

Abstract

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.

Funder

National Institutes of Health

National Cancer Institute Cancer Center

Research Council of Norway

University of Oslo

South-Eastern Norway Regional Health Authority

German Children Cancer Foundation

Deutsche Kinderkrebsstiftung

Friedberg Charitable Foundation

Making Headway Foundation

Publisher

Oxford University Press (OUP)