Next-generation personalised medicine for high-risk paediatric cancer patients - The INFORM pilot study

被引：254

作者：

Worst, Barbara C. ^{[1
,2
,3
]}

van Tilburg, Cornelis M. ^{[2
,3
,4
,5
]}

Balasubramanian, Gnana Prakash ^{[3
,6
,7
]}

Fiesel, Petra ^{[3
,8
,9
,12
]}

Witt, Ruth ^{[4
]}

Freitag, Angelika ^{[4
]}

Boudalil, Miream ^{[3
,8
,9
]}

Previti, Christopher ^{[10
]}

Wolf, Stephan ^{[10
]}

Schmidt, Sabine ^{[10
]}

Chotewutmontri, Sasithorn ^{[10
]}

Bewerunge-Hudler, Melanie ^{[10
]}

Schick, Matthias ^{[10
]}

Schlesner, Matthias ^{[3
,11
]}

Hutter, Barbara ^{[3
,6
,7
]}

Taylor, Lenka ^{[12
]}

Borst, Tobias ^{[13
]}

Sutter, Christian ^{[14
]}

Bartram, Claus R. ^{[14
]}

Milde, Till ^{[2
,3
,5
]}

Pfaff, Elke ^{[1
,2
,3
]}

Kulozik, Andreas E. ^{[2
]}

von Stackelberg, Arend ^{[15
]}

Meisel, Roland ^{[16
]}

Borkhardt, Arndt ^{[16
]}

Reinhardt, Dirk ^{[17
]}

Klusmann, Jan-Henning ^{[18
]}

Fleischhack, Gudrun ^{[17
]}

Tippelt, Stephan ^{[17
]}

Dirksen, Uta ^{[19
]}

Juergens, Heribert ^{[19
]}

Kramm, Christof M. ^{[20
]}

von Bueren, Andre O. ^{[20
,21
]}

Westermann, Frank ^{[3
,22
]}

Fischer, Matthias ^{[23
,24
,25
]}

Burkhardt, Birgit ^{[19
]}

Wossmann, Wilhelm ^{[26
]}

Nathrath, Michaela ^{[27
,28
]}

Bielack, Stefan S. ^{[29
]}

Fruehwald, Michael C. ^{[30
]}

Fulda, Simone ^{[3
,31
]}

Klingebiel, Thomas ^{[32
]}

Koscielniak, Ewa ^{[29
]}

Schwab, Matthias ^{[3
,33
,34
,35
]}

Tremmel, Roman ^{[33
,34
,35
]}

Driever, Pablo Hernaiz ^{[15
]}

Schulte, Johannes H. ^{[15
,17
]}

Brors, Benedikt ^{[3
,6
,7
]}

von Deimling, Andreas ^{[3
,8
,9
]}

Lichter, Peter ^{[3
,36
]}

机构：

[1] German Canc Res Ctr, Div Pediat Neurooncol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[2] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Neuenheimer Feld 430, D-69120 Heidelberg, Germany

[3] German Canc Consortium DKTK, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[4] Natl Ctr Tumor Dis, NCT Trial Ctr, Neuenheimer Feld 130-3, D-69120 Heidelberg, Germany

[5] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr, Div Appl Bioinformat, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[7] Natl Ctr Tumor Dis NCT, Neuenheimer Feld 460, D-69120 Heidelberg, Germany

[8] Univ Heidelberg Hosp, Dept Neuropathol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany

[9] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany

[10] German Canc Res Ctr, Genom & Prote Core Facil, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[11] German Canc Res Ctr, Div Theoret Bioinformat, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[12] Univ Heidelberg Hosp, Dept Pharm, Neuenheimer Feld 670, D-69120 Heidelberg, Germany

[13] Erlangen Univ Hosp, Dept Pharm, Palmsanlage 3, D-91054 Erlangen, Germany

[14] Univ Heidelberg Hosp, Inst Human Genet, Neuenheimer Feld 366, D-69120 Heidelberg, Germany

[15] Charite, Dept Pediat Oncol & Hematol, Augustenburger Pl 1, D-13353 Berlin, Germany

[16] Dusseldorf Univ Hosp, Dept Pediat Oncol Hematol & Clin Immunol, Fac Med, Moorenstr 5, D-40225 Dusseldorf, Germany

[17] Univ Hosp Essen, Pediat 3, Pediat Oncol & Hematol, Hufelandstr 55, D-45147 Essen, Germany

[18] Hannover Med Sch, Dept Pediat Hematol & Oncol, Carl Neuberg Str 1, D-30625 Hannover, Germany

[19] Univ Hosp Munster, Dept Pediat Hematol & Oncol, Albert Schweitzer Campus 1, D-48149 Munster, Germany

[20] Univ Med Ctr Gottingen, Div Pediat Hematol & Oncol, Robert Koch Str 40, D-37075 Gottingen, Germany

[21] Univ Hosp Geneva, Div Pediat Hematol & Oncol, Dept Pediat & Adolescent Med, Rue Gabrielle Perret Gentil 4, CH-1205 Geneva, Switzerland

[22] German Canc Res Ctr, Div Neuroblastoma Genom, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[23] Univ Hosp Cologne, Dept Pediat Hematol & Oncol, Kerpener Str 62, D-50937 Cologne, Germany

[24] Univ Cologne, Fac Med, CMMC, Robert Koch Str 21, D-50931 Cologne, Germany

[25] Max Planck Inst Metab Res, Gleueler Str 50, D-50931 Cologne, Germany

[26] Univ Hosp Giessen, Dept Pediat Hematol & Oncol, Feulgenstr 12, D-35392 Giessen, Germany

[27] Klinikum Kassel, Dept Pediat Oncol, Monchebergstr 41-43, D-34125 Kassel, Germany

[28] Tech Univ Munich, Pediat Oncol Ctr, Kolner Pl 1, D-80804 Munich, Germany

[29] Klinikum Stuttgart Olgahosp, Dept Pediat Oncol Hematol & Immunol, Kriegsbergstr 62, D-70174 Stuttgart, Germany

[30] Klinikum Augsburg, Childrens Hosp, Swabian Childrens Canc Ctr, Stenglinstr 2, D-86156 Augsburg, Germany

[31] Univ Hosp Frankfurt, Inst Expt Canc Res Pediat, Komturstr 3a, D-60528 Frankfurt, Germany

[32] Univ Hosp Frankfurt, Dept Pediat Oncol & Hematol, Theodor Stern Kai 7, D-60590 Frankfurt, Germany

[33] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, D-70376 Stuttgart, Germany

[34] Univ Tubingen, Dept Clin Pharmacol, Morgenstelle 8, D-72076 Tubingen, Germany

[35] Univ Tubingen, Dept Biochem & Pharm, Morgenstelle 8, D-72076 Tubingen, Germany

[36] German Canc Res Ctr, Div Mol Genet, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

来源：

EUROPEAN JOURNAL OF CANCER | 2016年 / 65卷

关键词：

Personalised medicine; Oncology; Paediatrics; Precision medicine; Molecular targeted therapy; Deep sequencing; Cancer; Sarcoma; Brain; RETROSPECTIVE ANALYSIS; DRUG RESPONSE; PHASE-I; THERAPY; RELAPSE; ADOLESCENTS; RECURRENCE; ONCOLOGY; CHILDREN; SURVIVAL;

D O I：

10.1016/j.ejca.2016.06.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The 'Individualized Therapy for Relapsed Malignancies in Childhood' (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of 'intermediate' or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase-mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：91 / 101

页数：11

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