Autor: Kogner, Per - Prolib Integro

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Tytuł:: Frequency and prognostic impact of ALK amplifications and mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)
Autorzy:: Popovic-Beck, Maja
Bown, Nick
Font de Mora, Jaime
Noguera, Rosa
Taschner-Mandl, Sabine
Muhlethaler-Mottet, Annick
Laureys, Genevieve
Malis, Josef
Pierron, Gaelle
Kogner, Per
Rossing, Maria
Combaret, Valerie
Chesler, Louis
Castel, Victoria
Luksch, Roberto
Tweddle, Deborah A.
Bellini, Angela
de Preter, Katleen
Ladenstein, Ruth
George, Sally L.
Ambros, Peter F.
Baulande, Sylvain
Beiske, Klaus
Marques, Barbara
Ash, Shifra
Clement, Nathalie
van Roy, Nadine
Valteau-Couanet, Dominique
Balwierz, Walentyna
Schleiermacher, Gudrun
Martinsson, Tommy
Vicha, Ales
Delattre, Olivier
Auger, Nathalie
Jeison, Marta
Morini, Martina
Betts, David R.
Bhalshankar, Jaydutt
Lapouble, Eve
Elliott, Martin
Bernkopf, Marie
Mazzocco, Katia
Potschger, Ulrike
Bernard, Virginie
Jimenez, Irene
Opis:: 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.
Dostawca treści:: Repozytorium Uniwersytetu Jagiellońskiego

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