MLAB 2401: Clinical Chemistry Keri Brophy-Martinez

1. MLAB 2401: Clinical ChemistryKeri Brophy-Martinez Tumor Markers

2. Introduction • Cancer is the second leading cause of death in North America, accounting for > 2.7 million deaths annually. • Although it is often specified as a single disorder, cancer is a broad term used to describe > 200 different diseases that affect more than 50 tissues.

3. Introduction • Cancer • Uncontrolled growth of cells that can develop into a solid mass or tumor and spread to other areas of the body • Severity is classified by tumor size, histology, regional lymph node involvement and presence of metastasis • Detected and monitored by tumor markers

4. Cancer and deaths from cancer in USA

5. Terms • Tumorigenesis • Formation of tumors • Occur due to mutation of growth factors and oncogenes • Metastasis • Spreading of tumors • Oncofetal • Expressed during the development of the fetus, then reexpressed in tumors

6. Terms • Sensitivity • The likelihood that given the presence of disease, an abnormal test result predicts the disease • No false negatives • Specificity • The likelihood that given the absence of disease, a normal test result excludes disease • No false positives

7. What is a Tumor Marker? • Produced directly by the tumor or as an effect of the tumor on healthy tissue • Concentration increases with tumor progression, highest levels when tumors metastasize • Include diverse molecules such as serum proteins, oncofetal antigens, hormones, metabolites, receptors and enzymes

8. Tumor Marker Detection • Ideally, a tumor marker would be: • A substance that is released directly into the bloodstream detectable at small concentrations • Tumor specific ( high specificity) • absent in healthy individuals • readily detectable in body fluids. • Unfortunately, all of the presently available tumor markers do not fit this ideal model.

9. Application of tumor markers • Screening populations at risk • Not all tumor markers are good screening tools • Diagnosis • Use results from markers, imaging, risk factors, and symptoms • Prognosis • Concentration of the marker determines prognosis • Detection of recurrence • Once tumor is removed, elevations of marker can indicate regrowth • Monitoring response to treatment • Decreased levels of tumor marker indicate therapy is working • Increased levels of tumor marker may indicate need for a change to therapy

10. Methods for Detection • Immunoassay • Most common measurement method • Challenges • Markers often above linearity • Hook effect: excessive high marker concentrations result in false lows • Heterophile Antibodies • Interfere with testing due to the presence of circulating antibodies against animal immunoglobulin • Lipemia, hemolysis and antibody cross reactivity cause interferences

11. Tumor markers: Enzymes • Increase due to metabolic demands of cells • Indicate tumor burden • Examples • Alkaline phosphatase • Bone, liver, intestine • Creatine kinase • Prostate, lung, breast, colon, ovarian • Lactate dehydrogenase • Liver, lymphomas, leukemias • Prostatic acid phosphatase • Prostate

12. Frequently Ordered Tumor Markers • Prostate Specific Antigen (PSA) • Produced in the epithelial cells of the prostatic ducts • Consists of two forms: free and complexed • In healthy men, some amounts of PSA can be detected • PSA is elevated in prostate infection, irritation and benign prostate enlargement • Methodology detects both forms

13. Tumor markers: endocrine/ hormones • Detect secreting tumors • Helpful in identification of: • Neuroblastoma • Pituitary tumor • Adrenal tumor • Examples • Beta-human chorionic gonadotropin • Calcitonin • Adrenocorticotropin hormone (ACTH)

14. Tumor Markers: Hormones • Human Chorionic Gonadotropin (hCG) • Hormone normally secreted in the placenta to maintain pregnancy • Molecule consists of two subunits: alpha & beta • Elevated in trophoblastic tumors, choriocarcinoma and germ cell tumors of the ovary and testis • Most immunoassays detect either the subunits or the total molecule

15. Tumor markers: proteins • Used to monitor therapy • Examples • Beta-2-Microglobulin • Reflects cell turnover • Immunoglobulins

16. Tumor markers: oncofetal antigens • Considered normal in fetal development • Become detectable in tumor formation • Examples • Carcino-embryonic antigen(CEA) • Alpha-fetoprotein

17. Frequently Ordered Tumor Markers • Carcinoembryonic Antigen (CEA) • Expressed during fetal development then re-expressed in tumor growth • Clinical use • Used to detect colorectal, lung, breast ovarian, and GI cancers • Monitor therapy

18. Frequently Ordered Tumor Markers • Alpha(α) – Fetoprotein (AFP) • Synthesized by the fetal liver • Re-expresses in certain types of tumors • Normally functions as a transport protein and helps to regulate oncotic pressure in the fetus • Used to diagnose hepatocellular carcinoma and germ cell tumors (testes, ovaries)

19. Notable mentions • Breast cancer • CA 15-3 • Monitoring • HER-2 • Monitoring • CA 27.29 • Monitoring • Ovarian cancer • CA 125 • Monitoring • Pancreatic cancer • CA19-9 • Monitoring

22. References • Bishop, M., Fody, E., & Schoeff, l. (2010). Clinical Chemistry: Techniques, principles, Correlations. Baltimore: Wolters Kluwer Lippincott Williams & Wilkins • Rhea, J. M., & Molinaro, R. J. (2011, March). Cancer Biomarkers: Surviving the Journey From Bench to Bedside. MLO, 43(3), 10-18. • Sunheimer, R., & Graves, L. (2010). Clinical Laboratory Chemistry. Upper Saddle River: Pearson .