Tumor Markers

1. Tumor Markers Lecture two By Dr. Reem Sallam

2. Objectives • To briefly enumerate the most commonly used methods to test for tumor markers • To describe examples of the most commonly ordered tumor markers, their regulation and physiology, their clinical application and interpretation, and their pathophysiology • To be familiar with the most common tumor marker used in various cancers. • To be able to choose a tumor marker (or markers) in examples of clinical situation.

3. Lecture outlines • Examples of methods used to measure tumor markers • Examples of tumor markers • Alpha-fetoprotein • CA125 • CEA • hCG • PSA • Others

4. Examples of methods used to measure tumor markers • Immunoassays • HPLC • Immunohistochemistry • Enzyme assays

5. Examples of Frequently ordered tumor markers • Alpha-fetoprotein • CA-125 • CEA • hCG • PSA • Her-2/neu • P53 • BrCa1 • BrAa2 • CA-15.3 • CS-19.9 • Estrogen and progesterone receptor • VMA

6. Alpha feto protein (-FP) • Introduction & Description: • AFP is an abundant serum protein normally synthesized by the fetal liver that is reexpressed in certain types of tumors. i.e. it is a carcinoembryonic protein (or oncofetal antigen)

7. AFP continued… • Clinical Application & Interpretation: • Used for the diagnosis, staging, prognosis, and treatment monitoring of hepatocellular carcinoma (HCC; i.e. hepatoma). • However, AFP is not completely specific for HCC. • AFP might be increased in pregnancy & benign liver disease.

8. AFP continued… • Several expert groups now recommend that AFP be used in conjunction with ultrasound imaging every 6 months in patients at high risk of developing HCC. • This includes patients with hepatitis B virus- and/or hepatitis C virus-induced liver cirrhosis. • i.e. AFP is used for early detection (in the lead period) which is ~ 6 months before clinical manifestations of the cancer appear.

9. AFP continued… • AFP is also used as a tumor marker for classification and monitoring therapy for nonseminomatous testicular cancer. • This is in combination with another tumor marker: -human chorionic gonadotropin (-hCG)

10. Cancer Antigen 125 (CA-125) • Introduction and Description: • CA-125 may be useful for detecting ovarian tumors at an early stage and for monitoring treatments without surgical restaging • CA-125 is not considered specific enough for ovarian cancer, as it may be elevated in patients with endometriosis, during the first trimester of pregnancy, or during menstruation.

11. CA-125, continued… • Clinical application and interpretation: • CA-125 is the only clinically accepted serologic marker of ovarian cancer.

12. CA-125, continued… • Application and Pathophysiology: • CA-125 is predominantly used to monitor therapy and to distinguish benign masses from ovarian cancer.

13. Carcinoembryonic Antigen (CEA) • Introduction and Description: • CEA is an example of an oncofetal antigen • It is expressed druing development and then reexpressed in tumors. • It is the most widely used tumor marker for colorectal cancer.

14. CEA, continued… • Clinical Application and Interpretation: • The main clinical use of CEA is as a tumor marker for colorectal cancer • In colon cancer, CEA is used for prognosis, in postsurgery surveillance and to monitor response to chemotherapy.

15. Human Chorionic Gonadotropin (hCG) • Introduction and Description: • hCG is a hormone normally secreted by trophoblasts in the placenta during pregnancy. • It is a glycoprotein consisting of  and  subunits.

16. hCG, continued… • Clinical Application and Interpretation: • It is the most useful marker for detection of gestational trophoblastic diseases (GTDs) • GTDs include: • Hydatiform mole (vesicular mole) • Choriocarcinoma • It is also elevated in nonseminomas.

17. Prostate Specific Antigen (PSA) • Introduction and Description: • PSA is a glycoprotein produced only in the epithelial cells of the acini and ducts of the prostatic ducts in the prostate. • PSA is a serine protease.

18. PSA, continued… • Regulation and Physiology: • There are 2 major forms of PSA that are found circulating in the blood: • Free • Complexed: • Complexed to 1-antichymotrypsin or 2-macroglobulin. • The detection of total PSA has been used in screening for and in monitoring of prostate cancer • The measurement of free PSA can help to differentiate levels of PSA that are in the grey zone: i.e. not high enough to diagnose cancer prostate, but not low enough to rule out the diagnosis of cancer prostate: Patient with cancer prostate have a lower % of free PSA.

19. PSA, continued… • Clinical Application and Interpretation: • Annual PSA testing for screening of prostate cancer: • in men over 50 years old • in younger men at high risk: e.g. • Those with a family history of prostate cancer.

20. PSA, continued… • To increase the accuracy of the PSA testing, it is essential to use age-adjusted cutoff values of PSA • Reasons other than prostate cancer that can  elevated PSA: • Prostate infection • Prostate irritation • Benign prostatic hyperplasia (enlargement)

21. PSA, continued… • Application & Pathophysiology: • The best clinical use & first clinical applications of PSA testing was to monitor for the progression of prostate cancer after therapy (e.g. radical prostatectomy)

22. Common Cancer Terms Physiological Pathological The process is persistent and out of regulation (out of control) e.g. tumorogenesis Example of marker for angiogenesis: Vascular Endothelial Growth Factor (VEGF) Application: treatment that can target more than one tumor (because it will cut the blood supply from the tumor, i.e. nonspecific) The process is transient and regulated e.g. Wound healing, Pregnancy, Menestruation, development

23. Her-2/neu • It is a proto-oncogene that upon: • Mutation (especially point mutation) or • Altered (over) expression will encode an Epidermal Factor Receptor (EGF-R) that mediate tumorigenesis (i.e. It is an activation mutation) • Marker for breast and ovarian cancers • Application: It is now routinely measured in breast cancer to determine the type of therapy: • Breast cancer positive for Her-2/neu is responsive to treatment (Herceptin) • Breast cancer negative for Her-2/neu is NOT responsive to treatment

24. Tumor suppressor genes, e.g. p53 • The gene is located on chromosome 17 (together with the genes of BrCa1 and Her-2/neu • Encodes a protein of 53 kDa • Encodes a protein that normally result in cell cycle arrest and induces apoptosis • Upon mutation: loss of function mutation  cancer

25. Suggested Recommended Markers for diagnosis/prognosis

26. Suggested Recommended Markers for diagnosis/prognosis, continued

27. Tools for early detection of cancer • Find a marker that will be detected in the lead time (~ 6 months before clinically detected) • Use prognostic markers for cancer progression • Find targets for new therapeutic application • Follow up the treatment

28. Case study: • A 50 years old female suffered from cancer breast 5 years ago, and underwent radical surgical procedure. She did not have any family history for cancer breast. Recently, metastases were detected in her liver. Which one of the following tumor markers is the best for diagnosis, prognosis, & monitoring therapeutic intervention of this case? • BrCa1 • BrCa2 • Alpha feto protein (AFP) • CA 15-3

29. Case study: • A 50 years old female suffered from cancer breast 5 years ago, and underwent radical surgical procedure. She did not have any family history for cancer breast. Recently, metastases were detected in her liver. Which one of the following tumor markers is the best for diagnosis, prognosis, & monitoring therapeutic intervention of this case? • BrCa1 • BrCa2 • Alpha feto protein (AFP) • CA 15-3

30. Things to remember • No ideal tumor marker is known so far • Therefore, the best approach is: • Take a good history • Perform thorough physical examination. • Use a battery of markers (>1 marker/tumor) • Use confirmatory investigations: Histopathology, ultrasonography, per rectal examination, x rays

31. THANK YOU 