Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group

Inge M Ambros; Gian-Paolo Tonini; Ulrike Pötschger; Nicole Gross; Véronique Mosseri; Klaus Beiske; Ana P Berbegall; Jean Bénard; Nick Bown; Huib Caron; Valérie Combaret; Jerome Couturier; Raffaella Defferrari; Olivier Delattre; Marta Jeison; Per Kogner; John Lunec; Barbara Marques; Tommy Martinsson; Katia Mazzocco; Rosa Noguera; Gudrun Schleiermacher; Alexander Valent; Nadine Van Roy; Eva Villamon; Dasa Janousek; Ingrid Pribill; Evgenia Glogova; Edward F Attiyeh; Michael D Hogarty; Tom F Monclair; Keith Holmes; Dominique Valteau-Couanet; Victoria Castel; Deborah A Tweddle; Julie R Park; Sue Cohn; Ruth Ladenstein; Maja Beck-Popovic; Bruno De Bernardi; Jean Michon; Andrew D J Pearson; Peter F Ambros

doi:10.1200/JCO.18.02132

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group

Inge M Ambros, Gian-Paolo Tonini, Ulrike Pötschger, Nicole Gross, Véronique Mosseri, Klaus Beiske, Ana P Berbegall, Jean Bénard, Nick Bown, Huib Caron, Valérie Combaret, Jerome Couturier, Raffaella Defferrari, Olivier Delattre, Marta Jeison, Per Kogner, John Lunec, Barbara Marques, Tommy Martinsson, Katia MazzoccoRosa Noguera, Gudrun Schleiermacher, Alexander Valent, Nadine Van Roy, Eva Villamon, Dasa Janousek, Ingrid Pribill, Evgenia Glogova, Edward F Attiyeh, Michael D Hogarty, Tom F Monclair, Keith Holmes, Dominique Valteau-Couanet, Victoria Castel, Deborah A Tweddle, Julie R Park, Sue Cohn, Ruth Ladenstein, Maja Beck-Popovic, Bruno De Bernardi, Jean Michon, Andrew D J Pearson, Peter F Ambros

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.

RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038).

CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.

Original language	English
Pages (from-to)	3685-3697
Number of pages	13
Journal	Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume	38
Issue number	31
DOIs	https://doi.org/10.1200/JCO.18.02132
Publication status	Published - Nov 1 2020

Keywords

Age Factors
Chromosome Aberrations
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 11
Clinical Trials as Topic
Diploidy
Gene Amplification
Genomics
Humans
Infant
N-Myc Proto-Oncogene Protein/genetics
Neoplasm Staging
Neuroblastoma/genetics
Prognosis
Progression-Free Survival
Survival Rate

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Ambros, I. M., Tonini, G-P., Pötschger, U., Gross, N., Mosseri, V., Beiske, K., Berbegall, A. P., Bénard, J., Bown, N., Caron, H., Combaret, V., Couturier, J., Defferrari, R., Delattre, O., Jeison, M., Kogner, P., Lunec, J., Marques, B., Martinsson, T., ... Ambros, P. F. (2020). Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(31), 3685-3697. https://doi.org/10.1200/JCO.18.02132

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group. / Ambros, Inge M; Tonini, Gian-Paolo; Pötschger, Ulrike; Gross, Nicole; Mosseri, Véronique; Beiske, Klaus; Berbegall, Ana P; Bénard, Jean; Bown, Nick; Caron, Huib; Combaret, Valérie; Couturier, Jerome; Defferrari, Raffaella; Delattre, Olivier; Jeison, Marta; Kogner, Per; Lunec, John; Marques, Barbara; Martinsson, Tommy; Mazzocco, Katia; Noguera, Rosa; Schleiermacher, Gudrun; Valent, Alexander; Van Roy, Nadine; Villamon, Eva; Janousek, Dasa; Pribill, Ingrid; Glogova, Evgenia; Attiyeh, Edward F; Hogarty, Michael D; Monclair, Tom F; Holmes, Keith; Valteau-Couanet, Dominique; Castel, Victoria; Tweddle, Deborah A; Park, Julie R; Cohn, Sue; Ladenstein, Ruth; Beck-Popovic, Maja; De Bernardi, Bruno; Michon, Jean; Pearson, Andrew D J; Ambros, Peter F.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 38, No. 31, 01.11.2020, p. 3685-3697.

Research output: Contribution to journal › Article › peer-review

Ambros, IM, Tonini, G-P, Pötschger, U, Gross, N, Mosseri, V, Beiske, K, Berbegall, AP, Bénard, J, Bown, N, Caron, H, Combaret, V, Couturier, J, Defferrari, R, Delattre, O, Jeison, M, Kogner, P, Lunec, J, Marques, B, Martinsson, T, Mazzocco, K, Noguera, R, Schleiermacher, G, Valent, A, Van Roy, N, Villamon, E, Janousek, D, Pribill, I, Glogova, E, Attiyeh, EF, Hogarty, MD, Monclair, TF, Holmes, K, Valteau-Couanet, D, Castel, V, Tweddle, DA, Park, JR, Cohn, S, Ladenstein, R, Beck-Popovic, M, De Bernardi, B, Michon, J, Pearson, ADJ & Ambros, PF 2020, 'Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 38, no. 31, pp. 3685-3697. https://doi.org/10.1200/JCO.18.02132

Ambros IM, Tonini G-P, Pötschger U, Gross N, Mosseri V, Beiske K et al. Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 Nov 1;38(31):3685-3697. https://doi.org/10.1200/JCO.18.02132

Ambros, Inge M ; Tonini, Gian-Paolo ; Pötschger, Ulrike ; Gross, Nicole ; Mosseri, Véronique ; Beiske, Klaus ; Berbegall, Ana P ; Bénard, Jean ; Bown, Nick ; Caron, Huib ; Combaret, Valérie ; Couturier, Jerome ; Defferrari, Raffaella ; Delattre, Olivier ; Jeison, Marta ; Kogner, Per ; Lunec, John ; Marques, Barbara ; Martinsson, Tommy ; Mazzocco, Katia ; Noguera, Rosa ; Schleiermacher, Gudrun ; Valent, Alexander ; Van Roy, Nadine ; Villamon, Eva ; Janousek, Dasa ; Pribill, Ingrid ; Glogova, Evgenia ; Attiyeh, Edward F ; Hogarty, Michael D ; Monclair, Tom F ; Holmes, Keith ; Valteau-Couanet, Dominique ; Castel, Victoria ; Tweddle, Deborah A ; Park, Julie R ; Cohn, Sue ; Ladenstein, Ruth ; Beck-Popovic, Maja ; De Bernardi, Bruno ; Michon, Jean ; Pearson, Andrew D J ; Ambros, Peter F. / Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 ; Vol. 38, No. 31. pp. 3685-3697.

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title = "Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group",

abstract = "PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038).CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.",

keywords = "Age Factors, Chromosome Aberrations, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 11, Clinical Trials as Topic, Diploidy, Gene Amplification, Genomics, Humans, Infant, N-Myc Proto-Oncogene Protein/genetics, Neoplasm Staging, Neuroblastoma/genetics, Prognosis, Progression-Free Survival, Survival Rate",

author = "Ambros, {Inge M} and Gian-Paolo Tonini and Ulrike P{\"o}tschger and Nicole Gross and V{\'e}ronique Mosseri and Klaus Beiske and Berbegall, {Ana P} and Jean B{\'e}nard and Nick Bown and Huib Caron and Val{\'e}rie Combaret and Jerome Couturier and Raffaella Defferrari and Olivier Delattre and Marta Jeison and Per Kogner and John Lunec and Barbara Marques and Tommy Martinsson and Katia Mazzocco and Rosa Noguera and Gudrun Schleiermacher and Alexander Valent and {Van Roy}, Nadine and Eva Villamon and Dasa Janousek and Ingrid Pribill and Evgenia Glogova and Attiyeh, {Edward F} and Hogarty, {Michael D} and Monclair, {Tom F} and Keith Holmes and Dominique Valteau-Couanet and Victoria Castel and Tweddle, {Deborah A} and Park, {Julie R} and Sue Cohn and Ruth Ladenstein and Maja Beck-Popovic and {De Bernardi}, Bruno and Jean Michon and Pearson, {Andrew D J} and Ambros, {Peter F}",

year = "2020",

month = nov,

day = "1",

doi = "10.1200/JCO.18.02132",

language = "English",

volume = "38",

pages = "3685--3697",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

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TY - JOUR

T1 - Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group

AU - Ambros, Inge M

AU - Tonini, Gian-Paolo

AU - Pötschger, Ulrike

AU - Gross, Nicole

AU - Mosseri, Véronique

AU - Beiske, Klaus

AU - Berbegall, Ana P

AU - Bénard, Jean

AU - Bown, Nick

AU - Caron, Huib

AU - Combaret, Valérie

AU - Couturier, Jerome

AU - Defferrari, Raffaella

AU - Delattre, Olivier

AU - Jeison, Marta

AU - Kogner, Per

AU - Lunec, John

AU - Marques, Barbara

AU - Martinsson, Tommy

AU - Mazzocco, Katia

AU - Noguera, Rosa

AU - Schleiermacher, Gudrun

AU - Valent, Alexander

AU - Van Roy, Nadine

AU - Villamon, Eva

AU - Janousek, Dasa

AU - Pribill, Ingrid

AU - Glogova, Evgenia

AU - Attiyeh, Edward F

AU - Hogarty, Michael D

AU - Monclair, Tom F

AU - Holmes, Keith

AU - Valteau-Couanet, Dominique

AU - Castel, Victoria

AU - Tweddle, Deborah A

AU - Park, Julie R

AU - Cohn, Sue

AU - Ladenstein, Ruth

AU - Beck-Popovic, Maja

AU - De Bernardi, Bruno

AU - Michon, Jean

AU - Pearson, Andrew D J

AU - Ambros, Peter F

PY - 2020/11/1

Y1 - 2020/11/1

N2 - PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038).CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.

AB - PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038).CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.

KW - Age Factors

KW - Chromosome Aberrations

KW - Chromosomes, Human, Pair 1

KW - Chromosomes, Human, Pair 11

KW - Clinical Trials as Topic

KW - Diploidy

KW - Gene Amplification

KW - Genomics

KW - Humans

KW - Infant

KW - N-Myc Proto-Oncogene Protein/genetics

KW - Neoplasm Staging

KW - Neuroblastoma/genetics

KW - Prognosis

KW - Progression-Free Survival

KW - Survival Rate

U2 - 10.1200/JCO.18.02132

DO - 10.1200/JCO.18.02132

M3 - Article

C2 - 32903140

VL - 38

SP - 3685

EP - 3697

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 31

ER -