Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)-Reference-Cited by-同舟云学术

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Published:2021-10-20 Issue:30 Volume:39 Page:3377-3390
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Bellini Angela¹²³,Pötschger Ulrike⁴⁵^ORCID,Bernard Virginie⁶,Lapouble Eve⁷^ORCID,Baulande Sylvain⁶^ORCID,Ambros Peter F.⁵^ORCID,Auger Nathalie⁸,Beiske Klaus⁹^ORCID,Bernkopf Marie⁵,Betts David R.¹⁰,Bhalshankar Jaydutt¹²³,Bown Nick¹¹,de Preter Katleen¹²,Clément Nathalie¹²³,Combaret Valérie¹³,Font de Mora Jaime¹⁴^ORCID,George Sally L.¹⁵^ORCID,Jiménez Irene¹²³,Jeison Marta¹⁶,Marques Barbara¹⁷,Martinsson Tommy¹⁸^ORCID,Mazzocco Katia¹⁹^ORCID,Morini Martina²⁰^ORCID,Mühlethaler-Mottet Annick²¹^ORCID,Noguera Rosa²²^ORCID,Pierron Gaelle⁷^ORCID,Rossing Maria²³,Taschner-Mandl Sabine⁵^ORCID,Van Roy Nadine¹²,Vicha Ales²⁴,Chesler Louis²⁵^ORCID,Balwierz Walentyna²⁶^ORCID,Castel Victoria²⁷^ORCID,Elliott Martin²⁸,Kogner Per²⁹^ORCID,Laureys Geneviève³⁰,Luksch Roberto³¹,Malis Josef²⁴,Popovic-Beck Maja³²^ORCID,Ash Shifra³³,Delattre Olivier²³⁶^ORCID,Valteau-Couanet Dominique³⁴,Tweddle Deborah A.³⁵^ORCID,Ladenstein Ruth³⁶³⁷^ORCID,Schleiermacher Gudrun¹²³^ORCID

Affiliation:

1. Equipe SiRIC RTOP Recherche Translationelle en Oncologie Pédiatrique, Institut Curie, Paris, France

2. INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France

3. SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France

4. Department for Studies and Statistics and Integrated Research, Vienna, Austria

5. St Anna Children's Cancer Research Institute, Vienna, Austria

6. Institut Curie Genomics of Excellence (ICGex) Platform, Research Center, Institut Curie, Paris, France

7. Unité de Génétique Somatique, Service de Génétique, Hospital Group, Institut Curie, Paris, France

8. Service de Génétique des tumeurs; Institut Gustave Roussy, Villejuif, France

9. Department of Pathology, Oslo University Hospital, and Medical Faculty, University of Oslo, Oslo, Norway

10. Department of Clinical Genetics, Children's Health Ireland at Crumlin, Dublin, Ireland

11. Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

12. Ghent University, Ghent, Belgium

13. Translational Research Laboratory, Centre Léon Bérard, Lyon, France

14. Instituto de Investigación Sanitaria La Fe, Valencia, Spain

15. Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom

16. Schneider Children's Medical Center of Israel, Tel Aviv University, Tel Aviv, Israel

17. Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal

18. Sahlgrenska University Hospital, Göteborg, Sweden

19. Department of Pathology, IRCCS Istituto Giannina Gaslini, Genova, Italy

20. Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Genova, Italy

21. Pediatric Hematology-Oncology Research Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

22. Department of Pathology, Medical School, University of Valencia-Incliva Health Research Institute/CIBERONC, Madrid, Spain

23. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

24. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

25. Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, United Kingdom

26. Department of Pediatric Oncology and Hematology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland

27. Clinical and Translational Oncology Research Group, Health Research Institute La Fe, Valencia, Spain

28. Leeds Children's Hospital, Leeds General Infirmary, Leeds, United Kingdom

29. Karolinska University Hospital, Stockholm, Sweden

30. Department of Paediatric Haematology and Oncology, Princess Elisabeth Children's Hospital, Ghent University Hospital, Ghent, Belgium

31. Paediatric Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy

32. Pediatric Hematology-Oncology Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

33. Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel

34. Département d'Oncologie Pédiatrique, Gustave Roussy, Villejuif, France

35. Wolfson Childhood Cancer Research Centre, Newcastle Centre for Cancer, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

36. Department for Studies and Statistics and Integrated Research, St Anna Children's Hospital, St Anna Children's Cancer Research Institute, Vienna, Austria

37. Department of Paediatrics, Medical University of Vienna, Vienna, Austria

Abstract

PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS Genomic ALK amplification ( ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no- ALKa [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA ( P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.21.00086

Reference55 articles.

1. Neuroblastoma

2. Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study

3. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial

4. Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1)

5. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial

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