Angela Bellini1,2,3, Ulrike Pötschger4,5, Virginie Bernard6, Eve Lapouble7, Sylvain Baulande6, Peter F Ambros5, Nathalie Auger8, Klaus Beiske9, Marie Bernkopf5, David R Betts10, Jaydutt Bhalshankar1,2,3, Nick Bown11, Katleen de Preter12, Nathalie Clément1,2,3, Valérie Combaret13, Jaime Font de Mora14, Sally L George15, Irene Jiménez1,2,3, Marta Jeison16, Barbara Marques17, Tommy Martinsson18, Katia Mazzocco19, Martina Morini20, Annick Mühlethaler-Mottet21, Rosa Noguera22, Gaelle Pierron7, Maria Rossing23, Sabine Taschner-Mandl5, Nadine Van Roy12, Ales Vicha24, Louis Chesler25, Walentyna Balwierz26, Victoria Castel27, Martin Elliott28, Per Kogner29, Geneviève Laureys30, Roberto Luksch31, Josef Malis24, Maja Popovic-Beck32, Shifra Ash33, Olivier Delattre2,3,6, Dominique Valteau-Couanet34, Deborah A Tweddle35, Ruth Ladenstein36,37, Gudrun Schleiermacher1,2,3. 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.
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.
Authors: Navin Pinto; Arlene Naranjo; Emily Hibbitts; Susan G Kreissman; M Meaghan Granger; Meredith S Irwin; Rochelle Bagatell; Wendy B London; Emily G Greengard; Julie R Park; Steven G DuBois Journal: Eur J Cancer Date: 2019-04-01 Impact factor: 9.162
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