Post on 15-Jul-2020
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Bridging Genomics and Therapy
– Creating a Theranostics
Paradigm
Samuel Abraham, PhDVP Strategic Relationships
BC Cancer Agency
Diponkar Banerjee MBChB, PhD, FRCPCExecutive Medical Director
PHSA Laboratories
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Provincial - Implementation of Cancer Control
DawsonCreekPrince Rupert
Terrace
Kitimat
PrinceGeorge
Kelowna
Vernon
Kamloops
Cranbrook
Nelson
Powell River
Creston
Vancouver
Trail
Fraser Valley (Surrey)
Chilliwack
Penticton
Vancouver Island(Victoria)
Nanaimo
Port Alberni
Comox
Campbell River
Whitehorse, Yukon
• Central Agency office
•Cancer Research Centre (Vanc. Vict)
•Regional Cancer Centres
•Community Cancer Centres
•Community Cancer Clinics
•70 regional pharmacies
•Networks:
•hereditary cancer
•cervical cytology
•colposcopy clinics
•screening mammography centres
•palliative care
•surgical oncology council & network
Cancer Centre and
Research Centre
Cancer Centre
Consultative Clinic
Screening
Mammography
Centres, Cervical
Cytology Screening
Program
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Theranostics
Theranostics is the term coined by PharmaNetics [Ltd] to describe the use of diagnostic testing to diagnose a given disease, choose the correct treatment regimen and dose, and monitor the patient response to therapy on an individualized basis.
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Utility of Theranostics
• Disease risk prediction
• Disease diagnosis
• Disease prognosis
• Patient stratification
• Therapeutic stratification
• Monitoring therapeutic response
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The Limitations of Today’s Drug Therapies –
selected examples
25%
30%
30%
47%
48%
50%
50%
57%
60%
60%
62%
70%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Cancer (all)
Hypertension
Alzheimer's
Hepatitis C
Osteoporosis
Rheumatoid Arthritis
Migraine (Acute)
Diabetes
Asthma
Schizophrenia
Depression
Hypercholesterolemia
Dis
ease T
yp
e
Efficacy Rates
Average of all drugs = 60%)
From: Spear B et al. Trends in Molecular medicine Vol 7 201-204, 2001
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Drug Costs (Retail) in Canada
Estimated costs in 2006 = $25 billion
If, on average, 40% of drugs are ineffective, we are wasting $10 billion on useless therapy.
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IMPERATIVES
0
10000
20000
30000
40000
50000
1995
/96
1997
/98
1999
/00
2001
/02
2003
/04
2005
/06
2007
/08
2009
/10
2011
/12
Incidence Prevalence
• Incidence of Cancer
• Prevalence of Patients Receiving Drug Therapy
BC Cancer Agency Projections
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BC Cancer AgencyProjected Growth in Chemotherapy Drug Costs
($ Millions)
$0
$50
$100
$150
$200
$250
$300
95/9
6
96/9
7
97/9
8
98/9
999
/200
0
00/0
1
'01/
02
'02/
03
'03/
04
'04/
05
'05/
06
'06/
07
'07/
08
'08/
09
'09/
10
Non-drug global budget
Chemotherapy drug costs
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Emerging Paradigms Novel therapies will likely be gene-based
20% of current pharmaceutical R&D is gene-based – over 1600 gene based therapies are in development (66% in preclinical stage)*
Patient selection is required for targeted therapy (e.g. Herceptin) thus a predictive test for every new targeted therapy will be mandatory
Genetic analysis may predict for drug toxicity or efficacy (pharmacogenomics)
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Gene based R&D
51%
18%
12%8% 6% 5%
Cancer
Anti-Infective
Cardiovascular
Musculoskeletal
Neuro
Blood
Gene-based drug R&D programmes by therapy area
Source: R&Dfocus 2000
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Epithelial
progression
Survival
Predictive Diagnostic & Prognostic
Markers therapeutic Markers
Cancer
control
spectrumPrevention Early detection Diagnosis Treatment Palliation
End
points
Genomics
Cytology
Conventional Imaging
Histopathology
Surgery
Radiation
Systemic Therapy
DysplasiaCarcinoma
in Situ MetastasisHyperplasiaNormal
epitheliumLocally
Invasive Cancer
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Predictive and Personalized Oncology
Concept
All treated withchemotherapy
80% No therapy required
20% Therapy required
Unselected group Poor prognostic gene signature group
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Cost avoidance calculations for low grade
low stage breast cancer 2003
New
cases Node Neg Drug cost Radiation cost
Avoidable
costs @80%
BC 2,757 1,737 $7 million $5 million $10 million
Canada 21,200 13,356 $56 million $39 million $76 million
Developed
World 579,285 364,950 $1.5 billion $1 billion $2.1 billion
Global
1.05
million 661,500 $2.7 billion $2 billion $3.7 billion
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Cost avoidance calculations for low grade low
stage breast cancer - 2013
New cases Node
Negative
Drug cost Radiation
cost
Avoidable
costs @80%
BC 3,705 2,334 $100
million
$70
million
$136 million
Canada 27,505 17,328 $744
million
$517
million
$1 billion
Developed
World
751,579 473,495 $20 billion $14 billion $27 billion
Global 1.4
million
882,000 $38 billion $26 billion $51 billion
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When her hairdresser asked her last fall whether she would continue wearing her hair long, Elizabeth Sloan broke down crying.
Unbeknown to the hairstylist, Ms. Sloan had recently had a breast tumor removed and was expecting to begin chemotherapy, which would probably mean losing her hair.
But later that day, Ms. Sloan received the results of a new $3,500 genetic test, which indicated that her cancer probably would not come back even if she skipped chemotherapy.
"It was a huge relief," said Ms. Sloan, 40, a mother of two young boys who lives in Manhattan. "I did not want to napalm-bomb my body with chemicals."
The test taken by Ms. Sloan, known as Oncotype DX and offered by a company called Genomic Health, is part of a new wave of sophisticated genetic or protein tests that are starting to remake the diagnostics business, both for the technology they use and the way they are developed and sold.
April 13, 2006A Crystal Ball Submerged in a Test TubeBy ANDREW POLLACK
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Oncotype-DX
21 gene set (16 genes + 5 reference genes) – stratifies into low (score <18), intermediate (>18 < 30))and high (≥30) risk of recurrence at 10yrs
Works on formalin-fixed tissue
Recurrence score has predictive power beyond that of the St. Gallen or National Comprehensive Cancer Network risk stratification guidelines, sufficient to change some patient decisions about chemotherapy
About half of the 92% of patients who were in the high-risk National Comprehensive Cancer Network category were reclassified as low-risk by the recurrence score, with a 10-year relapse risk of 7% (CI, 4% to 11%)
From: Paik S. The Oncologist 2007; 12:631-635
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MammaPrint
70-gene signature Requires frozen tissue 40% of patients would fall into a good prognosis
group with 15% 10 yr recurrence rate (vs. 15% of patients being classified as within the good prognostic group by St. Gallen index)
33% of St. Gallen high risk group reclassified as low risk
From van de Vijver MJ et al. NEJM 2002 347: 199-2009
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Barriers to Theranostics The Pharmaceutical Industry’s blockbuster-drug business
model
The lack of interest in predictive tests from the drug industry – fear of loss of profits
Subset analysis of clinical trials results is discouraged
Funding mechanisms for drugs, physicians, and laboratories
Entrenched physician behaviour and unfamiliarity with concepts of genetic factors that influence response to drugs
Glacial pace of translating research discoveries to the clinical arena
Lack of funding from granting agencies for true translational research
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The Pharmaceutical Industry
Needs a Paradigm-Shift - 1
Threats
Drug companies spend ~$500 million in research for every drug that makes it to market (Includes the cost of drugs that fail).
Developing a predictive test could add an extra $100 million per drug.
For many targeted cancer drugs only a tenth of patients might be helped.
So investors backing the drug firm would spend 20% more to reach 90% fewer patients.
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Opportunities Rescue failed drugs
Reduce R&D costs
Faster FDA approval if trials are designed with biomarker-based stratification
Better results
Longer drug use to control disease
Reduce toxicity and side-effects
Partner with Health Authorities to reallocate resources from cost avoidance to introducing new targeted therapies.
The Pharmaceutical Industry
Needs a Paradigm-Shift - 2
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Challenges: Variations in the Human
genome
Type Frequency in human genome
Single nucleotide polymorphism (SNP)
12 million
Deletions/Insertions >1 million
Varying number of tandem repeats (VNTR)
>500,000
Copy number variations (CNV) >1500 loci (12% of genome)
Acquired Karyotypic and genetic abnormalities (mutations)
DNA methylation >20% of genome
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Post-transcription modifications that
influence gene product dose or function
MicroRNA (miRNA) – translational repression or mRNA degradation
Splice-variants
Post-translational modifications of proteins
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Quality Assurance Issues: Example Her2neu tests
in BC
Technologists and pathologists must be highly skilled
Need to test >100 cases a month to be proficient (JNCI 2002 94:788-789; 855-857)
Up to 33% of patients may be misclassified as Her2neu+ by small labs, with the following drawbacks:
Patients may inappropriately receive an expensive ($46,788) potentially cardiotoxic drug
No therapeutic benefit (the drug only works on a subset of true+ cases).
Decentralised testing may result in unnecessary drug expenditures of $12 million in an adjuvant setting
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Ethical Issues of Personalized
Therapy A technology that identifies patients who will
benefit from a given therapy automatically identifies those who won’t benefit – denial of therapy
“Never underestimate the desperation of a patient to obtain a drug” – Jan Platner (National Breast Coalition)
How accurate is the predictive test? –“Shopping” for a positive test
Offering toxic therapy to unselected patients (current practice)
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Thank you
Any questions?