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  1. AACC WORKSHOP #2102[LECTURE #1]Tumor Markers: How We Use Them In The Clinic And New DevelopmentsFaculty:Eleftherios P. Diamandis, MD, PhD, FRCPC(Workshop Leader: ediamandis@mtsinai.on.ca)Daniel W.Chan,Ph.D(dchan@jhmi.edu)Martin Fleisher, PhD(fleishem@mskcc.org)AACC 2005

  2. TUMOR MARKERS: HOW WE USE THEM IN THE CLINIC AND NEW DEVELOPMENTS9:30 - 10:15AM - Tumor Markers: Historical Perspective and Current Clinical Applications [E.P. Diamandis]10:15 - 10:45AM - Guidelines for Use of Tumor Markers [M. Fleisher] 10:45 - 11:00AM -Break11:00 - 12:00PMGuidelines for Use of Tumor Markers (Continued)[M. Fleisher]12:00 - 12:30PM Questions / Discussion12:30 - 1:30PM - Lunch1:30 - 2:30PM - Tumor Markers-Present and Future [E.P.Diamandis]2:30 - 2:45PM - Clinical Cases [D.W.Chan]2:45 - 3:00PM Break3:00 -4:00 PM - Clinical Cases (Continued) [D.W.Chan]4:00 - 4:30PM Panel Discussion / Questions [All Faculty] AACC2005

  3. Where could you find the presentations? • Go to my website • www.acdclab.org • Click on ‘Workshops” • Find AACC 2005 workshops • Follow the instructions as to how to download the files AACC2005

  4. Available by AACC Press (published 2002) Special discount if ordered at this meeting AACC 2005

  5. Tumor Markers - General InformationbyEleftherios P. DiamandisAACC 2005

  6. AACC 2005

  7. AACC 2005

  8. Death Rates from Cancer and Heart Disease in USA from 1975-2001 Cancer: The #1 Killer Jemal A et al. CA Cancer J Clin 2005;55:10-30

  9. #1 Killer

  10. Lung & Bronchus Rate per 100,000 Males Stomach Prostate Colon & Rectum Pancreas Liver Leukemia Year of Death Annual Cancer Death Rates Among Males for Selected Cancer Types, US 1930-2001 Jemal et al. CA Cancer J Clin 2005; 55: 10-30

  11. What is a “tumor marker”? • a substance present in or produced by a tumor OR • a substance produced by the hostin response to the tumor’s presence • present in cells, tissues, bodily fluids

  12. What is a tumor marker used for? Use: • to determine the presence of a tumor Measurement: • qualitative or quantitative methods:• chemical• immunological• molecular biological

  13. Historical Background

  14. The “Ideal” Tumor Marker (TM) • Measured easily, reliably and cost-effectively using an assay with highanalyticalsensitivity and specificity. • Quantitative level of TM reflects tumor burden with highdiagnosticsensitivity (few FNs) with specificity (few FPs). • Test results influence patient care and especially outcome.

  15. Clinical Uses of Tumor Markers • Screening - limited • Diagnosis -limited • Prognosis - limited • Tumor staging - limited • Tumor localization / radiotherapy - limited • Monitoring the effectiveness of therapy - important • Detecting tumor recurrence or remission - important

  16. Types of Tumor Markers•Hormones (hCG; calcitonin; gastrin; prolactin; growth hormone, etc.)•Enzymes (acid phosphatase; alkaline phos- phatase; PSA)•Proteins & Glycoproteins (CA 125; CA 15.3; CA 19.9, etc.)•Oncofetal antigens (CEA, AFP)• Receptors (ER, PR, EGFR)•Oncogenes (Ras; Myc; abl-bcr)•Tumor suppressor genes (BRCA1; p53; Rb)AACC 2005

  17. Usefulness of Laboratory Tests• Affected by analytical and diagnostic sensitivity and specificity AND a test’s positive predictive value (PPV).• PPV: Probability that an individual with a positive test result has the disease for which the test was developed to assist in diagnosing.• PPV, unlike NPV, markedly influenced by the prevalence of disease in the population tested.AACC 2005

  18. Analytical vs Diagnostic Sensitivity• Analytical sensitivity: minimum detectable concentration (MDC) of an antigen that an immunoassay can reliably distinguish from “zero” concentration with 95% confidence.• Diagnostic sensitivity: proportion of individuals with disease who yield a positive test for antigen [i.e. TP / (TP + FN)].AACC 2005

  19. Analytical vs Diagnostic Specificity•Analytical specificity: ability of an immunoassay to measure only the analyte of interest (freedom from interferences); expressed typically as % cross-reactivity.• Diagnostic specificity: proportion of individuals without disease who yield a negative test for antigen [i.e. TN / (TN + FP)].AACC 2005

  20. Calculation of Predictive Value Parameters (2x2 Table)________________________________________________Assumptions: Disease prevalence = 1% Population tested = 100,000 No. w/disease (0.01 x 100,000)= 1,000 Test sensitivity = 95% Test specificity = 95%-------------------------------------------------------------------------Test ResultsNo. with DiseaseNo. w/o DiseaseTotalPos 950 (TP) 4,950 (FP) 5,900Neg 50 (FN) 94,050 (TN) 94,100Total 1,000 99,000 100,000-------------------------------------------------------------------------Sensitivity = TP/ (TP + FN) = 950/ (950 + 50) = 950/ 1,000 = 95%Specificity = TN/ (TN + FP) = 94,500/ (94,050 + 4,950) = 94,050/ 99,000 = 95%PPV = TP/ (TP + FP) = 950/ (950 + 4,950) = 950/ 5,900 = 16.10%NPV = TN/ (TN + FN) = 94,050/ (94,050 + 50) = 99.95% or ~100%Eff = (TP + TN)/ Grand Tot = (950 + 94,050)/ 100,000 = 95,000/ 100,000 = 95%AACC 2005

  21. Effect of Prevalence of Disease on PPV and NPV_________________________________________________Disease PPV of pos NPV of negprevalence, % test result, % test result, %0.1 1.9 99.9 1 16.1 99.9 10 67.9 99.4 50 95 95.0 100 100.0 n.a._________________________________________________* For a test with 95% diagnostic sensitivity and 95% diagnostic specificity; n.a. - not applicableAACC 2005

  22. How To Improve PPV•To improve the PPV of a laboratory test, clinicians should increase the prevalence of disease by appropriate selection of patients for whom the test is ordered.AACC 2005

  23. Critical Clinical Questions1.Does a patient have cancer?2. If yes, which organ is afflicted?3. Is the cancer localized or disseminated?4. How aggressive is the cancer?5. Will the patient likely relapse or not relapse if no adjuvant therapy is given post-primary treatment?6. Will the patient respond better if one treatment type is given instead of another one?7. Can cancer relapse post-primary therapy be detected before the patient has symptoms?8. If yes, can the patient get a benefit with early treatment of relapse?AACC 2005

  24. Clinical Uses of Tumor Markers•Screening for cancer - limited• Diagnosing cancer - limited• Evaluating cancer prognosis-limited• Tumor staging-limited• Detecting Tumor Recurrence or remission-important• Localizing tumor and directing chemo- or radio-therapeutic agents- limited• Monitoring the effectiveness of cancer therapy-important AACC 2005

  25. Outcome•Screening for cancer using assays for TMs should increase the early detection of cancer and the long-term survival of treated patients and decrease their morbidity and mortality.• None of the currently available TMs are “perfect” (i.e. 100% diagnostic sensitivity and 100% diagnostic specificity). AACC 2005

  26. Reference (Normal) Ranges For Cancer Markers• Healthy subjects (how many?)• Sex• Relevant age population• Benign conditions• Selection of patient population (stage, grade, histological type, etc.)• Selection of appropriate cutoff: - maximize sensitivity - maximize specificity - maximize predictive valueAACC 2005

  27. Receiver Operating Characteristic (ROC) Curve • Plot of: • sensitivity(true positive rate) [y-axis] vs. • 1-specificity(false positive rate) [x-axis] • Displays performance of a test over the entire range of cutoff values. • You can select a cutoff value that offers the desired sensitivity and/or specificity. • Predictive value of various markers on the same plot.

  28. AACC 2005

  29. 1 2 4 0.2 6 0.3 10 0.4 20 0.6 0.8 1.2

  30. Discovery of New Tumor MarkersVery good prospects•Human Genome Project will unravel all genes and all proteins• Tissue-specific expression will be established (microarrays; 2 years)• Differential expression of genes in normal vs diseased tissues (microarrays; 2 years)• All proteins and antibodies will become available (3-5 years)• Disease profiling with biomarkers (microarrays; mass spectrometry)AACC 2005

  31. The FuturePredictions about the future will be presented in another lecture[1:30-2:30 PM]AACC 2005