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

In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameter...

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Veröffentlicht in:Journal of clinical oncology 2021-10, Vol.39 (30), p.3377-3390
Hauptverfasser: Bellini, Angela, Pötschger, Ulrike, Bernard, Virginie, Lapouble, Eve, Baulande, Sylvain, Ambros, Peter F, Auger, Nathalie, Beiske, Klaus, Bernkopf, Marie, Betts, David R, Bhalshankar, Jaydutt, Bown, Nick, de Preter, Katleen, Clément, Nathalie, Combaret, Valérie, Font de Mora, Jaime, George, Sally L, Jiménez, Irene, Jeison, Marta, Marques, Barbara, Martinsson, Tommy, Mazzocco, Katia, Morini, Martina, Mühlethaler-Mottet, Annick, Noguera, Rosa, Pierron, Gaelle, Rossing, Maria, Taschner-Mandl, Sabine, Van Roy, Nadine, Vicha, Ales, Chesler, Louis, Balwierz, Walentyna, Castel, Victoria, Elliott, Martin, Kogner, Per, Laureys, Geneviève, Luksch, Roberto, Malis, Josef, Popovic-Beck, Maja, Ash, Shifra, Delattre, Olivier, Valteau-Couanet, Dominique, Tweddle, Deborah A, Ladenstein, Ruth, Schleiermacher, Gudrun
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Sprache:eng
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Zusammenfassung:In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied 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 amplification status (n = 330), mutational profile (n = 191), or both (n = 571). Genomic amplification ( a) was detected in 4.5% of cases (41 out of 901), all except one with amplification (MNA). a was associated with a significantly poorer overall survival (OS) (5-year OS: a [n = 41] 28% [95% CI, 15 to 42]; no- a [n = 860] 51% [95% CI, 47 to 54], [ < .001]), particularly in cases with metastatic disease. mutations ( 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 m and MNA ( < .001). Among 571 cases with known a and m status, a statistically significant difference in OS was observed between cases with a or clonal m versus subclonal m or no alterations (5-year OS: a [n = 19], 26% [95% CI, 10 to 47], clonal m [n = 65] 33% [95% CI, 21 to 44], subclonal m (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; < .001), a (HR, 2.38; = .004), and clonal (HR, 1.77; = .001) were independent predictors of poor outcome. Genetic alterations of (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 alterations.
ISSN:0732-183X
1527-7755
1527-7755
DOI:10.1200/JCO.21.00086