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

被引：45

作者：

Bellini, Angela ^{[1
,2
,3
]}

Poetschger, Ulrike ^{[4
,5
]}

Bernard, Virginie ^{[6
]}

Lapouble, Eve ^{[7
]}

Baulande, Sylvain ^{[6
]}

Ambros, Peter F. ^{[5
]}

Auger, Nathalie ^{[8
,9
]}

Beiske, Klaus ^{[10
,11
]}

Bernkopf, Marie ^{[5
]}

Betts, David R. ^{[12
]}

Bhalshankar, Jaydutt ^{[1
,2
,3
]}

Bown, Nick ^{[13
]}

de Preter, Katleen ^{[14
]}

Clement, Nathalie ^{[1
,2
,3
]}

Combaret, Valerie ^{[15
]}

de Mora, Jaime Font ^{[16
]}

George, Sally L. ^{[17
]}

Jimenez, Irene ^{[1
,2
,3
]}

Jeison, Marta ^{[18
]}

Marques, Barbara ^{[19
]}

Martinsson, Tommy ^{[20
]}

Mazzocco, Katia ^{[21
]}

Morini, Martina ^{[22
]}

Muehlethaler-Mottet, Annick ^{[23
,24
]}

Noguera, Rosa ^{[25
]}

Pierron, Gaelle ^{[7
]}

Rossing, Maria ^{[26
]}

Taschner-Mandl, Sabine ^{[5
]}

Van Roy, Nadine ^{[14
]}

Vicha, Ales ^{[27
,28
]}

Chesler, Louis ^{[29
]}

Balwierz, Walentyna ^{[30
]}

Castel, Victoria ^{[31
]}

Elliott, Martin ^{[32
]}

Kogner, Per ^{[33
]}

Laureys, Genevieve ^{[34
]}

Luksch, Roberto ^{[35
]}

Malis, Josef ^{[27
,28
]}

Popovic-Beck, Maja ^{[24
,36
]}

Ash, Shifra ^{[37
]}

Delattre, Olivier ^{[2
,3
,6
]}

Valteau-Couanet, Dominique ^{[38
]}

Tweddle, Deborah A. ^{[39
]}

Ladenstein, Ruth ^{[40
,41
]}

Schleiermacher, Gudrun ^{[1
,2
,3
]}

机构：

[1] Inst Curie, Equipe SiR RTOP Rech Translat Oncol Pediat, Paris, France

[2] Inst Curie, Lab Genet & Biol Canc, INSERM U830, Paris, France

[3] Inst Curie, SIREDO Care Innovat & Res Children Adolescents &, Paris, France

[4] Dept Studies & Stat & Integrated Res, Vienna, Austria

[5] St Anna Childrens Canc Res Inst, Vienna, Austria

[6] Inst Curie, Inst Curie Genom Excellence ICGex Platform, Res Ctr, Paris, France

[7] Inst Curie, Hosp Grp, Serv Genet, Unite Genet Somat, Paris, France

[8] Serv Genet Tumeurs, Villejuif, France

[9] Inst Gustave Roussy, Villejuif, France

[10] Univ Oslo, Oslo Univ Hosp, Dept Pathol, Oslo, Norway

[11] Univ Oslo, Med Fac, Oslo, Norway

[12] Childrens Hlth Ireland Crumlin, Dept Clin Genet, Dublin, Ireland

[13] Newcastle upon Tyne Hosp NHS Fdn Trust, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England

[14] Univ Ghent, Ghent, Belgium

[15] Ctr Leon Berard, Translat Res Lab, Lyon, France

[16] Inst Invest Sanitaria La Fe, Valencia, Spain

[17] Inst Canc Res, Div Clin Studies, London, England

[18] Tel Aviv Univ, Schneider Childrens Med Ctr Israel, Tel Aviv, Israel

[19] Inst Nacl Saude Doutor Ricardo Jorge, Dept Genet Humana, Lisbon, Portugal

[20] Sahlgrens Univ Hosp, Gothenburg, Sweden

[21] IRCCS Ist Giannina Gaslini, Dept Pathol, Genoa, Italy

[22] IRCCS Ist Giannina Gaslini, Lab Mol Biol, Genoa, Italy

[23] Lausanne Univ Hosp, Pediat Hematol Oncol Res Lab, Lausanne, Switzerland

[24] Univ Lausanne, Lausanne, Switzerland

[25] Univ Valencia, Med Sch, Dept Pathol, Incl Hlth Res Inst CIBERONC, Madrid, Spain

[26] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark

[27] Charles Univ Prague, Fac Med 2, Dept Paediat Haematol & Oncol, Prague, Czech Republic

[28] Univ Hosp Motol, Prague, Czech Republic

[29] Inst Canc Res, Div Clin Studies, Paediat Tumour Biol, Sutton, Surrey, England

[30] Jagiellonian Univ Med Coll, Inst Pediat, Dept Pediat Oncol & Hematol, Krakow, Poland

[31] Hlth Res Inst La Fe, Clin & Translat Oncol Res Grp, Valencia, Spain

[32] Leeds Childrens Hosp, Leeds Gen Infirm, Leeds, W Yorkshire, England

[33] Karolinska Univ Hosp, Stockholm, Sweden

[34] Ghent Univ Hosp, Princess Elisabeth Childrens Hosp, Dept Paediat Haematol & Oncol, Ghent, Belgium

[35] Ist Nazl Tumori, Fdn IRCCS, Paediat Oncol, Milan, Italy

[36] Lausanne Univ Hosp, Pediat Hematol Oncol Unit, Lausanne, Switzerland

[37] Ruth Rappaport Childrens Hosp, Rambam Hlth Care Campus, Haifa, Israel

[38] Gustave Roussy, Dept Oncol Pediat, Villejuif, France

[39] Newcastle Univ, Wolfson Childhood Canc Res Ctr, Newcastle Ctr Canc, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[40] St Anna Childrens Hosp, St Anna Childrens Canc Res Inst, Dept Studies & Stat & Integrated Res, Vienna, Austria

[41] Med Univ Vienna, Dept Paediat, Vienna, Austria

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2021年 / 39卷 / 30期

关键词：

SEGMENTAL CHROMOSOMAL ALTERATIONS; ACTIVATING MUTATIONS; PEDIATRIC-PATIENTS; CRIZOTINIB; REVEALS; RELAPSE; KINASE; REARRANGEMENTS; HETEROGENEITY; CHEMOTHERAPY;

D O I：

10.1200/JCO.21.00086

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 421; 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 En = 19], 26% [95% CI, 10 to 47], clonal ALKm En = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration En = 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. (C) 2021 by American Society of Clinical Oncology

引用

页码：3377 / +

页数：28

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