PAEDIATRIC MALIGNANCIES- an overview

Amos BurkeConsultant Paediatric Oncologist

Lectures in Cancer Biology & Medicine 21st May 2020

Overview

• Children’s Cancer – incidence and survival• Treatment – past, present and future• Unmet clinical needs

Overview

• Children’s Cancer – incidence and survival• Treatment – past, present and future• Unmet clinical needs

Childhood cancer is rare

• What is rare?• Prevalence <50/100 000 population (EU definition)• Affecting less than 200 000 people (US Orphan Drug Act of 1983)• Incidence less than 6 per 100 000 persons per year (RARECARE)• Incidence less than 2 per 100 00 per year (NCRI IRCI)

• By any definition, childhood cancer is rare• 71% cancer under 20 years is rare

DeSantis, C. E., Kramer, J. L. & Jemal, A. The burden of rare cancers in the United States. CA Cancer J Clin 67, 261-272, (2017).

Childhood cancer is different from cancer at other ages

340 000 cases per year 1800 cases per year 2300 cases per year

The highest incidence rates for all children's cancers combined are in the under-fives for both sexes, with almost half (46%) of all cases in children being diagnosed in this age group (UK, 2015-2017)

There has been a 15% increase in incidence since the 1990sCopyright ©2020 ACCO. All Rights Reserved.

A GP with an average list size may see 2 children with cancer in a working lifetime

All Childhood Cancers: 1988-1997World Age-Standardised Incidence Rates per Million Population, Children (0-14), Europe

Cancer remains single commonest cause of death for children aged 1-15 years

Table 1: Percentage of childhood deaths by underlying cause, England and Wales, 2016

ICD-10 code Underlying cause group %

C00-D48 Neoplasms (cancers) 20.6

U509, V01-Y89External causes of morbidity and mortality 16.4

J00-J99 Diseases of the respiratory system 10.8

G00-G99 Diseases of the nervous system 10.3

Q00-Q99Congenital malformations, deformations and chromosomal abnormalities 10.0

Source: Office for National Statistics

Statistical bulletin:Child mortality in England and Wales: 2016

Paediatric malignancies

Gatta et al, Lancet Oncol 2014

Increase in the Number of Children (aged 0-14) Alive Ten Years After Their Cancer Diagnosis, Great Britain, 1971-2010

Source: cruk.org/cancerstats

You are welcome to reuse this Cancer Research UK statistics content for your own work. Credit us as authors by referencing Cancer Research UK as the primary source. Suggested style: Cancer Research UK, full URL of the page, Accessed [month] [year].

Risk factors for Malignant Disease

Miscellaneous

Fruit and vegetable intake and the risk ofcardiovascular disease, total cancer and all-cause mortality—a systematic review and dose-response meta-analysis of prospective studies

Dagfinn Aune1,2,3*, Edward Giovannucci4,5,6, Paolo Boffetta7,Lars T Fadnes8, NaNa Keum5,6, Teresa Norat2, Darren C Greenwood9,Elio Riboli2, Lars J Vatten1 and Serena Tonstad10

1Department of Public Health and General Practice, Norwegian University of Science and Technology,Trondheim, Norway, 2Department of Epidemiology and Biostatistics, Imperial College London, London,UK, 3Bjørknes University College, Oslo, Norway, 4Channing Division of Network Medicine, Brigham andWomen’s Hospital and Harvard Medical School, Boston, MA, USA, 5Department of Epidemiology,6Department of Nutrition, Harvard T. Chan School of Public Health, Boston, MA, USA, 7Tisch CancerInstitute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 8Department of Global PublicHealth and Primary Care & Department of Clinical Dentistry, University of Bergen, Bergen, Norway,9Biostatistics Unit, University of Leeds, Leeds, UK and 10Department of Preventive Cardiology, OsloUniversity Hospital Ulleval, Oslo, Norway

*Corresponding author. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London,

St Mary’s Campus, Norfolk Place, London W2 1PG, UK. E-mail: d.aune@imperial.ac.uk

Accepted 13 October 2016

Abstract

Background: Questions remain about the strength and shape of the dose-response rela-tionship between fruit and vegetable intake and risk of cardiovascular disease, cancerand mortality, and the effects of specific types of fruit and vegetables. We conducted asystematic review and meta-analysis to clarify these associations.Methods: PubMed and Embase were searched up to 29 September 2016. Prospectivestudies of fruit and vegetable intake and cardiovascular disease, total cancer and all-cause mortality were included. Summary relative risks (RRs) were calculated using a ran-dom effects model, and the mortality burden globally was estimated; 95 studies (142publications) were included.Results: For fruits and vegetables combined, the summary RR per 200 g/day was 0.92 [95%confidence interval (CI): 0.90–0.94, I2! 0%, n! 15] for coronary heart disease, 0.84 (95% CI:0.76–0.92, I2!73%, n!10) for stroke, 0.92 (95% CI: 0.90–0.95, I2!31%, n!13) for cardiovas-cular disease, 0.97 (95% CI: 0.95–0.99, I2!49%, n!12) for total cancer and 0.90 (95% CI:0.87–0.93, I2!83%, n!15) for all-cause mortality. Similar associations were observed forfruits and vegetables separately. Reductions in risk were observed up to 800 g/day for alloutcomes except cancer (600 g/day). Inverse associations were observed between the intake

VC The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association 1029This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),

which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact

journals.permissions@oup.com

International Journal of Epidemiology, 2017, 1029–1056

doi: 10.1093/ije/dyw319

Advance Access Publication Date: 22 February 2017

Original article

Downloaded from https://academic.oup.com/ije/article-abstract/46/3/1029/3039477/Fruit-and-vegetable-intake-and-the-risk-ofby gueston 21 September 2017

The European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk)

http://www.srl.cam.ac.uk/epic/

Smoking

38% cancers in UK preventable (CRUK)

Risk factors for paediatric malignancy

Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscript

Spector et al.Page 17

Table 1

Results of selected meta-analyses of environmental risk factors and childhood ALL.

Exposure Time period N studies Findings Ref

Maternal alcohol use Pregnancy 10 No association of any alcohol use during pregnancy with ALL [mOR* = 1.10 (0.93-1.29) (11)

Maternal coffee use Pregnancy 5 Small association of any coffee consumption during pregnancy with ALL [mOR = 1.16 (1.00-1.34)] (8)

Daycare attendance Postnatal 14 Small reduced risk of ALL associated with daycare attendance [mOR = 0.76 (0.67-0.87)] (13)

Electromagnetic field exposure Postnatal 9 No association of electromagnetic field exposure >=0.2 µT with ALL [mOR = 1.25 (0.97-1.60)] (15)

Occupational pesticide exposure Pregnancy 5 Strong association of maternal occupational exposure to pesticides during pregnancy and ALL [mOR = 2.64 (1.40-5.00)] (14)

Maternal prenatal vitamins Pregnancy 3 Small reduced risk of ALL associated with maternal prenatal vitamin consumption [mOR = 0.61 (0.50-0.74)] (9)

Paternal smoking Preconception 10 Small association of any paternal preconceptional smoking with ALL [mOR = 1.15 (1.06-1.24)] (12)

Maternal smoking Pregnancy 20 No association of any maternal smoking during pregnancy with ALL [mOR = 1.03 (0.95-1.12)] (10)

*mOR = meta-analytic odds ratio

Pediatr Clin N

orth Am. A

uthor manuscript; available in PM

C 2015 April 03.

Pediatr Clin N Am 62 (2015) 11–25

Zhang et al, N Engl J Med. 2015

• Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer who participated in this study.

• Family history did not predict the presence of an underlying predisposition syndrome in most patients.

Germline Mutations in Predisposition Genes in Pediatric Cancer

Collectively, the accumulated evidence derived from epidemiological studies, GWAS, genome sequencing, biological scrutiny of the natural history and molec-ular pathogenesis of BCP- ALL and mechanistic and modelling studies provide us with a more substantive and credible version of the original7,17 two- hit model for childhood ALL, as summarized in FIG.!3. The model applies selectively to the common, B cell precursor sub-set of ALL, although the evidence is currently more compelling for the ETV6–RUNX1+ subset of BCP- ALL than for the hyperdiploid subset. The rarer pro- B ALL in infants appears likely to have a different causation and molecular pathogenesis, as does childhood AML and childhood lymphoma. There are insufficient data for thymic or T!cell precursor ALL (T- ALL) in this respect. Other causal associations in leukaemia and cancer in general might be revealed or strengthened by a focus on well- defined subtypes, as suggested for breast cancer138.

The causal mechanism proposed here is multifac-torial, involving patterns of infection, inherited genet-ics and other modulators of risk including chance and, probably, diet (BOX!4). It has a logical coherence139 and is grounded in the fundamental biology of leukaemia and evolutionary logic of the immune system net-work functions. The central thesis posits BCP- ALL as a paradox of progress in developed societies con-tingent upon a mismatch between the historical or evolutionary programming of the immune system and contemporary lifestyles that restrain opportu-nities for early- life microbial exposures. Childhood ALL is probably not the only unanticipated, dele-terious health consequence of diminished infec-tious exposure in infancy93. Similar epidemiological associations exist for Hodgkin lymphoma in young adults140 as well as for childhood allergies and auto-immune disease141 (Supplementary Box 4). In all these clinical situations, the common theme is that acquisi-tion of common microbial infections in early life has an impact on later responses of the immune system to challenge and the subsequent presence or absence of pathology93,141,142. Diminished exposure early in life to microorganisms that are pathological has been highly beneficial, reducing infant mortality, but it seems plausible that a suite of illnesses prevalent now in young people in more developed societies, including BCP- ALL, could be due to an unanticipated consequence of this advance93,141.

The infection hypothesis would benefit from fur-ther scrutiny, including validation and extension of the animal modelling, but its public health impli-cation is clear. Most cases of childhood ALL are potentially preventable. But how? Lifestyle changes including day care attendance or protracted breast-feeding in the first year of life can be advocated but would be difficult to achieve. A more realistic pros-pect might be to design a prophylactic vaccine that mimics the protective impact of natural infections in infancy, correcting the deficit in modern societies. Reconstitution or manipulation of the natural micro-biome143–146 or helminth injections147,148 are strategies under consideration for early- life immune disorders

Step 1: Developmental ‘error’ in utero

Covert pre-leukaemia

Promoting mutations: CNAs or SNVs

Initiating mutation:ETV6–RUNX1 orhyperdiploidy

Step 2: Dysregulated immune response to infection(occurs in ~1% of individuals with pre-leukaemia)

TGF!

AID, RAG1 and/or RAG2

Birth 1 2–6Age (years)

ALL

Inherited genetic background

Immune deficit

Fig. 3 | Summary of the two- hit model for role of infections in B cell precursor ALL. Genetic, inherited risk alleles are depicted (top of figure) as having effects at any or several stages of the stepwise process of acute lymphoblastic leukaemia (ALL) development. Step 1 is the prenatal initiation lesion (ETS translocation variant 6 (ETV6)–runt- related transcription factor 1 (RUNX1) or hyperdiploidy), which is common (~100 times clinical ALL frequency) and postulated to arise as a spontaneous, developmental error. This generates a clinically silent pre- leukaemic clone that can persist for up to 14 years. Step 2 is that in a small fraction (~1%) of patients with a covert pre- leukaemic clone, an abnormal immune response to one or more common infections triggers (probably via transforming growth factor- " (TGF") and possibly other cytokines) activation- induced cytidine deaminase (AID) activation, which, in combination with V(D)J recombination- activating protein 1 (RAG1) and/or RAG2, induces secondary genetic changes (predominantly copy number alterations (CNAs)). This occurs in patients who carry a covert pre- leukaemic clone and have a deficit of infectious exposures in infancy. The postulated immune deficit in infancy may increase the risk of Step 2 either by failure of immune network modulation and/or by affecting the persistence of a pre- leukaemic clone. SNV, single nucleotide variant.

mice with ETV6–RUNX1 developed BCP- ALL after exposure to common pathogens135. These experiments provide evidence, albeit in murine models, that com-mon infections can have, as predicted, a promotional role in ALL.

Another mouse model has provided evidence that early stimulation of the immune system can be protec-tive. Exposure of mice with transgenic E!- Ret or E2A (also known as TCF3)–PBX1 to oligodeoxynucleotides (which bind to TLR9) at 4 weeks depleted both normal and pre- leukaemic precursors and both delayed and diminished the risk of progression to ALL136. This effect was dependent upon IFN#. By contrast, binding of poly-inosinic:polycytidylic acid (poly(I:C)), a TLR3 ligand that does not induce IFN#, resulted in an expansion of the pre- leukaemic cell pool. These data hint that the nature of infectious exposures in infancy and responses of the innate immune system may influence not only subsequent immune responses but also the fate of pre- leukaemic cells.

Conclusions: paradoxes of progress

We incline on our evidence to the belief that the solution of the problem of leukaemia lies rather in some peculiar reaction to infection than in the existence of some specific infective agent. F. J. Poynton, H. Thursfield and D. Paterson, Great Ormond Street Hospital for Sick Children, 1922 (REF.137)

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

www.nature.com/nrc

REV IEWS

Greaves, Nature Reviews Cancer. 2018

A causal mechanism for childhood acute lymphoblastic leukaemia

One sentence summary Clonal expansions within normal kidney tissue, some of which harbor driver variants, often precede the most common type of childhood kidney cancer, Wilms tumor (nephroblastoma).

Overview

• Children’s Cancer – incidence and survival• Treatment – past, present and future• Unmet clinical needs

Historical Landmarks Acute Lymphoblastic Leukaemia

• 1860 Würzberg Germany – Maria The Cure of Childhood Leukaemia : Into the Age of Miralces John Laszlo Rutgers University Press, New Jersey 1995

• 1948 Boston, Aminopterin

• 1972 Memphis, 50% cure rate

Treatment of paediatric cancer

Most tumours chemo-sensitive

Surgery –goal is usually total removal

Radiotherapy for some tumours

Chemotherapy agents commonly used in paediatric cancer

Class of drug Examples Mode of actionAlkylating agents Cyclophosphamide

BuslphanDNA damaging

Anti-metabolites 6-mercaptopurineCytarabine arabinoside

Prevent synthesis of normal DNA/RNA

Anti-tumour antibiotics DaunorubicinDoxorubicin

Topoisomerase II inhibition

Topoisomerase inhibitors Irinotecan (CPT-11) Topoisomerase I inhibitor

Etoposide Topoisomerase II inhibitor

Vinca alkaloids VincristineVinblastine

Mitotic inhibitors

Glucocorticoids DexamethasonePrednisolone

Poorly understood

Novel agents Class Examples Applications Tyrosine kinase inhibitors imatinib mesylate

gefitiniberlotinib Lapatinibcanertinibsorafenib

ALL, HCC…..

Other small molecules Venetoclax (BCL2) ALL

Proteosome inhibitors Bortezomib, Cafilzomib ALL

poly-ADP ribose polymerase (PARP) inhibitors

Olaparib, Veliparib, Rucaparib, Talazoparib

? Ewing sarcoma

BRAF inhibitors Vemurafenib dabrafenib Brain tumours, Langerhans cell histiocytosis, melanoma

Rational development of new drugs for childhood cancer

• Unmet clinical needs must be identified• Prioritisation of drugs

must occur• International

collaboration required

• Access to drugs remains a challenge• Infrastructure required

to deliver novel therapies in childhood cancer

The Immunotherapy revolution

Majzner et al Cancer Cell 2017

Fig. 1 Engineered T cells: design of TCR versus CAR T cells.

Carl H. June et al. Science 2018;359:1361-1365

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 378;5 nejm.org February 1, 2018 439

The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Maude at 3012 Colket Translational Research Bldg., 3501 Civic Center Blvd., Philadelphia, PA 19104, or at maude@ email . chop . edu.

Drs. Pulsipher and Grupp contributed equally to this article.

N!Engl!J!Med!2018;378:439-48.DOI:!10.1056/NEJMoa1709866Copyright © 2018 Massachusetts Medical Society.

BACKGROUNDIn a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

METHODSWe conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.

RESULTSFor this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remis-sion was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.

CONCLUSIONSIn this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)

A BS TR AC T

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

S.L. Maude, T.W. Laetsch, J. Buechner, S. Rives, M. Boyer, H. Bittencourt, P. Bader, M.R. Verneris, H.E. Stefanski, G.D. Myers, M. Qayed, B. De Moerloose,

H. Hiramatsu, K. Schlis, K.L. Davis, P.L. Martin, E.R. Nemecek, G.A. Yanik, C. Peters, A. Baruchel, N. Boissel, F. Mechinaud, A. Balduzzi, J. Krueger,

C.H. June, B.L. Levine, P. Wood, T. Taran, M. Leung, K.T. Mueller, Y. Zhang, K. Sen, D. Lebwohl, M.A. Pulsipher, and S.A. Grupp

Original Article

The New England Journal of Medicine Downloaded from nejm.org on May 20, 2020. For personal use only. No other uses without permission.

Copyright © 2018 Massachusetts Medical Society. All rights reserved.

n engl j med 378;5 nejm.org February 1, 2018 443

Tisagenlecleucel in B-Cell Lymphoblastic Leukemia

B-Cell AplasiaAll patients with a response to treatment had B-cell aplasia, and most patients in the study received immunoglobulin replacement in accor-dance with local practice. The median time to B-cell recovery was not reached (Fig. S4 in the Supplementary Appendix). The probability of maintenance of B-cell aplasia at 6 months after infusion was 83% (95% CI, 69 to 91).

Cytokine ResponseAmong the 75 patients who received tisagenlec-leucel, transient increases in serum interleu-kin-6, interferon gamma, and ferritin levels oc-curred during the cytokine release syndrome after infusion; these increases tended to be more pronounced in patients with grade 4 cytokine release syndrome than in patients with lower grades (Fig. S5 in the Supplementary Appendix). Similar trends were observed in the levels of other cytokines, including interleukin-10, inter-leukin-12p70, interleukin-1!, interleukin-2, inter-leukin-4, interleukin-8, and tumor necrosis fac-tor ". A transient increase in the C-reactive

protein level was observed in most patients, but with large variability.

SafetyThe safety analysis set included all 75 patients who received an infusion of tisagenlecleucel; the median time from infusion to data cutoff was 13.1 months (range, 2.1 to 23.5). Eighteen pa-tients (24%) received their infusions in an outpa-tient setting. All patients had at least one adverse event during the study; 71 of 75 patients (95%)

Prob

abili

ty!o

f!Con

tinue

d!Re

mis

sion

1.0

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.00 4 8 12 14 16 2220

Months!since!Onset!of!Remission

B Event-free!and!Overall!Survival

A Duration!of!Remission

No. of patients, 61No. of events, 17Median duration of remission, not reached

No.!at!Risk 61 43

2

54 23

6

33 8

10

18 7 3 0

18

1

Prob

abili

ty

1.0

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.00 4 8 12 14 16 2220

Months!since!Tisagenlecleucel!Infusion

Overall!SurvivalEvent-free

Survival

7575

1927

19.1not

reached

90 (81–95)73 (60–82)

No.!ofPatients

No.!ofEvents

MedianSurvival Rate!at!6!Mo

mo % (95% CI)

No.!at!RiskOverall survivalEvent-free survival

7575

6451

2

7264

5533

6

5837

3013

10

4019

208

123

00

18

83

21

Overall survival

Event-free survival

Figure!2.!Duration!of!Remission,!Event-free!Survival,!and!Overall!Survival.

Panel A shows the duration of remission, defined as the time to relapse after the onset of remission, in the 61 patients who had a best overall response of either complete remission or complete remission with incom-plete hematologic recovery. Panel B shows event-free survival among the 75 patients who received an infusion, defined as the time from tisagenlecleucel infusion to the earliest of the following events: no response (8 pa-tients), relapse before response was maintained for at least 28 days (2), or relapse after having complete re-mission or complete remission with incomplete hema-tologic recovery (17). A total of 32 patients had still not had an event at the time of data cutoff. Data for 16 more patients were censored for event-free survival — 8 pa-tients for allogeneic stem-cell transplantation during remission, 7 patients for new cancer therapy other than stem-cell transplantation during remission (4 received humanized anti-CD19 CAR T cells, 1 received ponatinib, 1 received vincristine sulfate and blinatumomab, and 1 received antithymocyte globulin), and 1 patient for lack of adequate assessment. Ten patients were followed for relapse after new therapy, 4 of whom had a relapse or died. Panel B also shows overall survival among the 75 patients who received an infusion from the date of tisagenlecleucel infusion to the date of death from any cause. Nineteen patients died after tisagenlecleucel in-fusion, and 56 patients had their data censored at the time of the last follow-up. Tick marks indicate the time of censoring.

The New England Journal of Medicine Downloaded from nejm.org on May 20, 2020. For personal use only. No other uses without permission.

Copyright © 2018 Massachusetts Medical Society. All rights reserved.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 378;5 nejm.org February 1, 2018 439

The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Maude at 3012 Colket Translational Research Bldg., 3501 Civic Center Blvd., Philadelphia, PA 19104, or at maude@ email . chop . edu.

Drs. Pulsipher and Grupp contributed equally to this article.

N!Engl!J!Med!2018;378:439-48.DOI:!10.1056/NEJMoa1709866Copyright © 2018 Massachusetts Medical Society.

BACKGROUNDIn a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

METHODSWe conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.

RESULTSFor this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remis-sion was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.

CONCLUSIONSIn this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)

A BS TR AC T

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

S.L. Maude, T.W. Laetsch, J. Buechner, S. Rives, M. Boyer, H. Bittencourt, P. Bader, M.R. Verneris, H.E. Stefanski, G.D. Myers, M. Qayed, B. De Moerloose,

H. Hiramatsu, K. Schlis, K.L. Davis, P.L. Martin, E.R. Nemecek, G.A. Yanik, C. Peters, A. Baruchel, N. Boissel, F. Mechinaud, A. Balduzzi, J. Krueger,

C.H. June, B.L. Levine, P. Wood, T. Taran, M. Leung, K.T. Mueller, Y. Zhang, K. Sen, D. Lebwohl, M.A. Pulsipher, and S.A. Grupp

Original Article

The New England Journal of Medicine Downloaded from nejm.org on May 20, 2020. For personal use only. No other uses without permission.

Copyright © 2018 Massachusetts Medical Society. All rights reserved.

A CAR-T revolution?

• Ionising radiation damages DNA by interacting with lipids and protein signaling pathways

• Ionising radiation will damage normal and cancer cells

• Radiation therapy is especially damaging to the developing body (esp. brain)

Biologic Basis of Radiation TherapyArno J. Mundt, MD, John C. Roeske, PhD, Theodore D. Chung, MD, PhD, and Ralph R. Weichselbaum, MD.Holland-Frei Cancer Medicine. 6th edition.

Radiotherapy

Protons

Overview

• Children’s Cancer – incidence and survival• Treatment – past, present and future• Unmet clinical needs

Chemotherapy – acute toxicity

doi: 10.1136/bmj.i4351 ! BMJ 2016;354:i4351 ! the"bmj

RESEARCH

4

Deaths due to recurrence or progressionAmong !"#$ deaths due to cancer, #%#% (&%.'%) were attributed to recurrence or progression of the original cancer, which equated to "#.! (()% confidence interval "*.& to "!.() excess deaths per $* *** person years (table # ). All types of first primary neoplasms, except non-heritable retinoblastoma, were found to have excess deaths due to recurrence or progression, but noticeable excesses were observed for survivors of CNS neoplasms (excluding primitive neuroectodermal tumour) (absolute excess risk %".'), CNS primitive neu-roectodermal tumour ($$).*), leukaemia (excluding acute myeloid leukaemia) ()&.$), and bone sarcoma (%$.(), where more than )* excess deaths per $* *** person years were observed (table ! ). With regards to treatment period, the absolute excess risk significantly decreased among those treated more recently (P for trend <*.*$) (table "); compared with survivors with a diagnosis before $(&*, those with a diagnosis from $((* to #**% experienced !*% (excess mortality ratio *.!, ()% confidence interval *.# to *.!) of the excess deaths due to recurrence or progression, after adjusting for sex, type of first primary neoplasm, age at diagnosis, and attained age.

When treatment period was assessed by type of first primary neoplasm, survivors of CNS neoplasms (excluding primitive neuroectodermal tumour) (P for trend <*.*$), CNS primitive neuroectodermal tumour (P for trend <*.*$), leukaemia (excluding acute myeloid leukaemia) (P for trend <*.*$), acute myeloid leukae-mia (P for trend *.*#), Hodgkin’s lymphoma (P for trend <*.*$), non-Hodgkin’s lymphoma (P for trend *.*#), and other types of first primary neoplasm (P for trend <*.*$) were found to have significantly fewer excess numbers of deaths among those with a most recent diagnosis, after adjustment (table )). The stron-gest decline in the excess number of deaths due to recurrence or progression was observed for survivors of

leukaemia ( excluding acute myeloid leukaemia) and Hodgkin’s lymphoma, as survivors with a diagnosis from $((* to #**% experienced $*% (both excess mor-tality ratios *.$, ()% confidence interval *.* to *.$) of the excess number of deaths due to recurrence or pro-gression observed among those with a diagnosis before $(&*; for both types of first primary neoplasm the strongest decline in excess number of deaths due to recurrence or progression was observed from the treat-ment period before $(&* to the treatment period of $(&*-&(. Survivors of CNS neoplasms (excluding primi-tive neuroectodermal tumour) with a diagnosis from $((* to #**% experienced !*% (excess mortality ratio *.!, ()% confidence interval *.! to *.") of the excess number of deaths due to recurrence or progression observed among those with a diagnosis before $(&*; the corresponding percentage for survivors of CNS primitive neuroectodermal tumour (*.", *.# to *.)), acute myeloid leukaemia (*.", *.* to #.&), and non-Hod-gkin’s lymphoma (*.", *.# to *.() was "*%.

Deaths due to subsequent primary neoplasmsSurvivors of childhood cancer were %.! times (()% con-fidence interval ).' to %.&) more at risk of death due to a subsequent primary neoplasm than expected in the general population (table # ). Survivors of CNS primitive neuroectodermal tumour and heritable retinoblastoma had the greatest risk of death related to subsequent pri-mary neoplasms, with standardised mortality ratios of #$.% (()% confidence interval $%.( to #&.#) and #$.* ($&.* to #).)), respectively (table ! ). After adjusting for sex, type of first primary neoplasm, age at diagnosis, and attained age, there was no statistical evidence of an overall decline in the excess numbers of deaths from subsequent primary neoplasms with more recent treat-ment period (P for trend *.$*, table ").

After adjustment, survivors of Wilms’s tumour (P for trend *.*#) with a more recent diagnosis experienced a lower number of excess deaths due to subsequent pri-mary neoplasms (table )). Conversely, among survivors of soft tissue sarcoma, the excess number of deaths from subsequent primary neoplasms increased among those with a more recent diagnosis (P for trend *.*"); more specifically, survivors of soft tissue sarcoma diag-nosed during $(&*-&(, $('*-'(, and $((*-#**% experi-enced &.! times (()% confidence interval $.& to !$.%), ".& times, (*.( to #!.&), and %.' times ($.! to !).$) more excess deaths due to subsequent primary neoplasms than those with a diagnosis before $(&*, respectively. A significant positive or negative trend for excess number of deaths related to subsequent primary neoplasms was not observed with treatment period for any other type of first primary neoplasm (all P for trend >*.*)).

Deaths due to non-neoplastic causesSurvivors of childhood cancer were #.( times (()% con-fidence interval #.& to !.$) more likely to die from a non-neoplastic cause of death than expected from the general population, which equated to $$.$ (()% confi-dence interval $*.$ to $#.$) excess deaths due to non-neo-plastic causes per $* *** person years (table # ).

Table ! | Observed and expected deaths, standardised mortality ratio, and absolute excess risk of speci"c causes of death

Causes of death Observed/expected SMR (#$% CI)Absolute excess risk (#$% CI)

All causes !!"#/!$%.$ $.& ('.$ to $.!) (!.) (().& to ((.*)Recurrence or progression )()(/%.% NA !).* (!%." to !*.$)Subsequent primary neoplasm "$#/&)(.$ (.* (#.' to (.") &%.' ($.$ to &&.")Non-neoplastic &%#!/*(!.% ).$ ()." to *.&) &&.& (&%.& to &).&) Circulatory *%%/"'.% *.' (*.! to !.*) *.( (*.% to !.&) Respiratory &(!/)!.) (.' (#.' to ".$) ).* (&.' to ).") Nervous $'/)*.% !.* (*.# to #.)) &.) (%.$ to &.#) Infection ("/$.& ".! (#." to $.!) %.$ (%." to &.)) Digestive (*/*%.( ).& (&.( to ).() %.# (%.* to %.') Perinatal !)/$.# !.! (*.) to (.%) %.# (%.* to %.") Endocrine *)/&%.# *.& ().& to !.*) %.* (%.) to %.#) Genitourinary *%/*.* $.) ((.) to &*.)) %.! (%.* to %.() Musculoskeletal &'/*.% (.% (*.# to $.!) %.) (%.& to %.!) Mental &#/&*.* &.& (%.( to &.$) %.% (!%.& to %.&) Blood &(/).& ".# (!.* to &).)) %.) (%.& to %.*) External* &''/&#&." &.) (&.& to &.!) %.( (%.) to &.%) Other )&/#." *." ().* to #.") %.) (%.& to %.!)SMR=standardised mortality ratio; NA=not applicable.*Includes deaths due to transportation accidents, falls, drowning, +re, suicide, etc.

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RESEARCH

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!Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham B!" #TT, UK #Department of Oncology, Birmingham Children’s Hospital, NHS Foundation Trust, Birmingham, UK$Department of Paediatric and Adolescent Haematology and Oncology, and Children’s BMT Unit, Great North Children’s Hospital, Royal Victoria In%rmary, Newcastle upon Tyne, UKCorrespondence to: M M Hawkins m.m.hawkins@bham.ac.ukAdditional material is published online only. To view please visit the journal online.Cite this as: BMJ !"#$;%&':i'%&#http://dx.doi.org/!&.!!$'/bmj.i($"!

Accepted: #) July #&!'

Long term cause speci!c mortality among 34 489 !ve year survivors of childhood cancer in Great Britain: population based"cohort studyMiranda M Fidler,! Raoul C Reulen,! David L Winter,! Julie Kelly,! Helen C Jenkinson,# Rod Skinner,$ Clare Frobisher,! Michael M Hawkins! On behalf of the British Childhood Cancer Survivor Study Steering Group

ABSTRACTOBJECTIVETo determine whether modern treatments for cancer are associated with a net increased or decreased risk of death from neoplastic and non-neoplastic causes among survivors of childhood cancer.DESIGNPopulation based cohort study.SETTINGBritish Childhood Cancer Survivor Study.PARTICIPANTSNationwide population based cohort of !" "#$ %ve year survivors of childhood cancer with a diagnosis from &$"' to ('') and followed up until (# February ('&".MAIN OUTCOME MEASURESCause speci%c standardised mortality ratios and absolute excess risks are reported. Multivariable Poisson regression models were utilised to evaluate the simultaneous e*ect of risk factors. Likelihood ratio tests were used to test for heterogeneity or trend.RESULTSOverall, ""+, deaths were observed, which was $.& ($,% con%dence interval #.$ to $.") times that expected in the general population, corresponding to )".( ($,% con%dence interval )(.& to )).!) excess deaths per &' ''' person years. The number of excess deaths from all causes declined among those treated

more recently; those treated during &$$'-('') experienced !'% of the excess number of deaths experienced by those treated before &$+'. The corresponding percentages for the decline in excess deaths from recurrence or progression and non-neoplastic causes were !'% and )'%, respectively. Among survivors aged ,'-,$ years, "&% and ((% of excess deaths were attributable to subsequent primary neoplasms and circulatory conditions, respectively, whereas the corresponding percentages among those aged )' years or more were !&% and !+%.CONCLUSIONSThe net e*ects of changes in cancer treatments, and surveillance and management for late e*ects, over the period &$"' to ('') was to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently. Among survivors aged )' years or more, the excess number of deaths from circulatory causes exceeds the excess number of deaths from subsequent primary neoplasms. The important message for the evidence based surveillance aimed at preventing excess mortality and morbidity in survivors aged )' years or more is that circulatory disease overtakes subsequent primary neoplasms as the leading cause of excess mortality.

IntroductionLong term survivors of childhood cancer remain at an increased risk of mortality when compared with that expected from the general population.!-" Previous reports have shown that the principal cause of excess mortality in the short term is recurrence or progression of the initial cancer,!-# $ whereas subsequent primary neoplasms and non-neoplastic causes account for the majority of excess deaths long term.! % &

Treatment intensity has typically decreased more recently for children with a diagnosis of neoplasms with relatively good prognosis in order to prevent premature morbidity and mortality from treatment related side e'ects; conversely, treatment has intensified for neo-plasms with poor prognoses in order to improve sur-vival. Few studies have addressed late mortality in relation to treatment period,# ( "-) and those that have were restricted by narrow treatment time spans, insu*-cient person years at risk, and small numbers of deaths, which limited statistical power and inhibited detailed classification and investigation of cause specific deaths.

Thus, in this study we aimed to address these previ-ous limitations by investigating the risk of late cause

WHAT IS ALREADY KNOWN ON THIS TOPICSurvivors of childhood cancer are at an increased risk of death compared with the general populationThe principal cause of excess mortality in the short term is recurrence or progression of the initial cancer, whereas subsequent primary neoplasms and non-neoplastic causes account for most excess deaths long termFew previous studies have addressed late mortality in relation to treatment period, and those that have were restricted by narrow treatment periods, insu-cient person years at risk, and small numbers of deaths, which limited statistical power and inhibited detailed classi%cation and investigation of cause speci%c deaths

WHAT THIS STUDY ADDSAmong survivors of childhood cancer aged at least )' years, !&% and !+% of excess numbers of deaths observed were due to subsequent primary neoplasms and circulatory conditions, respectivelyThe net e*ects of changes in cancer treatments, and surveillance and management for late e*ects, over the period &$"' to ('') is to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently

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OPEN ACCESS

!Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham B!" #TT, UK #Department of Oncology, Birmingham Children’s Hospital, NHS Foundation Trust, Birmingham, UK$Department of Paediatric and Adolescent Haematology and Oncology, and Children’s BMT Unit, Great North Children’s Hospital, Royal Victoria In%rmary, Newcastle upon Tyne, UKCorrespondence to: M M Hawkins m.m.hawkins@bham.ac.ukAdditional material is published online only. To view please visit the journal online.Cite this as: BMJ !"#$;%&':i'%&#http://dx.doi.org/!&.!!$'/bmj.i($"!

Accepted: #) July #&!'

Long term cause speci!c mortality among 34 489 !ve year survivors of childhood cancer in Great Britain: population based"cohort studyMiranda M Fidler,! Raoul C Reulen,! David L Winter,! Julie Kelly,! Helen C Jenkinson,# Rod Skinner,$ Clare Frobisher,! Michael M Hawkins! On behalf of the British Childhood Cancer Survivor Study Steering Group

ABSTRACTOBJECTIVETo determine whether modern treatments for cancer are associated with a net increased or decreased risk of death from neoplastic and non-neoplastic causes among survivors of childhood cancer.DESIGNPopulation based cohort study.SETTINGBritish Childhood Cancer Survivor Study.PARTICIPANTSNationwide population based cohort of !" "#$ %ve year survivors of childhood cancer with a diagnosis from &$"' to ('') and followed up until (# February ('&".MAIN OUTCOME MEASURESCause speci%c standardised mortality ratios and absolute excess risks are reported. Multivariable Poisson regression models were utilised to evaluate the simultaneous e*ect of risk factors. Likelihood ratio tests were used to test for heterogeneity or trend.RESULTSOverall, ""+, deaths were observed, which was $.& ($,% con%dence interval #.$ to $.") times that expected in the general population, corresponding to )".( ($,% con%dence interval )(.& to )).!) excess deaths per &' ''' person years. The number of excess deaths from all causes declined among those treated

more recently; those treated during &$$'-('') experienced !'% of the excess number of deaths experienced by those treated before &$+'. The corresponding percentages for the decline in excess deaths from recurrence or progression and non-neoplastic causes were !'% and )'%, respectively. Among survivors aged ,'-,$ years, "&% and ((% of excess deaths were attributable to subsequent primary neoplasms and circulatory conditions, respectively, whereas the corresponding percentages among those aged )' years or more were !&% and !+%.CONCLUSIONSThe net e*ects of changes in cancer treatments, and surveillance and management for late e*ects, over the period &$"' to ('') was to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently. Among survivors aged )' years or more, the excess number of deaths from circulatory causes exceeds the excess number of deaths from subsequent primary neoplasms. The important message for the evidence based surveillance aimed at preventing excess mortality and morbidity in survivors aged )' years or more is that circulatory disease overtakes subsequent primary neoplasms as the leading cause of excess mortality.

IntroductionLong term survivors of childhood cancer remain at an increased risk of mortality when compared with that expected from the general population.!-" Previous reports have shown that the principal cause of excess mortality in the short term is recurrence or progression of the initial cancer,!-# $ whereas subsequent primary neoplasms and non-neoplastic causes account for the majority of excess deaths long term.! % &

Treatment intensity has typically decreased more recently for children with a diagnosis of neoplasms with relatively good prognosis in order to prevent premature morbidity and mortality from treatment related side e'ects; conversely, treatment has intensified for neo-plasms with poor prognoses in order to improve sur-vival. Few studies have addressed late mortality in relation to treatment period,# ( "-) and those that have were restricted by narrow treatment time spans, insu*-cient person years at risk, and small numbers of deaths, which limited statistical power and inhibited detailed classification and investigation of cause specific deaths.

Thus, in this study we aimed to address these previ-ous limitations by investigating the risk of late cause

WHAT IS ALREADY KNOWN ON THIS TOPICSurvivors of childhood cancer are at an increased risk of death compared with the general populationThe principal cause of excess mortality in the short term is recurrence or progression of the initial cancer, whereas subsequent primary neoplasms and non-neoplastic causes account for most excess deaths long termFew previous studies have addressed late mortality in relation to treatment period, and those that have were restricted by narrow treatment periods, insu-cient person years at risk, and small numbers of deaths, which limited statistical power and inhibited detailed classi%cation and investigation of cause speci%c deaths

WHAT THIS STUDY ADDSAmong survivors of childhood cancer aged at least )' years, !&% and !+% of excess numbers of deaths observed were due to subsequent primary neoplasms and circulatory conditions, respectivelyThe net e*ects of changes in cancer treatments, and surveillance and management for late e*ects, over the period &$"' to ('') is to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently

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Current challenges in paediatric oncology

• Integration of molecular classification into clinical practice • Effective therapy for poor risk tumours• Effective therapy for relapsed disease• Reduction of acute toxicity• Conducting clinical trials in the face of high cure rates in rare disease

support an etiological role for canonical Wnt signaling in

the pathogenesis of this group of tumors, and lead to the

nomenclature of ‘Wnt subgroup medulloblastomas’.

Nearly all of the Wnt medulloblastomas studied to date

have classic histology. Wnt medulloblastomas are fre-

quently described as having CTNNB1 mutations, nuclear

Fig. 2 Comparison of the various subgroups of medulloblastoma including their affiliations with previously published papers onmedulloblastoma molecular subgrouping

Fig. 1 Dendrogram depicting the classification of embryonal tumorsof the cerebellum. Medulloblastomas should be differentiated fromthe less common ATRTs and ETANTRs of the cerebellum. Under thecurrent consensus classification of medulloblastoma four principlesubgroups are identified: Wnt, Shh, Group 3, and Group 4. Theevidence suggests that each of the four principle subgroups will likelyhave distinct ‘subsets’ that are biologically and clinically

homogeneous as compared to other subsets from within the samesubgroup. As the nature and number of subsets for each subgroup arecurrently unknown, the consensus classification suggests that eachsubset be named using a Greek letter (a, b, c, etc.) until such time asthey are sufficiently characterized to be named based on theirmolecular etiology

Acta Neuropathol (2012) 123:465–472 467

123

epigenetic inhibitors. Specifically, dasatinib and nilotinib are identified as promising therapeutics for group 2 ATRTs.

INTRODUCTIONRhabdoid tumors (RT) are highly malignant, multi-lineage neoplasms of early childhood originally described in kidneys and soft tissues, but most frequently seen in the CNS where they are called atypical teratoid rhabdoid tumors (ATRTs). ATRTs were historically considered incurable, and although outcomes have improved with intensified multimodal therapy, most patients survive less than 1 year after diagnosis (Chi et al., 2008; Hilden, 2004; Lafay-Cousin et al., 2012; Tekautz, 2005).

Biallelic SMARCB1 loss-of-function alterations are diagnostic of all RTs (Versteege et al., 1998). Up to 35% of ATRTs patients have heritable SMARCB1 alterations, which predispose to multiple RTs (Eaton et al., 2011). Indeed, Smarcb1+/− mice also develop soft-tissue- or neural-crest-derived RTs (Klochendler-Yeivin et al., 2000; Roberts et al., 2002), and ATRTs can arise from conditional inactivation of Smarcb1 (Han et al., 2016). SMARCB1 is a constitutive component of the SWI/SNF chromatin-remodeling complex, which exhibits substantial structural and functional diversity during neurogenesis. Loss of SMARCA4 (Hasselblatt et al., 2011), which encodes another component of the SWI/SNF complex in some ATRTs, further underscores SWI/SNF-directed epigenetic mechanisms as critical in ATRT development. Although cumulative data support a central role for SMARCB1 in RT initiation, specific mechanisms driving tumor development remain unclear. SMARCB1 deficiency leads to aberrant nucleosomal positioning by the SWI/SNF complex and is associated with upregulation of EZH2, a histone methyl transferase of the repressive PRC2 complex (Roberts and Orkin, 2004) with consequent deregulation of multiple downstream signaling pathways. These observations have led to RT therapies targeting EZH2 and other downstream pathways (Kim and Roberts, 2016; Wilson et al., 2010).

Torchia et al. Page 2

Cancer Cell. Author manuscript; available in PMC 2017 July 07.

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CONSENSUS PAPER

Molecular subgroups of medulloblastoma: the current consensus

Michael D. Taylor • Paul A. Northcott • Andrey Korshunov • Marc Remke • Yoon-Jae Cho •

Steven C. Clifford • Charles G. Eberhart • D. Williams Parsons • Stefan Rutkowski • Amar Gajjar •

David W. Ellison • Peter Lichter • Richard J. Gilbertson • Scott L. Pomeroy • Marcel Kool •

Stefan M. Pfister

Received: 6 October 2011 / Revised: 19 November 2011 / Accepted: 22 November 2011 / Published online: 2 December 2011! The Author(s) 2011. This article is published with open access at Springerlink.com

Abstract Medulloblastoma, a small blue cell malignancyof the cerebellum, is a major cause of morbidity and mor-

tality in pediatric oncology. Current mechanisms for clinical

prognostication and stratification include clinical factors(age, presence of metastases, and extent of resection) as well

as histological subgrouping (classic, desmoplastic, and large

cell/anaplastic histology). Transcriptional profiling studiesof medulloblastoma cohorts from several research groups

around the globe have suggested the existence of multipledistinct molecular subgroups that differ in their demo-

graphics, transcriptomes, somatic genetic events, and

clinical outcomes. Variations in the number, composition,and nature of the subgroups between studies brought about a

consensus conference in Boston in the fall of 2010. Dis-

cussants at the conference came to a consensus that theevidence supported the existence of four main subgroups of

M. D. Taylor (&)Division of Neurosurgery, Hospital for Sick Children,University of Toronto, Toronto, Canadae-mail: mdtaylor@sickkids.ca

M. D. Taylor ! P. A. NorthcottProgram in Developmental and Stem Cell Biology,Arthur and Sonia Labatt Brain Tumour Research Centre,Hospital for Sick Children, University of Toronto,Toronto, Canada

A. KorshunovClinical Cooperation Unit Neuropathology,German Cancer Research Center, Heidelberg, Germany

M. Remke ! P. Lichter ! M. Kool ! S. M. Pfister (&)Division of Molecular Genetics, German Cancer ResearchCenter, Heidelberg, Germanye-mail: s.pfister@dkfz.de

M. Remke ! S. M. PfisterDepartment of Pediatric Hematology and Oncology,Heidelberg University Hospital, Heidelberg, Germany

Y.-J. ChoDepartment of Neurology and Neurological Sciences,Stanford University School of Medicine, Stanford, USA

S. C. CliffordNorthern Institute for Cancer Research, Newcastle University,Newcastle upon Tyne, UK

C. G. EberhartDepartments of Pathology, Ophthalmology and Oncology,Johns Hopkins University School of Medicine, Baltimore, USA

D. W. ParsonsDepartment of Pediatrics, Texas Children’s Cancer Center,Baylor College of Medicine, Houston, USA

S. RutkowskiDepartment of Pediatric Hematology and Oncology,University Medical Center Hamburg-Eppendorf,Hamburg, Germany

A. GajjarDepartment of Oncology, St. Jude Children’s Research Hospital,Memphis, USA

D. W. EllisonDepartment of Pathology, St. Jude Children’s Research Hospital,Memphis, USA

R. J. GilbertsonDepartment of Developmental Neurobiology, St. Jude Children’sResearch Hospital, Memphis, USA

S. L. PomeroyDepartment of Neurology, Children’s Hospital Boston,Harvard Medical School, Boston, USA

123

Acta Neuropathol (2012) 123:465–472

DOI 10.1007/s00401-011-0922-z

CONSENSUS PAPER

Molecular subgroups of medulloblastoma: the current consensus

Michael D. Taylor • Paul A. Northcott • Andrey Korshunov • Marc Remke • Yoon-Jae Cho •

Steven C. Clifford • Charles G. Eberhart • D. Williams Parsons • Stefan Rutkowski • Amar Gajjar •

David W. Ellison • Peter Lichter • Richard J. Gilbertson • Scott L. Pomeroy • Marcel Kool •

Stefan M. Pfister

Received: 6 October 2011 / Revised: 19 November 2011 / Accepted: 22 November 2011 / Published online: 2 December 2011! The Author(s) 2011. This article is published with open access at Springerlink.com

Abstract Medulloblastoma, a small blue cell malignancyof the cerebellum, is a major cause of morbidity and mor-

tality in pediatric oncology. Current mechanisms for clinical

prognostication and stratification include clinical factors(age, presence of metastases, and extent of resection) as well

as histological subgrouping (classic, desmoplastic, and large

cell/anaplastic histology). Transcriptional profiling studiesof medulloblastoma cohorts from several research groups

around the globe have suggested the existence of multipledistinct molecular subgroups that differ in their demo-

graphics, transcriptomes, somatic genetic events, and

clinical outcomes. Variations in the number, composition,and nature of the subgroups between studies brought about a

consensus conference in Boston in the fall of 2010. Dis-

cussants at the conference came to a consensus that theevidence supported the existence of four main subgroups of

M. D. Taylor (&)Division of Neurosurgery, Hospital for Sick Children,University of Toronto, Toronto, Canadae-mail: mdtaylor@sickkids.ca

M. D. Taylor ! P. A. NorthcottProgram in Developmental and Stem Cell Biology,Arthur and Sonia Labatt Brain Tumour Research Centre,Hospital for Sick Children, University of Toronto,Toronto, Canada

A. KorshunovClinical Cooperation Unit Neuropathology,German Cancer Research Center, Heidelberg, Germany

M. Remke ! P. Lichter ! M. Kool ! S. M. Pfister (&)Division of Molecular Genetics, German Cancer ResearchCenter, Heidelberg, Germanye-mail: s.pfister@dkfz.de

M. Remke ! S. M. PfisterDepartment of Pediatric Hematology and Oncology,Heidelberg University Hospital, Heidelberg, Germany

Y.-J. ChoDepartment of Neurology and Neurological Sciences,Stanford University School of Medicine, Stanford, USA

S. C. CliffordNorthern Institute for Cancer Research, Newcastle University,Newcastle upon Tyne, UK

C. G. EberhartDepartments of Pathology, Ophthalmology and Oncology,Johns Hopkins University School of Medicine, Baltimore, USA

D. W. ParsonsDepartment of Pediatrics, Texas Children’s Cancer Center,Baylor College of Medicine, Houston, USA

S. RutkowskiDepartment of Pediatric Hematology and Oncology,University Medical Center Hamburg-Eppendorf,Hamburg, Germany

A. GajjarDepartment of Oncology, St. Jude Children’s Research Hospital,Memphis, USA

D. W. EllisonDepartment of Pathology, St. Jude Children’s Research Hospital,Memphis, USA

R. J. GilbertsonDepartment of Developmental Neurobiology, St. Jude Children’sResearch Hospital, Memphis, USA

S. L. PomeroyDepartment of Neurology, Children’s Hospital Boston,Harvard Medical School, Boston, USA

123

Acta Neuropathol (2012) 123:465–472

DOI 10.1007/s00401-011-0922-z

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

A full list of authors and affiliations appears at the end of the article.

SUMMARYWe recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

In BriefTorchia et al. show that atypical teratoid rhabdoid tumors (ATRTs) are composed of three epigenetic subgroups that correlate with differential cellular responses to a panel of signaling and

*Correspondence: ddecarv@uhnresearch.ca (D.D.D.C.), james.rutka@sickkids.ca (J.T.R.), nada.jabado@mcgill.ca (N.J.), annie.huang@sickkids.ca (A.H.).73Co-first author74Lead ContactACCESSION NUMBERSData for whole-genome/exome DNA and RNA sequencing, ChIP sequencing for H3K27Ac, ATAC sequencing, gene expression, methylation and SNP genotyping array data have been deposited at the European Genome-Phenome Archive, EGA Study Accession ID EGAS00001000506.SUPPLEMENTAL INFORMATIONSupplemental Information includes Supplemental Experimental Procedures, eight figures, and eight tables and can be found with this article online at http://dx.doi.org/10.1016/j.ccell.2016.11.003.AUTHOR CONTRIBUTIONSA.H., D.D.C., N.J., and J.T.R. conceived the projects. J.T. analyzed WGS/WES data assisted by L.L., M.B., S.M., A.V., B.G., M.D., P.S.C., and supervised by A.H., G.D.B., A.M., G.Bu., N.J., and M.Br. A.H. supervised RNA-seq analyses by J.T., D.M.G., and J.D.N.; gene expression and correlative analyses were carried out by J.T. with assistance from D.P. and G.D.B.; methylation data were collected by J.T. with assistance from D.P. and D.K.Q. ATAC and ChIP assays were performed by S.F., C.Z., K.C.H., T.M., and N.R.A. under supervision of D.D.C. Cellular, biochemical assays, and xenograft studies were performed by B.G., L.G., P.A., and K.C.H. with help from N.R.A., M.L., and M.Y. and supervised by A.H. A.C.P. performed 3C experiments supervised by D.D.C. J.T. performed analysis of ChIP and ATAC-seq data supervised by A.H. and D.D.C. in consultation with Ma.L. and P.G. Sequencing validation was performed under supervision of A.M., all other validation experiments were performed by B.G. and K.C.H. with assistance from T.S.C., A.N.R., and M.Y. under the supervision of A.H. and J.T.R. D.B., L.L.-C., Y.R., V.R., M.R., C.P.D., S.Y., H.-k.N., J.L., S.A., J.P., J.A.C., G.R.S., C.C.F., L.R., M.F., L.M.H., A.S.M., Y.W., S.A.C., J.R.H., D.C., D.K.B., N.F., D.S., A.K., M.G., P.H., T.H., L.B., B.W., J.H., A.C., T.E.V., E.I.H., S.C., H.N., H.T., I.F., H.D., D.F., T.W., C.F., D.D.E., K.S., D.J., J.M., S.Z., R.H., D.A.R., A.J..F., N.S., N.L., S.H., R.R.L., J.R.F., U.B., R.G., Da.M., U.S., T.N., T.T., J.Ph., J.Ma., S.Af., A.T.R., M.W.M., J.C.M., S.R., Y.G.G., M.D.T., U.T., T.P., A.R.J., E.B., S.K., A.E., P.D., and C.H.A. provided tumor materials/clinical data, and/or cell lines used in this study. Statistical analyses were performed by J.T. Histopathological analyses were performed by C.E.H. and M.Ba. J.T. and A.H. wrote the manuscript with input from B.G., D.D.C., N.J., and J.T.R.

HHS Public AccessAuthor manuscriptCancer Cell. Author manuscript; available in PMC 2017 July 07.

Published in final edited form as:Cancer Cell. 2016 December 12; 30(6): 891–908. doi:10.1016/j.ccell.2016.11.003.

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Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

A full list of authors and affiliations appears at the end of the article.

SUMMARYWe recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

In BriefTorchia et al. show that atypical teratoid rhabdoid tumors (ATRTs) are composed of three epigenetic subgroups that correlate with differential cellular responses to a panel of signaling and

*Correspondence: ddecarv@uhnresearch.ca (D.D.D.C.), james.rutka@sickkids.ca (J.T.R.), nada.jabado@mcgill.ca (N.J.), annie.huang@sickkids.ca (A.H.).73Co-first author74Lead ContactACCESSION NUMBERSData for whole-genome/exome DNA and RNA sequencing, ChIP sequencing for H3K27Ac, ATAC sequencing, gene expression, methylation and SNP genotyping array data have been deposited at the European Genome-Phenome Archive, EGA Study Accession ID EGAS00001000506.SUPPLEMENTAL INFORMATIONSupplemental Information includes Supplemental Experimental Procedures, eight figures, and eight tables and can be found with this article online at http://dx.doi.org/10.1016/j.ccell.2016.11.003.AUTHOR CONTRIBUTIONSA.H., D.D.C., N.J., and J.T.R. conceived the projects. J.T. analyzed WGS/WES data assisted by L.L., M.B., S.M., A.V., B.G., M.D., P.S.C., and supervised by A.H., G.D.B., A.M., G.Bu., N.J., and M.Br. A.H. supervised RNA-seq analyses by J.T., D.M.G., and J.D.N.; gene expression and correlative analyses were carried out by J.T. with assistance from D.P. and G.D.B.; methylation data were collected by J.T. with assistance from D.P. and D.K.Q. ATAC and ChIP assays were performed by S.F., C.Z., K.C.H., T.M., and N.R.A. under supervision of D.D.C. Cellular, biochemical assays, and xenograft studies were performed by B.G., L.G., P.A., and K.C.H. with help from N.R.A., M.L., and M.Y. and supervised by A.H. A.C.P. performed 3C experiments supervised by D.D.C. J.T. performed analysis of ChIP and ATAC-seq data supervised by A.H. and D.D.C. in consultation with Ma.L. and P.G. Sequencing validation was performed under supervision of A.M., all other validation experiments were performed by B.G. and K.C.H. with assistance from T.S.C., A.N.R., and M.Y. under the supervision of A.H. and J.T.R. D.B., L.L.-C., Y.R., V.R., M.R., C.P.D., S.Y., H.-k.N., J.L., S.A., J.P., J.A.C., G.R.S., C.C.F., L.R., M.F., L.M.H., A.S.M., Y.W., S.A.C., J.R.H., D.C., D.K.B., N.F., D.S., A.K., M.G., P.H., T.H., L.B., B.W., J.H., A.C., T.E.V., E.I.H., S.C., H.N., H.T., I.F., H.D., D.F., T.W., C.F., D.D.E., K.S., D.J., J.M., S.Z., R.H., D.A.R., A.J..F., N.S., N.L., S.H., R.R.L., J.R.F., U.B., R.G., Da.M., U.S., T.N., T.T., J.Ph., J.Ma., S.Af., A.T.R., M.W.M., J.C.M., S.R., Y.G.G., M.D.T., U.T., T.P., A.R.J., E.B., S.K., A.E., P.D., and C.H.A. provided tumor materials/clinical data, and/or cell lines used in this study. Statistical analyses were performed by J.T. Histopathological analyses were performed by C.E.H. and M.Ba. J.T. and A.H. wrote the manuscript with input from B.G., D.D.C., N.J., and J.T.R.

HHS Public AccessAuthor manuscriptCancer Cell. Author manuscript; available in PMC 2017 July 07.

Published in final edited form as:Cancer Cell. 2016 December 12; 30(6): 891–908. doi:10.1016/j.ccell.2016.11.003.

Author Manuscript

Author Manuscript

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