Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

Author:

Nobre Liana1,Zapotocky Michal12,Ramaswamy Vijay134,Ryall Scott1,Bennett Julie1,Alderete Daniel5,Balaguer Guill Julia6,Baroni Lorena5,Bartels Ute1,Bavle Abhishek7,Bornhorst Miriam8,Boue Daniel R.9,Canete Adela6,Chintagumpala Murali10,Coven Scott L.11,Cruz Ofelia12,Dahiya Sonika13,Dirks Peter1415,Dunkel Ira J.16,Eisenstat David17,Faure Conter Cecile18,Finch Elizabeth19,Finlay Jonathan L.9,Frappaz Didier18,Garre Maria Luisa20,Gauvain Karen13,Bechensteen Anne Grete21,Hansford Jordan R.22,Harting Inga23,Hauser Peter24,Hazrati Lili-Naz25,Huang Annie114,Injac Sarah G.10,Iurilli Valentina20,Karajannis Matthias16,Kaur Gurcharanjeet16,Kyncl Martin2,Krskova Lenka2,Laperriere Normand1,Larouche Valerie26,Lassaletta Alvaro27,Leary Sarah28,Lin Frank10,Mascelli Samantha20,McKeown Tara1,Milde Till23,Morales La Madrid Andres12,Morana Giovanni20,Morse Helena29,Mushtaq Naureen30,Osorio Diana S.9,Packer Roger8,Pavelka Zdenek31,Quiroga-Cantero Eduardo32,Rutka James1415,Sabel Magnus33,Salgado Duarte34,Solano Palma32,Sterba Jaroslav31,Su Jack10,Sumerauer David2,Taylor Michael D.314152535,Toledano Helen36,Tsang Derek S.1,Valente Fernandes Mariana34,van Landeghem Frank17,van Tilburg Cornelis M.23,Wilson Bev17,Witt Olaf23,Zamecnik Josef2,Bouffet Eric1,Hawkins Cynthia142537,Tabori Uri114

Affiliation:

1. Department of Hematology and Oncology, Hospital for Sick Children, Toronto, ON, Canada

2. Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

3. Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada

4. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

5. Hospital of Pediatrics SAMIC Prof. Dr Juan P. Garrahan, Buenos Aires, Argentina

6. Hospital Universitario y Politecnico La Fe, University of Valencia, Valencia, Spain

7. Jimmy Everest Section of Pediatric Heamatology/Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

8. Children’s National Health System, Washington, DC

9. Nationwide Children’s Hospital and Ohio State University, Columbus, OH

10. Texas Children’s Cancer Center, Houston, TX

11. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Indiana University, Indianapolis, IN

12. Hospital Sant Joan de Déu, Barcelona, Spain

13. Washington University School of Medicine, St Louis, MO

14. Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada

15. Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada

16. Memorial Sloan Kettering Cancer Center, New York, NY

17. Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada

18. Institute d’Hémato-Oncologie Pédiatrique, Centre Leon Berard, Lyon, France

19. University of North Carolina at Chapel Hill, Chapel Hill, NC

20. G. Gaslini Children’s Hospital, Genoa, Italy

21. Oslo University Hospital, Oslo, Norway

22. Royal Children’s Hospital, Murdoch Children’s Research Institute, University of Melbourne, Melbourne, VIC, Australia

23. Hopp Children’s Cancer Center Heidelberg, Heidelberg, Germany

24. Semmelweis University, Budapest, Hungary

25. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

26. Universite Laval, Quebec City, QC, Canada

27. Hospital Infantil Universitario Niño Jesús, Madrid, Spain

28. Seattle Children’s Hospital, Seattle, WA

29. Lund University, Lund, Sweden

30. Aga Khan University Hospital, Karachi, Pakistan

31. University Hospital Brno, Masaryk University, and ICRC Brno, Brno, Czech Republic

32. Hospital Infantil Virgen del Rocío, Sevilla, Spain

33. Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden

34. Portuguese Oncology Institute, Lisbon, Portugal

35. Department of Surgery, University of Ontario, Toronto, ON, Canada

36. Schneiders Children’s Medical Center of Israel, Petah Tikva, Israel

37. Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada

Abstract

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Cited by 89 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3