The maturation of genomic technologies has enabled new discoveries in disease pathogenesis as well as new approaches to patient care. In pediatric oncology, patients may now receive individualized genomic analysis to identify molecular aberrations of relevance for diagnosis and/or treatment. Several recent clinical studies have begun to explore the feasibility and utility of genomics-driven precision medicine.

1. PERSONALIZED MEDICINE IN
PAEDIATRIC CANCER
Amir Abbas Hedayati-Asl
Ped. Hematologist Oncologist /BMT
Tehran University of Medical Sciences, HORC-SCT
Royan Institute
Cancer Personalized Medicine Program
Stem Cell Biology and Technology Department

2. INTRODUCTION
 The maturation of genomic technologies has enabled
new discoveries in disease pathogenesis as well as new
approaches to patient care.
 In pediatric oncology, patients may now receive
individualized genomic analysis to identify molecular
aberrations of relevance for diagnosis and/or treatment.
 Several recent clinical studies have begun to explore the
feasibility and utility of genomics-driven precision
medicine.
 We review the major developments in this field, discuss
current limitations, and explore aspects of the clinical
implementation of precision medicine, which lack
consensus.
 Lastly, we discuss ongoing scientific efforts in this arena,
which may yield future clinical applications.

3. SINCE THE 1990S:
PROGRESS BY MANY MEASURES
Treatment
• New therapies
• Imaging,
radiation
oncology and
surgery
advances
• Precision
medicine
• Immunotherapy
Prevention
• Interventions for
infection-related
cancers
• Cancer
susceptibility
genes
• Drug and
surgical risk
reduction
strategies
Quality of
Life
• Better toxicity
management
• Less intensive
therapies
• Palliative care
integration
Survivorship
• Growing
research area
• Late effects
identified
• Surveillance
strategies
established

4. SINCE THE 1990S:
MORTALITY DOWN, SURVIVORSHIP UP
In the United States…

5. PRECISION MEDICINE/ NIH
 Precision medicine is broadly defined by the
National Institutes of Health as “an emerging
approach for disease treatment and prevention that
takes into account individual variability in genes,
environment, and lifestyle for each person.”
 The Obama administration's January 2015
announcement of the Precision Medicine Initiative
(PMI) takes a step forward in efforts to move
precision medicine into clinical practice.[

6. OBAMA’S PRECISION MEDICINE
INITIATIVE
“Most medical treatments have been designed for the “average patient”.
As a result of this ‘one-size-fits-all-approach,’ treatments can be very
successful for some patients but not for others.”
The promise: $215 million investment split among the NIH, NCI, FDA, &
ONC
The objectives:
 More and better treatments for cancer
 Creation of a voluntary national research cohort
 Commitment to protecting privacy
 Regulatory modernization
 Public-private partnerships
State of the Union, 2015
https://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative

7. PMI
 With $215 million in planned funding for fiscal year
2016, the PMI aims to leverage next-generation
sequencing capabilities, improved biospecimen
analytics, and tools for the management of large
data sets to generate outcome data that will
facilitate movement from the research realm into
clinical care.
 Recently, the National Cancer Moonshot Initiative,
announced by President Obama during the 2016
State of the Union address and motivated by the
death of Vice President Joseph Biden's son to brain
cancer, has proposed expanding governmental
involvement and financial support upwards of $4
billion.

9. DEFINITIONS
 Pharmacogenomics: the study of the role genetics
plays in drug response
 Precision medicine: customization of medical
decisions and courses of treatment based on the
individual patient
 Personalized medicine: creation of new
treatments in response to a particular patient’s
need

10. GENOMICS VS GENETICS
 Genomics refers to the study of the entire genome
of an organism
 Genetics refers to the study of a particular gene

20. What is targeted therapy ?

21.  Will personalized therapy replace treatment
protocols for childhood cancer in the future?
 Yes
 No
 Maybe for some tumor
 Maybe for relapsed patients

30. Germline
Variation
Somatic
Mutation
Personalized
Care
PRECISION MEDICINE:
SCIENCE SERVING PATIENTS

31. CHILDHOOD CANCER GENOMICS:
The Current Landscape and Future
Directions
 Leading international researchers and pediatric cancer
advocates will discuss opportunities and gaps in the
research in 4 main tumor types:
 Brain cancers
 Leukemias
 Embryonal tumors
 Sarcomas

32. WHAT ABOUT PREDICTIONS?
In Silico Predictive models
Predict the optimal treatment/ therapy
outcome

33. CANCER GENOMICS
Genetic subtypes of
glioblastoma, gastric
and other cancers
identified via TCGA
research
2005
Hallmarks of
Cancer published
2000 2010-2014
• Advent of the “precision medicine” era
• But cancer’s biology is far more complex than we had imagined
The Cancer Genome
Atlas (TCGA)
launches

34. Cancer Genomics
Genomic Landscape of 5,000 Human Cancers

35. PRECISION MEDICINE
Cancers classified by molecular abnormalities and site of origin
Exceptional success when treatment is matched to a driver
mutation
20011998
First targeted
drug: rituximab
Trastuzumab
introduced for
HER2+ breast
cancer Imatinib
introduced
1997-2016
100+ FDA-
approved targeted
cancer drug
indications
1997

36. RISE OF IMMUNOTHERAPY
20142011
• Long-term disease control against recalcitrant cancers
• Game-changing discoveries – more coming
Ipilimumab
introduced for
melanoma
Pembrolizumab,
nivolumab
approved for
melanoma
2015-2016
PD-1/L-1 drugs
benefit even
more of
cancers
2016 ASCO
Advance of the Year

37. On the Horizon:
 CART-cell therapy
 Customized vaccines
Rise of Immunotherapy

40. MULTIDISCIPLINARY TUMOR BOARD
Medical
Monitor
Patient
Treatment
Tumor Board
B
Pharmacists
Ped .Oncologist Bioinformatics and
Genomics Experts
Medical Genetics Expert
Pathologist
BRadiologist

42. Pediatric Blood & Cancer
Volume 64, Issue 3, 17 OCT 2016 DOI: 10.1002/pbc.26288
http://onlinelibrary.wiley.com/doi/10.1002/pbc.26288/full#pbc26288-fig-0001

43. Pediatric Blood & Cancer
Volume 64, Issue 3, 17 OCT 2016 DOI: 10.1002/pbc.26288
http://onlinelibrary.wiley.com/doi/10.1002/pbc.26288/full#pbc26288-fig-0002

52. Pilot patient INF_03 with myofibroblastic sarcoma.
(A) Schematic image of the CARS:ALK fusion. The copy number plots of the involved
chromosomes, generated by low-coverage whole-genome sequencing, indicate the genomic
break points.
(B) Magnetic resonance imaging (MRI, T1 with contrast agent, coronal view) of the tumour at
diagnosis (left) and after 6 weeks of ALK-inhibitor treatment.

55. CONCLUSION /INFORM
 The INFORM project is a comprehensive nationwide
approach to rapidly profile highly aggressive tumors of
children and young adults.
 Sample preparation, data generation and interpretation
have been optimized to allow for complete analysis within
4 weeks, enabling rapid translation into clinical decision
making.
 In addition, the data generated give new insights into
tumor evolution and possible resistance mechanisms in
relapsed disease.
 As a next step, access to such programs must be
expanded, and biomarker-driven, cross-entity phase I/II
combination trials for pediatric patients are required.