Tumor Markers Lecture two By Dr. Reem Sallam

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.

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

Examples of methods used to measure tumor markers  Immunoassays  HPLC  Immunohistochemistry  Enzyme assays

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

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)

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.

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.

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)

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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)

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)

Common Cancer Terms AngiogenesisDevelopment of new blood vessels to supply oxygen and nutrients to cells PhysiologicalPathological The process is transient and regulated e.g. Wound healing, Pregnancy, Menestruation, development 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)

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

Tumor suppressor genes, e.g. p53 Tumor suppressor gene Encodes a protein involved in protecting cells from unregulated growth 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

Suggested Recommended Markers for diagnosis/prognosis TumorTumor markers 1.Hepatoma (HCC) AFP 2.Cancer ovary  CA-125  Inherited ovarian cancer: BrCa1(on chromosome 17, which is the same chromosome having the p53 & Her-2/Neu) 3.Breast Cancer  CA15-3  CEA  Her-2/neu  Estrogen and progesterone receptors  If inherited: BrCa1, and BrCa2 (on chromosome 13)

Suggested Recommended Markers for diagnosis/prognosis, continued TumorTumor markers 4.Cancer head of the pancreasCA 19-9 CEA 5.Colorectal carcinomaCA 19-9 CEA 6.PheochromocytomaVanillylmandelic Acid (VMA) in urine 7.Nonseminomatous testicular cancerAFP -hCG CEA 8.Vesicular mole and Choriocarcinoma -hCG 9.Prostate cancerPSA

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

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

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

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

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