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

Angela Bellini; Ulrike Pötschger; Virginie Bernard; Eve Lapouble; Sylvain Baulande; Peter F Ambros; Nathalie Auger; Klaus Beiske; Marie Bernkopf; David R Betts; Jaydutt Bhalshankar; Nick Bown; Katleen de Preter; Nathalie Clément; Valérie Combaret; Jaime Font de Mora; Sally L George; Irene Jiménez; Marta Jeison; Barbara Marques; Tommy Martinsson; Katia Mazzocco; Martina Morini; Annick Mühlethaler-Mottet; Rosa Noguera; Gaelle Pierron; Maria Rossing; Sabine Taschner-Mandl; Nadine Van Roy; Ales Vicha; Louis Chesler; Walentyna Balwierz; Victoria Castel; Martin Elliott; Per Kogner; Geneviève Laureys; Roberto Luksch; Josef Malis; Maja Popovic-Beck; Shifra Ash; Olivier Delattre; Dominique Valteau-Couanet; Deborah A Tweddle; Ruth Ladenstein; Gudrun Schleiermacher

doi:10.1200/JCO.21.00086

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

Angela Bellini, Ulrike Pötschger, Virginie Bernard, Eve Lapouble, Sylvain Baulande, Peter F Ambros, Nathalie Auger, Klaus Beiske, Marie Bernkopf, David R Betts, Jaydutt Bhalshankar, Nick Bown, Katleen de Preter, Nathalie Clément, Valérie Combaret, Jaime Font de Mora, Sally L George, Irene Jiménez, Marta Jeison, Barbara MarquesTommy Martinsson, Katia Mazzocco, Martina Morini, Annick Mühlethaler-Mottet, Rosa Noguera, Gaelle Pierron, Maria Rossing, Sabine Taschner-Mandl, Nadine Van Roy, Ales Vicha, Louis Chesler, Walentyna Balwierz, Victoria Castel, Martin Elliott, Per Kogner, Geneviève Laureys, Roberto Luksch, Josef Malis, Maja Popovic-Beck, Shifra Ash, Olivier Delattre, Dominique Valteau-Couanet, Deborah A Tweddle, Ruth Ladenstein, Gudrun Schleiermacher

Department of Genomic Medicine

68 Citations (Scopus)

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.

Original language	English
Journal	Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume	39
Issue number	30
Pages (from-to)	3377-3390
Number of pages	14
ISSN	0732-183X
DOIs	https://doi.org/10.1200/JCO.21.00086
Publication status	Published - 20 Oct 2021

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

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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., ... Schleiermacher, G. (2021). Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 39(30), 3377-3390. https://doi.org/10.1200/JCO.21.00086

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). / Bellini, Angela; Pötschger, Ulrike; Bernard, Virginie et al.
In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 39, No. 30, 20.10.2021, p. 3377-3390.

Research output: Contribution to journal › Journal article › Research › peer-review

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 2021, 'Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 39, no. 30, pp. 3377-3390. https://doi.org/10.1200/JCO.21.00086

Bellini A, Pötschger U, Bernard V, Lapouble E, Baulande S, Ambros PF et al. Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021 Oct 20;39(30):3377-3390. doi: 10.1200/JCO.21.00086

@article{ed3422a60ae044c48ddbd73917700878,

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

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.",

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",

author = "Angela Bellini and Ulrike P{\"o}tschger and Virginie Bernard and Eve Lapouble and Sylvain Baulande and Ambros, \{Peter F\} and Nathalie Auger and Klaus Beiske and Marie Bernkopf and Betts, \{David R\} and Jaydutt Bhalshankar and Nick Bown and \{de Preter\}, Katleen and Nathalie Cl{\'e}ment and Val{\'e}rie Combaret and \{Font de Mora\}, Jaime and George, \{Sally L\} and Irene Jim{\'e}nez and Marta Jeison and Barbara Marques and Tommy Martinsson and Katia Mazzocco and Martina Morini and Annick M{\"u}hlethaler-Mottet and Rosa Noguera and Gaelle Pierron and Maria Rossing and Sabine Taschner-Mandl and \{Van Roy\}, Nadine and Ales Vicha and Louis Chesler and Walentyna Balwierz and Victoria Castel and Martin Elliott and Per Kogner and Genevi{\`e}ve Laureys and Roberto Luksch and Josef Malis and Maja Popovic-Beck and Shifra Ash and Olivier Delattre and Dominique Valteau-Couanet and Tweddle, \{Deborah A\} and Ruth Ladenstein and Gudrun Schleiermacher",

year = "2021",

month = oct,

day = "20",

doi = "10.1200/JCO.21.00086",

language = "English",

volume = "39",

pages = "3377--3390",

journal = "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",

issn = "0732-183X",

publisher = "Lippincott Williams and Wilkins",

number = "30",

}

TY - JOUR

T1 - Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

AU - Bellini, Angela

AU - Pötschger, Ulrike

AU - Bernard, Virginie

AU - Lapouble, Eve

AU - Baulande, Sylvain

AU - Ambros, Peter F

AU - Auger, Nathalie

AU - Beiske, Klaus

AU - Bernkopf, Marie

AU - Betts, David R

AU - Bhalshankar, Jaydutt

AU - Bown, Nick

AU - de Preter, Katleen

AU - Clément, Nathalie

AU - Combaret, Valérie

AU - Font de Mora, Jaime

AU - George, Sally L

AU - Jiménez, Irene

AU - Jeison, Marta

AU - Marques, Barbara

AU - Martinsson, Tommy

AU - Mazzocco, Katia

AU - Morini, Martina

AU - Mühlethaler-Mottet, Annick

AU - Noguera, Rosa

AU - Pierron, Gaelle

AU - Rossing, Maria

AU - Taschner-Mandl, Sabine

AU - Van Roy, Nadine

AU - Vicha, Ales

AU - Chesler, Louis

AU - Balwierz, Walentyna

AU - Castel, Victoria

AU - Elliott, Martin

AU - Kogner, Per

AU - Laureys, Geneviève

AU - Luksch, Roberto

AU - Malis, Josef

AU - Popovic-Beck, Maja

AU - Ash, Shifra

AU - Delattre, Olivier

AU - Valteau-Couanet, Dominique

AU - Tweddle, Deborah A

AU - Ladenstein, Ruth

AU - Schleiermacher, Gudrun

PY - 2021/10/20

Y1 - 2021/10/20

N2 - 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.

AB - 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.

KW - Anaplastic Lymphoma Kinase/genetics

KW - Child, Preschool

KW - Clinical Trials, Phase III as Topic

KW - Europe

KW - Female

KW - Follow-Up Studies

KW - Gene Amplification

KW - Humans

KW - Infant

KW - Male

KW - Mutation Rate

KW - N-Myc Proto-Oncogene Protein/genetics

KW - Neuroblastoma/genetics

KW - Prognosis

KW - Randomized Controlled Trials as Topic

KW - Risk Factors

KW - Survival Rate

UR - https://www.scopus.com/pages/publications/85116378004

U2 - 10.1200/JCO.21.00086

DO - 10.1200/JCO.21.00086

M3 - Journal article

C2 - 34115544

SN - 0732-183X

VL - 39

SP - 3377

EP - 3390

JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

IS - 30

ER -

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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