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

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Date
2021-06-11ICR Author
Author
Bellini, A
Pötschger, U
Bernard, V
Lapouble, E
Baulande, S
Ambros, PF
Auger, N
Beiske, K
Bernkopf, M
Betts, DR
Bhalshankar, J
Bown, N
de Preter, K
Clément, N
Combaret, V
Font de Mora, J
George, SL
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, DA
Ladenstein, R
Schleiermacher, G
Type
Journal Article
Metadata
Show full item recordAbstract
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 ( ALK a) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALK a was associated with a significantly poorer overall survival (OS) (5-year OS: ALK a [n = 41] 28% [95% CI, 15 to 42]; no- ALK a [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALK m) 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 ALK m and MNA ( P < .001). Among 571 cases with known ALK a and ALK m status, a statistically significant difference in OS was observed between cases with ALK a or clonal ALK m versus subclonal ALK m or no ALK alterations (5-year OS: ALK a [n = 19], 26% [95% CI, 10 to 47], clonal ALK m [n = 65] 33% [95% CI, 21 to 44], subclonal ALK m (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), ALK a (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.
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Research team
Paediatric Solid Tumour Biology and Therapeutics
Paediatric Solid Tumour Biology and Therapeutics
Language
eng
Date accepted
2021-04-21
License start date
2021-06-11
Citation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021, pp. JCO2100086 - ?