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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 mesobel@asip.org http://www.asip.org/about/executive_officer.cfm.
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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 mesobel@asip.org http://www.asip.org/about/executive_officer.cfm
The Era of Molecular Medicine A transformation of the practice of medicine AND the public’s fears and expectations Molecular techniques Human Genome Project Information technology
Every Era Has Transformative Events Giovanni Battista Morgagni (1682—1771) Images from: EncyclopaediaBritannica, 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.
Definitions 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
Definitions Genotype – what the cell is capable of doing Genome analysis Phenotype- what the cell is doing Proteomic analysis (proteins) Germline or somatic? Germline- Inheritability 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 Biopsy 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 Frozen Fixed Formalin-fixed paraffin-embedded (FFPE) Alcohol-fixed 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? Donor Patient Family Ethnic group Physician Nurse 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? Temperature Humidity Light/dark 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 Physical Behavioral Medical
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 removed • 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 handicapped
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 Research Population and Public Health Translational Research Health Outcomes Research Research Involving Patients Reduce Costs Improve Health Clinical Trials of Devices Clinical Trials of Diagnostics Clinical Trials of Models of Care Clinical Trials of Drugs
The Translational Research Cycle The Biobank is Essential to Provide Solutions BiobankTissues, Cells, Fluids, & Products and Dry Data ToolsGenetics, Genomics, Proteomics, Imaging, Physiology, Biophysics, Biochemistry, Nanotechnology, Informatics, Sociology, Epidemiology, Statistics Investigative ModelsPatients as PartnersModels of Human Disease Translational Research Cycle Pathophysiological and Sociobiological Processes Research Questions Identification of Novel Markers and Targets Technology Transfer Biomarker or Target ValidationMulti-population Assessment, High-throughput ScreeningClinical Trials
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 cells • Estrogen Receptor Status • Treatment with SERMs- selective ER modulators • Tamoxifen • Raloxifene • 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 metabolites • 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 eicosanoids • 15 unknown function
Supergene family Family Subfamily Isoenzyme Allelic variant CYP Nomenclature CYP2D6*1 *1 is usually wild-type
Tamoxifen Approved by the US FDA for the treatment and prevention of breast cancer Anti-estrogen SERM: selective estrogen receptor modulator
Tamoxifen: A Prodrug Requiring Extensive Metabolism 4-hydroxyTAM Tamoxifen CYP2D6 MINOR METABOLITE - 100X POTENCY CYP3A4/5 CYP3A4/5 CYP2D6 N-desmethylTAM Endoxifen MAJOR METABOLITE- SAME POTENCY MODERATE METABOLITE- 100X POTENCY 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 • Poormetabolizers • Intermediatemetabolizers • Extensivemetabolizers • Ultrarapidmetabolizers • 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 Hot flashes 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.
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, 14:525540; http://dx.doi.org/10.1016/j.jmoldx.2012.04.006)
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 http://www.bioethics.gov
International Society for Biological and Environmental Repositories Communication among Repositories across the Globe www.isber.org 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 operation.