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    Who Will Be Writing Your

    Prescriptions in the Future?

    Jared N. Schwartz, MD, PhD, FCAPDirector, Pathology & Lab Medicine

    Presbyterian HealthcareCharlotte, NC

    President, College of American Pathologists

    In the beginning God created the heavens and the earth. Now the earth was formless and empty, darkness was over the surface

    of the deep, and the Spirit of God was hovering over the waters.

    And God said, Let there be light,

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    and the light microscope was born

    More than 100 years later, it is still the primary tool

    Majority of tissue-based diagnostics is still based on the interpretation of the morphologic characteristics of fixed and stained cells and tissues as seen under the microscope

    An experienced surgical pathologist may confidently render an unequivocal diagnosis of a malignant neoplasm with as few as 10 cells from a biopsy that contains thousands

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    These observations render it painfully obvious that unraveling the molecular features of cancer will

    take many years, probably decades, and that the crucial role microscopy will continue to play during

    this period will provide irreplaceable data if properly integrated with newer techniques.

    Any new technique must provide information of prognostic or

    therapeutic significance beyond that provided by the current gold


    Juan Rosai, MDLaboratory Investigation (2007) 87, 403408.

    doi:10.1038/labinvest.3700551; published online 2 April 2007

    Only if molecular markers are identified that robustly and specifically identify discrete cell populations will the need for histologic assessment disappear

    Christopher A Moskaluk MD, PhDDepartment of Pathology, University of Virginia

    Health System, Charlottesville, VA

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    I guess I was wrong

    This challenge is intended to lay the groundwork for changing the basis of tumor classification from morphological to molecular characteristics.

    1999 NIH Director Dr. Harold Varmus

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    Molecular profiling is a reality today Single Biomarker Analysis

    IgH and T cell receptor gene rearrangements, together with analysis of specific translocations increasingly applied to the diagnosis oflymphoma

    Microsatellite instability, either for diagnosis of hereditary nonpolyposiscolorectal cancer or for prognostication, is readily used in many centers

    Fluorescence in situ hybridization is still the preferred mode of analysis of HER2-neu amplification status in breast cancer

    EGFR mutation analysis is commonly used for therapeutic decision-making in lung cancer as is detection of KIT (c-kit) mutations in gastrointestinal stromal tumors

    Presence of 1p/19q loss of heterozygosity has diagnostic and prognostic implications in brain neoplasms

    Human papillomavirus subtype analysis by molecular testing advocated to play an important part in cervical screening

    Translocation-related sarcomas accurately diagnosed by PCR translocation detection

    Molecular fingerprinting revolutionizing analysis of putative metastases

    Molecular profiling is a reality today Whole-genome approaches to molecular

    diagnosis DNA microarray analysis used to assay DNA

    and RNA content Single nucleotide polymorphisms (SNPs) that

    can determine the presence of specific polymorphic sequences on chromosomes

    Mass spectrometry

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    What is driving the growth in molecular testing

    Many so-called blockbuster drugs show only limited efficacy in as many as 70% of treated patients

    Current roster of phenotypically derived drugs that often treat only the symptoms of diseases is no longer acceptable to the public

    High volume of adverse drug reactions caused by the failure to predict toxicity in individuals and toxic drug-drug interactions

    The Integration of Molecular Diagnostics With Therapeutics, AJCP, Jeffrey S. Ross, MD, Geoffrey S. Ginsburg, MD, PhD

    What is driving the growth in molecular testing

    As many as 20% to 40% of people receiving pharmaceutical agents may be receiving the wrong drug

    Discovery of the human genome and subsequent expansion of proteomics research combined with emerging technologies are producing unprecedented changes in today's health care

    An increasingly educated public demanding more information about their predisposition for serious diseases

    The Integration of Molecular Diagnostics With Therapeutics, AJCP, Jeffrey S. Ross, MD, Geoffrey S. Ginsburg, MD, PhD

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    Molecular diagnostics integration with therapeutics represents a major new opportunity for pathology

    to emerge as leaders of the new medicine Detection of disease predisposition Screening and early disease diagnosis Prognosis assessment Guiding the selection, dosage, route of administration,

    and multi-drug combinations Pharmacogenomic measurements of drug efficacy and

    risk of toxic effects Monitoring of the illness until the final disease outcome is


    The future consequence of this trend is clear: conventional surgical pathology will not be less importantbut molecular testing, rather than

    morphological characterization, may provide the decisive information for diagnosis and


    A Case for Integrated Morphomolecular Diagnostic PathologistsManuel Salto-Tellez

    Department of Pathology, National University Hospital, Yong Loo Lin Medical School and, Oncology Research Institute, National University of

    Singapore, Singapore

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    Clinical Chemistry 53: 1188-1190, 2007; 10.1373/clinchem.2007.088088

    The Traditional Model: Pre-Molecular

    Clinical Chemistry 53: 1188-1190, 2007; 10.1373/clinchem.2007.088088

    Likely Emerging Model

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    Think about it

    Your diagnosis of invasive malignancy triggers a course oftherapy for a breast cancer patient that may include a dangerous and traumatic course of surgery, chemotherapy and radiation

    Pathologists are clinicians guiding patient care


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    This expanded responsibility comes with challenges and


    Quality Control is largely assumed

    Treating physician assumes test is done right; pathologist assumes specimen was handled appropriately

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    State of the art QC practices for molecular diagnostic tests are lagging

    New and rapidly evolving technologies High expectations of accuracy for once-in-

    a-lifetime genetic tests Lack of quality control materials Lack of quantitative test system outputs The almost daily appearance of new

    genetic test targets

    Based on information from GeneTests, molecular genetic testing is presently performed for at least

    1,000 diseases

    Accuracy and reliability of molecular Dx tests can be influenced by many factors: Diversity of testing methodology Rate of technology evolution Variety of applications Regional differences in the tests

    offered and the populations tested Low-volume testing for many

    conditions and genetic targets Lack of standardization inherent in

    in-house methods developed by individual laboratories

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    Majority of molecular tests continue to lack effective QC

    What is needed: Determining error rates Availability of test system outputs

    useful for monitoring each test system Adopting traditional QC protocols to

    monitor system performance in order to prevent failure

    QC materials useful for generating data for system monitoring and error prevention

    increased proficiency requirements and samples for molecular tests

    Built-in software to facilitate QC strategies

    IVD Technology, Upgrading quality control in molecular diagnostics, Clark A. Rundell

    A systems solution is required Test selection Specimen handling Exclusion criteria Assay validation Laboratory testing Use of control materials Reporting criteria

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    Case in Point: HER2

    Results of clinical trials demonstrate significant benefit of HER2 targeted therapy for early stage breast cancer patients

    Results from the same trials show significant variation in HER2 testing

    Current quality assurance methods had not reduced testing variation

    HER2 testing: not simply a special stain; a single observation leads to a major difference in treatment Testing critical to patient and clinician since trastuzumab is effective

    only for patients whose HER2 test is positive Test interpretation assumed by both clinician and patient to be accurate

    Quantitative HER2 testing is different from the ordinary IHC stains QA systems and lab accreditation standards not specifically tailored

    to ensure accuracy and precision of FISH and IHC HER2 testing Only about 25% of labs perform technical validation before offering

    HER2 testing Only about 33% of labs offering HER2 testing participate in PT ~50% of labs that use FDA-approved IHC kits vary from the approved method

    Case: HER2 Testing

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    Impact on PatientsInappropriate Treatment

    Up to 18% of patients could receive HER2 targeted therapy unnecessarily

    Delays appropriate treatment Unnecessary expense ($70,000 $100,000 per

    patient) Up to 10% of patients may not receive

    appropriate HER2 targeted therapy

    41 pathologists at CAP '07 took the Pilot HER2 SAM

    HER2 Self-Assessment Module



    It's our feeling that anyone doing HER2 testing should be able to pass the test. If they couldn't, they had some knowledge gaps that need to be addressed.

    David Hicks, MD, FCAPDirector of Surgical PathologyUniversity of Rochester Medical CenterRochester, NY