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

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State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_69028FD04004
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).
Journal
Journal of clinical oncology
Author(s)
Bellini A., Pötschger U., Bernard V., Lapouble E., Baulande S., Ambros P.F., Auger N., Beiske K., Bernkopf M., Betts D.R., Bhalshankar J., Bown N., de Preter K., Clément N., Combaret V., Font de Mora J., George S.L., Jiménez I., Jeison M., Marques B., Martinsson T., Mazzocco K., Morini M., Mühlethaler-Mottet A., Noguera R., Pierron G., Rossing M., Taschner-Mandl S., Van Roy N., Vicha A., Chesler L., Balwierz W., Castel V., Elliott M., Kogner P., Laureys G., Luksch R., Malis J., Popovic-Beck M., Ash S., Delattre O., Valteau-Couanet D., Tweddle D.A., Ladenstein R., Schleiermacher G.
ISSN
1527-7755 (Electronic)
ISSN-L
0732-183X
Publication state
Published
Issued date
20/10/2021
Peer-reviewed
Oui
Volume
39
Number
30
Pages
3377-3390
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
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).
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.
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.
Keywords
Anaplastic Lymphoma Kinase/genetics, Child, Preschool, Clinical Trials, Phase III as Topic, Europe, Female, Follow-Up Studies, Gene Amplification, Humans, Infant, Male, Mutation Rate, N-Myc Proto-Oncogene Protein/genetics, Neuroblastoma/genetics, Prognosis, Randomized Controlled Trials as Topic, Risk Factors, Survival Rate
Pubmed
Open Access
Yes
Create date
14/06/2021 16:06
Last modification date
23/12/2021 6:34
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