How a Hospital Biobank Supports Patient Care and

How a Hospital Biobank Supports
Patient Care and Research Programs
National Cancer Center Hospital
Tokyo, Japan
October 25, 2012
Mark E. Sobel, MD, PhD
Executive Officer,
American Society for Investigative Pathology
[email protected]
The Era of Molecular Medicine
A transformation of the practice of
medicine AND the public’s fears and
•Molecular techniques
•Human Genome Project
•Information technology
Every Era Has Transformative Events
Giovanni Battista Morgagni
Images from: Encyclopaedia Britannica, adapted from Dr. Bruce McManus, University of British Columbia
To investigate the causes of
death, to examine carefully
the condition of organs, after
such changes have gone on in
them as to render existence
impossible and to apply such
knowledge to the prevention
and treatment of disease, is
one of the highest objects of
the physician.
—Sir William Osler (1849–1919)
Extracted from his Graduation thesis “Pathologic Anatomy”
Clinical Diagnostic Genome Sequencing
The introduction of high-throughput,
next-generation sequencing (NGS) in 2005
heralded a critical and transformative step
in the history of DNA sequencing.
•Human genome- the “whole genome” of a human
consists of 3 gigabytes of information
•3 billion base pairs of DNA
•46 chromosomes (diploid genome)
•Approximately 98% is “intergenic”
•“between genes”
•Junk DNA?
•Does not encode proteins
•Human exome
•2% of the genome
•22,000 pairs of genes
•On average, there are 8 exons (protein-encoding
segments) per gene = 176,000 exons
•Human transcriptome (DNA> RNA> protein)
•The expressed RNA transcripts of genes
•What a cell is doing at a particular point in time
•Genotype – what the cell is capable of doing
•Genome analysis
•Phenotype- what the cell is doing
•Proteomic analysis (proteins)
•Germline or somatic?
•Implications for immediate and extended family
•Implications for ethnic group
•“Normal” tissues
•Somatic•Acquired mutations
•Use of “diseased” tissues
•No heritable implications for family
Clinical Diagnostic Genome Sequencing
WGS: Whole genome sequencing
WGA: Whole genome analysis
Biospecimens are required!
Repository or Biobank?
•A repository is an organized collection of samples
•A biobank is a repository of biological samples
Biospecimens in a Human Biobank
•Tissue samples
•Resection of tissue (surgery)
•Dissection of tissue (autopsy)
•Blood, sputum, urine, bone marrow
•Associated data
•Clinical history
•Environmental history
•Family history
•Demographics (gender, age)
•How the sample was collected
Biospecimens in a Human Biobank
•Freshly obtained
•Formalin-fixed paraffin-embedded (FFPE)
•Other fixatives
Types of Biobanks
•Freezer banks or Cold storage rooms
•Glass slide collections
•Tissue blocks (FFPE)
•Liquid specimens (blood, urine…)
•Buccal (cheek) swabs
•Extracted analytes (DNA, RNA, protein, etc)
Who is Involved?
•Ethnic group
•Administrative assistants
•Laboratory technicians
•Ethical oversight
Requirements of Biobanks
•Record keeping
•Associated data
•Informed consent
•What permissions or restrictions are associated
with the use of the specimen?
•Controlled access – only authorized
individuals can retrieve specimens
Confidentiality and Privacy
•Confidentiality- the principle in medical ethics that the
information a patient reveals to a health care provider is
private and has limits on how and when it can be
disclosed to a third party
•Privacy - culturally specific concept defining the extent,
timing, and circumstances of sharing oneself
Identification of Specimens
• Anonymous- the sample was collected without the
identity of the donor
• Anonymized – the sample was collected with the
known identity, but the identification was
• Coded (Linked) – the sample is given a unique
identifier that cannot be easily deciphered
• Identified – the sample has a common identifier
(name, hospital number)
Personalized (Precision) Molecular Medicine
• Public’s expectations
– Improved health care
– Personalized medicine
• Public’s fears
– Loss of privacy
– Loss of employment
– Loss of insurance
– Social stigmatization
Why all the fuss?
Known abuses of populations and patients
Naxi experiments
Radiation experiments (U.S.)
Tuskegee Syphilis Study
Taking advantage of prisoners and mentally
Biomedical Research and Biobanks:
Translational Research involves interactions
between the laboratory bench and patient’s bed
•Increase knowledge
•Understand biological processes
•Improve public health
•New diagnostic tests
•New prognostic tests
•New or improved therapy
Biobanks and Clinical Research
Health Policy
Health Outcomes
Population and
Public Health
Research Involving Patients
Reduce Costs
Improve Health
Clinical Trials
Clinical Trials
Clinical Trials of
Clinical Trials of
of Drugs
of Devices
Models of Care
The Translational Research Cycle
The Biobank is Essential to Provide Solutions
Tissues, Cells, Fluids, &
Products and Dry Data
Genetics, Genomics, Proteomics,
Imaging, Physiology, Biophysics,
Biochemistry, Nanotechnology,
Informatics, Sociology, Epidemiology,
Investigative Models
Patients as Partners
Models of Human Disease
Pathophysiological and
Identification of Novel
Markers and Targets
Technology Transfer
Biomarker or Target
Assessment, Highthroughput Screening
Clinical Trials
Adapted from Dr. Bruce McManus, UBC
The Path to Clinical Implementation
from Translational Research
•Analytical validity - Technical feasibility and optimization
– does the test measure what we say?
•Clinical validity – Diagnostic accuracy - does the test
measure a value associated with a clinical condition?
•Sensitivity (false negatives)
•Specificity (false positives)
•Clinical utility
•will the test improve making a healthcare decision?
•Will the test be cost effective?
Goals of Personalized Medicine
50% of first treatments do not work
 Optimize treatment for individual patients
 Minimize adverse drug events
 Maximize drug efficacy
 Develop more targeted drugs
 The right drug at the right dose
Application to Oncology
Determine the preferred therapeutic agent
for each tumor
Ascertain which patients are most likely to
benefit from a given therapy
Patients with same diagnosis
Adapted, Courtesy Slide from Howard L. McLeod
Institute for Pharmacogenomics and Individualized Therapy
UNC – Chapel Hill, NC
All patients with same diagnosis
Toxic Responder: Lower dose or alternate drug
All patients with same diagnosis
Non-Responder: higher dose or alternate drug
Pharmacogenetics: The Study of Variations in Genes
that Affect Responses to Drugs
•Genetic changes specifically within malignant
tumor cells
•Inherited genetic variability in a targeted gene or
group of functionally-related genes affecting
response to drugs
Pharmacogenetics: The Study of Variations in Genes
that Affect Responses to Drugs
•Genetic changes specifically within malignant tumor
•Estrogen Receptor Status
•Treatment with SERMs- selective ER modulators
•Multigene analysis:
•OncoType DX assay (21 genes)
•MammaPrint assay (70 genes)
•Epidermal growth factor receptor (EGFR) Status
•HER2/neu (Herceptin therapy)
Pharmacogenetics: The Study of Variations in Genes
that Affect Responses to Drugs
•Genetic changes specifically within malignant
tumor cells
•Inherited genetic variability in a targeted gene or
group of functionally-related genes affecting
response to drugs
Pharmacokinetics: What the Body Does to the Drug
•Absorption – substance enters the body
•Distribution – drug disperses to fluids and tissues
•Metabolism – transform parent compound into
daughter compounds
•Excretion – elimination of parent drug and daughter
compounds from the body
Pharmacokinetic Metabolism:
transform parent compound into daughter
•Parent compounds are converted to metabolites
that are more water soluble so they can be more
easily excreted
•Bioactivation: Prodrugs are converted into
therapeutically active compounds
Cytochrome P450 Enzymes
•Supergene family
•Active in the liver and small intestine
•Named for the characteristic absorption spectra of
the protein products (450 nm)
•Human genome: 57 CYP genes
•15 genes involved in metabolism of xenobiotics
•75% of total metabolism of drugs
•14 genes involved in metabolism of sterols
•4 genes oxidize fat-soluble vitamins
•9 involved in metabolism of fatty acids and
•15 unknown function
CYP Nomenclature
CYP 2 D 6 *1
*1 is usually wild-type
Supergene family
Allelic variant
Approved by the US FDA for the treatment
and prevention of breast cancer
SERM: selective estrogen receptor
A Prodrug Requiring Extensive Metabolism
Genetic variants of CYP2D6 and drugs that modulate this enzyme
significantly affect outcome in tamoxifen-treated patients
Adapted from Goetz, M. P. et al. J Clin Oncol; 23:9312-9318 2005
CYP2D6 and Tamoxifen
•At least 70 CYP2D6 allelic variants
•Reduced activity of CYP2D6
→ reduced metabolism of tamoxifen
→ poor response to tamoxifen
•Classification of alleles
•Poor metabolizers
•Intermediate metabolizers
•Extensive metabolizers
•Ultrarapid metabolizers
•Ethnic variation –
•CYP2D6*4 – poor metabolizer
•12% - 21% Northern Europeans
•1% - 2% Asians and Black Africans
•CYP2D6*10 – intermediate metabolizer
•Most common allele in Asians
Tamoxifen Side Effects
Endometrial cancer
Thromoembolic events
Side effects of Tamoxifen and
Treatment with Antidepressants
•Hot flashes most common side effect
•Treated with antidepressants:
•SSRIs (selective serotonin reuptake inhibitors)
•Inhibit CYP2D6 activity
•Potent inhibitors (paroxetene, fluoxetine) reduce
endoxifen levels
•Less potent inhibitors (venlafaxine) have little effect
•Patients with decreased metabolism:
•Shorter time to recurrence
•Worse relapse-free survival
•Potent CYP2D6 inhibitors such as certain SSRIs are
contraindicated in tamoxifen-treated patients
CYP2D6 Poor Metabolizers
•Patients diagnosed with breast cancer should be
treated with alternatives to tamoxifen (e.g.
aromatase inhibitors)
•For breast cancer prevention, raloxifene is a
viable alternative to tamoxifen
Recommended reading:
Snozek CLH, O’Kane DJ, and Algeciras-Schimnich A.:
Pharmacogenetics of Solid Tumors: Directed Therapy in
reat, Lung, and Colorectal Cancer. J Mol Diagn 2009,
11:381-389, DOI: 10.2353/jmoldx.2009.090003
Clinical Diagnostic Genome Sequencing
The introduction of high-throughput,
next-generation sequencing (NGS) in 2005
heralded a critical and transformative step
in the history of DNA sequencing.
Coming to a clinic near you…
NGS Technology
All NGS technologies offer the ability to
simultaneously sequence thousands to
millions of relatively short nucleic acid
sequences in parallel. They can provide
orders of magnitude more information, at
competitive costs, when large regions of
the genome are sequenced.
This report of the Whole Genome Analysis group of the Association for Molecular Pathology
illuminates the opportunities and challenges associated with clinical diagnostic genome
sequencing. With the reality of clinical application of next-generation sequencing, technical aspects
of molecular testing can be accomplished at greater speed and with higher volume, while much
information is obtained. Although this testing is a next logical step for molecular pathology
laboratories, the potential impact on the diagnostic process and clinical correlations is
extraordinary and clinical interpretation will be challenging. We review the rapidly evolving
technologies; provide application examples; discuss aspects of clinical utility, ethics, and consent;
and address the analytic, postanalytic, and professional implications. (J Mol Diagn 2012,
The Potential of Tissue Based Analysis
Basic Ethical Principles
Ideal of respect for persons
•Public beneficence
•Responsible stewardship
•Intellectual freedom and responsibility
•Democratic deliberation
•Justice and fairness
Presidential Commission
for the Study of Bioethical Issues
Washington, DC
October 2012
Society for
Biological and
Communication among
Repositories across the Globe
A Division of American Society for Investigative Pathology
ISBER’s Mission
ISBER creates opportunities for
sharing ideas internationally and
harmonizing approaches to
evolving challenges in
biobanking and repository

similar documents