Who Will Be Writing Your Prescriptions in the Future? ?· Who Will Be Writing Your Prescriptions in…

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<ul><li><p>1</p><p>Who Will Be Writing Your </p><p>Prescriptions in the Future?</p><p>Jared N. Schwartz, MD, PhD, FCAPDirector, Pathology &amp; Lab Medicine</p><p>Presbyterian HealthcareCharlotte, NC</p><p>President, College of American Pathologists </p><p>In the beginning God created the heavens and the earth. Now the earth was formless and empty, darkness was over the surface </p><p>of the deep, and the Spirit of God was hovering over the waters. </p><p>And God said, Let there be light, </p></li><li><p>2</p><p>and the light microscope was born</p><p>More than 100 years later, it is still the primary tool</p><p> 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</p><p> 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</p></li><li><p>3</p><p>These observations render it painfully obvious that unraveling the molecular features of cancer will </p><p>take many years, probably decades, and that the crucial role microscopy will continue to play during </p><p>this period will provide irreplaceable data if properly integrated with newer techniques. </p><p>Any new technique must provide information of prognostic or </p><p>therapeutic significance beyond that provided by the current gold </p><p>standard</p><p>Juan Rosai, MDLaboratory Investigation (2007) 87, 403408. </p><p>doi:10.1038/labinvest.3700551; published online 2 April 2007</p><p>Only if molecular markers are identified that robustly and specifically identify discrete cell populations will the need for histologic assessment disappear</p><p>Christopher A Moskaluk MD, PhDDepartment of Pathology, University of Virginia </p><p>Health System, Charlottesville, VA</p></li><li><p>4</p><p>I guess I was wrong</p><p>This challenge is intended to lay the groundwork for changing the basis of tumor classification from morphological to molecular characteristics.</p><p>1999 NIH Director Dr. Harold Varmus</p></li><li><p>5</p><p>Molecular profiling is a reality today Single Biomarker Analysis</p><p> IgH and T cell receptor gene rearrangements, together with analysis of specific translocations increasingly applied to the diagnosis oflymphoma</p><p> Microsatellite instability, either for diagnosis of hereditary nonpolyposiscolorectal cancer or for prognostication, is readily used in many centers</p><p> Fluorescence in situ hybridization is still the preferred mode of analysis of HER2-neu amplification status in breast cancer</p><p> 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</p><p> Presence of 1p/19q loss of heterozygosity has diagnostic and prognostic implications in brain neoplasms</p><p> Human papillomavirus subtype analysis by molecular testing advocated to play an important part in cervical screening</p><p> Translocation-related sarcomas accurately diagnosed by PCR translocation detection</p><p> Molecular fingerprinting revolutionizing analysis of putative metastases</p><p>Molecular profiling is a reality today Whole-genome approaches to molecular </p><p>diagnosis DNA microarray analysis used to assay DNA </p><p>and RNA content Single nucleotide polymorphisms (SNPs) that </p><p>can determine the presence of specific polymorphic sequences on chromosomes</p><p> Mass spectrometry</p></li><li><p>6</p><p>What is driving the growth in molecular testing</p><p> Many so-called blockbuster drugs show only limited efficacy in as many as 70% of treated patients</p><p> Current roster of phenotypically derived drugs that often treat only the symptoms of diseases is no longer acceptable to the public</p><p> High volume of adverse drug reactions caused by the failure to predict toxicity in individuals and toxic drug-drug interactions</p><p>The Integration of Molecular Diagnostics With Therapeutics, AJCP, Jeffrey S. Ross, MD, Geoffrey S. Ginsburg, MD, PhD </p><p>What is driving the growth in molecular testing</p><p> As many as 20% to 40% of people receiving pharmaceutical agents may be receiving the wrong drug</p><p> Discovery of the human genome and subsequent expansion of proteomics research combined with emerging technologies are producing unprecedented changes in today's health care</p><p> An increasingly educated public demanding more information about their predisposition for serious diseases</p><p>The Integration of Molecular Diagnostics With Therapeutics, AJCP, Jeffrey S. Ross, MD, Geoffrey S. Ginsburg, MD, PhD </p></li><li><p>7</p><p>Molecular diagnostics integration with therapeutics represents a major new opportunity for pathology</p><p>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, </p><p>and multi-drug combinations Pharmacogenomic measurements of drug efficacy and </p><p>risk of toxic effects Monitoring of the illness until the final disease outcome is </p><p>known</p><p>The future consequence of this trend is clear: conventional surgical pathology will not be less importantbut molecular testing, rather than </p><p>morphological characterization, may provide the decisive information for diagnosis and </p><p>treatment.</p><p>A Case for Integrated Morphomolecular Diagnostic PathologistsManuel Salto-Tellez</p><p>Department of Pathology, National University Hospital, Yong Loo Lin Medical School and, Oncology Research Institute, National University of </p><p>Singapore, Singapore </p></li><li><p>8</p><p>Clinical Chemistry 53: 1188-1190, 2007; 10.1373/clinchem.2007.088088</p><p>The Traditional Model: Pre-Molecular</p><p>Clinical Chemistry 53: 1188-1190, 2007; 10.1373/clinchem.2007.088088</p><p>Likely Emerging Model</p></li><li><p>9</p><p>Think about it</p><p>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</p><p>Pathologists are clinicians guiding patient care</p><p>Pathology</p></li><li><p>10</p><p>This expanded responsibility comes with challenges and </p><p>expectations</p><p>Quality Control is largely assumed</p><p>Treating physician assumes test is done right; pathologist assumes specimen was handled appropriately</p></li><li><p>11</p><p>State of the art QC practices for molecular diagnostic tests are lagging</p><p> New and rapidly evolving technologies High expectations of accuracy for once-in-</p><p>a-lifetime genetic tests Lack of quality control materials Lack of quantitative test system outputs The almost daily appearance of new </p><p>genetic test targets</p><p>Based on information from GeneTests, molecular genetic testing is presently performed for at least </p><p>1,000 diseases</p><p>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 </p><p>offered and the populations tested Low-volume testing for many </p><p>conditions and genetic targets Lack of standardization inherent in </p><p>in-house methods developed by individual laboratories</p></li><li><p>12</p><p>Majority of molecular tests continue to lack effective QC </p><p>What is needed: Determining error rates Availability of test system outputs </p><p>useful for monitoring each test system Adopting traditional QC protocols to </p><p>monitor system performance in order to prevent failure</p><p> QC materials useful for generating data for system monitoring and error prevention</p><p> increased proficiency requirements and samples for molecular tests</p><p> Built-in software to facilitate QC strategies</p><p>IVD Technology, Upgrading quality control in molecular diagnostics, Clark A. Rundell</p><p>A systems solution is required Test selection Specimen handling Exclusion criteria Assay validation Laboratory testing Use of control materials Reporting criteria</p></li><li><p>13</p><p>Case in Point: HER2</p><p> Results of clinical trials demonstrate significant benefit of HER2 targeted therapy for early stage breast cancer patients </p><p> Results from the same trials show significant variation in HER2 testing </p><p> Current quality assurance methods had not reduced testing variation </p><p> 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 </p><p>only for patients whose HER2 test is positive Test interpretation assumed by both clinician and patient to be accurate</p><p> Quantitative HER2 testing is different from the ordinary IHC stains QA systems and lab accreditation standards not specifically tailored </p><p>to ensure accuracy and precision of FISH and IHC HER2 testing Only about 25% of labs perform technical validation before offering </p><p>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 </p><p>Case: HER2 Testing</p></li><li><p>14</p><p>Impact on PatientsInappropriate Treatment</p><p> Up to 18% of patients could receive HER2 targeted therapy unnecessarily</p><p> Delays appropriate treatment Unnecessary expense ($70,000 $100,000 per </p><p>patient) Up to 10% of patients may not receive </p><p>appropriate HER2 targeted therapy</p><p>41 pathologists at CAP '07 took the Pilot HER2 SAM</p><p>HER2 Self-Assessment Module</p><p>Passed78%</p><p>Failed22%</p><p>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.</p><p>David Hicks, MD, FCAPDirector of Surgical PathologyUniversity of Rochester Medical CenterRochester, NY</p></li><li><p>15</p><p>Pathologists cant do it alone</p><p>Cross specialty communication &amp; </p><p>education is essential</p><p>CAP &amp; ASCO collaborated on KRAS gene mutation testing</p><p> KRAS normal No mutation identified Report will specify assay type and </p><p>controls used KRAS abnormal</p><p> Treatment with anti-EGFR monoclonal antibody therapy not recommended</p><p> Mutation found in codon 12 or 13 Report will specify what mutation was </p><p>found, what assay was done, and what controls were used</p><p>Based on systematic reviews of the relevant literature, all patients with metastaticcolorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory.</p><p>CAP: www.cap.org/POETJCO: http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2009.21.9170</p></li><li><p>16</p><p>Opportunity knocks</p><p>If we are unable to find a way to implement molecular profiling into our practices, surgical pathologists will be </p><p>excluded from one of the most exciting and transformational </p><p>developments to come around in a long time. And that, in my opinion as </p><p>an academic and molecular pathologist, would be a real shame.</p><p>Thomas J. Giordano, MD, PhDUniversity of Michigan</p></li><li><p>17</p><p>Never forget that it is not a pneumonia, but a </p><p>pneumonic man who is your patient. Not a typhoid fever, but a typhoid man</p><p>~William Withey Gull</p><p>Modern HealthcareA Crain Communication Publication</p><p>Hot Topic: The Questionable Future of the Microscope / Page 7</p><p>THE ONLY HEALTHCARE BUSINESS NEWS WEEKLY JANUARY 6, 2020</p><p>CAP leads caucus on standards development worldwide / Page 23</p><p>Pathologists take center stage in patient care</p><p>Pathologists take center stage in patient care</p><p>Disease diagnosis and treatment determination using molecular imaging from your local pathologist / Page 45</p><p>Modern HealthcareA Crain Communication Publication</p><p>Hot Topic: The Questionable Future of the Microscope / Page 7</p><p>THE ONLY HEALTHCARE BUSINESS NEWS WEEKLY JANUARY 6, 2020</p><p>CAP leads caucus on standards development worldwide / Page 23</p><p>Pathologists take center stage in patient care</p><p>Pathologists take center stage in patient care</p><p>Disease diagnosis and treatment determination using molecular imaging from your local pathologist / Page 45</p><p>Who will be writing your prescriptions </p><p>in the future? </p></li></ul>

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