dc.contributor.author | Bellini, A | |
dc.contributor.author | Pötschger, U | |
dc.contributor.author | Bernard, V | |
dc.contributor.author | Lapouble, E | |
dc.contributor.author | Baulande, S | |
dc.contributor.author | Ambros, PF | |
dc.contributor.author | Auger, N | |
dc.contributor.author | Beiske, K | |
dc.contributor.author | Bernkopf, M | |
dc.contributor.author | Betts, DR | |
dc.contributor.author | Bhalshankar, J | |
dc.contributor.author | Bown, N | |
dc.contributor.author | de Preter, K | |
dc.contributor.author | Clément, N | |
dc.contributor.author | Combaret, V | |
dc.contributor.author | Font de Mora, J | |
dc.contributor.author | George, SL | |
dc.contributor.author | Jiménez, I | |
dc.contributor.author | Jeison, M | |
dc.contributor.author | Marques, B | |
dc.contributor.author | Martinsson, T | |
dc.contributor.author | Mazzocco, K | |
dc.contributor.author | Morini, M | |
dc.contributor.author | Mühlethaler-Mottet, A | |
dc.contributor.author | Noguera, R | |
dc.contributor.author | Pierron, G | |
dc.contributor.author | Rossing, M | |
dc.contributor.author | Taschner-Mandl, S | |
dc.contributor.author | Van Roy, N | |
dc.contributor.author | Vicha, A | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Balwierz, W | |
dc.contributor.author | Castel, V | |
dc.contributor.author | Elliott, M | |
dc.contributor.author | Kogner, P | |
dc.contributor.author | Laureys, G | |
dc.contributor.author | Luksch, R | |
dc.contributor.author | Malis, J | |
dc.contributor.author | Popovic-Beck, M | |
dc.contributor.author | Ash, S | |
dc.contributor.author | Delattre, O | |
dc.contributor.author | Valteau-Couanet, D | |
dc.contributor.author | Tweddle, DA | |
dc.contributor.author | Ladenstein, R | |
dc.contributor.author | Schleiermacher, G | |
dc.date.accessioned | 2021-09-07T08:33:02Z | |
dc.date.available | 2021-09-07T08:33:02Z | |
dc.date.issued | 2021-10-20 | |
dc.identifier.citation | Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021, pp. JCO2100086 - ? | |
dc.identifier.issn | 0732-183X | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4795 | |
dc.identifier.eissn | 1527-7755 | |
dc.identifier.doi | 10.1200/jco.21.00086 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | JCO2100086 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | LIPPINCOTT WILLIAMS & WILKINS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-04-21 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1200/jco.21.00086 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-06-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.publication-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
dc.contributor.icrauthor | George, Sally | |
dc.contributor.icrauthor | Chesler, Louis | |