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

Fecha de publicación: 20/10/2021 Fecha Ahead of Print: 11/06/2021

Autores de INCLIVA

Rosa Noguera Salva

Autor

Participantes ajenos a INCLIVA

Bellini, Angela
Potschger, 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
Clement, Nathalie
Combaret, Valerie
Font de Mora, Jaime
George, Sally L
Jimenez, Irene
Jeison, Marta
Marques, Barbara
Martinsson, Tommy
Mazzocco, Katia
Morini, Martina
Muhlethaler-Mottet, Annick
Pierron, Gaelle
Rossing, Maria
Taschner-Mandl, Sabine
Van Roy, Nadine
Vicha, Ales
Chesler, Louis
Balwierz, Walentyna
Castel, Victoria
Elliott, Martin
Kogner, Per
Laureys, Genevieve
Luksch, Roberto
Malis, Josef
Popovic-Beck, Maja
Ash, Shifra
Delattre, Olivier
Valteau-Couanet, Dominique
Tweddle, Deborah A
Ladenstein, Ruth
Schleiermacher, Gudrun

Grupos y Plataformas de I+D+i

Grupo de Investigación Translacional de Tumores Sólidos Pediátricos

Leading Researcher

Samuel Navarro Fos

Abstract

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.