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

2021-06-11Journal article Open access
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dc.contributor.authorBellini, Angela
dc.contributor.authorPötschger, Ulrike
dc.contributor.authorBernard, Virginie
dc.contributor.authorLapouble, Eve
dc.contributor.authorBaulande, Sylvain
dc.contributor.authorAmbros, Peter F.
dc.contributor.authorAuger, Nathalie
dc.contributor.authorBeiske, Klaus
dc.contributor.authorBernkopf, Marie
dc.contributor.authorBetts, David R.
dc.contributor.authorBhalshankar, Jaydutt
dc.contributor.authorBown, Nick
dc.contributor.authorde Preter, Katleen
dc.contributor.authorClément, Nathalie
dc.contributor.authorCombaret, Valérie
dc.contributor.authorFont de Mora, Jaime
dc.contributor.authorGeorge, Sally L.
dc.contributor.authorJiménez, Irene
dc.contributor.authorJeison, Marta
dc.contributor.authorMarques, Barbara
dc.contributor.authorMartinsson, Tommy
dc.contributor.authorMazzocco, Katia
dc.contributor.authorMorini, Martina
dc.contributor.authorMühlethaler-Mottet, Annick
dc.contributor.authorNoguera, Rosa
dc.contributor.authorPierron, Gaelle
dc.contributor.authorRossing, Maria
dc.contributor.authorTaschner-Mandl, Sabine
dc.contributor.authorVan Roy, Nadine
dc.contributor.authorVicha, Ales
dc.contributor.authorChesler, Louis
dc.contributor.authorBalwierz, Walentyna
dc.contributor.authorCastel, Victoria
dc.contributor.authorElliott, Martin
dc.contributor.authorKogner, Per
dc.contributor.authorLaureys, Geneviève
dc.contributor.authorLuksch, Roberto
dc.contributor.authorMalis, Josef
dc.contributor.authorPopovic-Beck, Maja
dc.contributor.authorAsh, Shifra
dc.contributor.authorDelattre, Olivier
dc.contributor.authorValteau-Couanet, Dominique
dc.contributor.authorTweddle, Deborah A.
dc.contributor.authorLadenstein, Ruth
dc.contributor.authorSchleiermacher, Gudrun
dc.date.accessioned2022-02-04T17:35:31Z
dc.date.available2022-02-04T17:35:31Z
dc.date.issued2021-06-11
dc.description.abstractPurpose: 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.pt_PT
dc.description.abstractKey Objective: High risk neuroblastoma (HR-NB) is one of the most difficult childhood cancers to cure. This study examined whether the presence of an ALK alteration (amplification or mutation) was associated with a poor prognosis in a large patient series treated on the prospective European high-risk neuroblastoma trial (HR-NBL1). Knowledge Generated: We found that ALK amplification or clonal mutation was associated with inferior prognosis in patients with HR-NB and both are independent prognostic variables on multivariate analysis. To our knowledge, this is the first study to report the highly prognostic significance of ALK amplification in HR-NB. Relevance: As ALK can be targeted therapeutically, this study convincingly argues for the introduction of ALK inhibitors for upfront management of patients with HR-NB with ALK aberrations. Importantly, the prognostic significance of ALK alterations included a subgroup of trial patients treated with the current standard of care for HR-NB including anti-GD2 immunotherapy.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Clin Oncol. 2021 Oct 20;39(30):3377-3390. doi: 10.1200/JCO.21.00086. Epub 2021 Jun 11.pt_PT
dc.identifier.doi10.1200/JCO.21.00086pt_PT
dc.identifier.issn0732-183X
dc.identifier.urihttp://hdl.handle.net/10400.18/7937
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society of Clinical Oncologypt_PT
dc.relation.publisherversionhttps://ascopubs.org/doi/10.1200/JCO.21.00086pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNeuroblastomapt_PT
dc.subjectALKpt_PT
dc.subjectPrognostic Impactpt_PT
dc.subjectEuropean Neuroblastoma Study Grouppt_PT
dc.subjectSIOPENpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleFrequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage3390pt_PT
oaire.citation.issue30pt_PT
oaire.citation.startPage3377pt_PT
oaire.citation.titleJournal of Clinical Oncologypt_PT
oaire.citation.volume39pt_PT
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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