Tumor Markers: Clinical Usefulness By Amr S. Moustafa, M.D.; Ph.D.

Objectives The most commonly used methods for the detection of tumor markers When to use tumor markers in various cancers? What tumor marker (or markers) to order in different cancers?

Tumor markers: Detection Immunoassays Immunohistochemistry FISH Enzyme assays HPLC

Common Tumor Markers -hCG Alpha-fetoprotein CEA CA-19.9 PSA CA-125 VMA CA-15.3 Estrogen receptor Progesterone receptor HER-2/NEU BRCA1 BRCA2 p53

Alpha feto protein (-FP) Introduction: Oncofetal antigen Abundant serum protein normally synthesized by the fetal liver Re-expressed in certain types of tumors

AFP continued… Clinical Applications: Diagnosis, prognosis, and treatment monitoring of hepatocellular carcinoma (HCC; hepatoma) Screening (High-risk; HBV or HCV patients) AFP is not completely specific for HCC AFP might be increased in pregnancy & benign liver disease

AFP continued… AFP be used in conjunction with ultrasound every 6 months in patients at high risk of developing HCC Patients with hepatitis B virus- and/or hepatitis C virus-induced liver cirrhosis Lead period i.e., early detection which is ~ 6 months before clinical manifestations

AFP continued… A tumor marker for classification and monitoring therapy for nonseminomatous testicular cancer “in combination with -human chorionic gonadotropin (-hCG)”

Cancer Antigen 125 (CA-125) Detection of ovarian tumors at an early stage monitoring treatments without surgical restaging CA-125 is not specific for ovarian cancer, as it may be elevated in: Menstruation First trimester of pregnancy Endometriosis

CA-125, continued… Currently, CA-125 is the only clinically accepted serologic marker of ovarian cancer

Carcinoembryonic Antigen (CEA) Introduction: CEA is an oncofetal antigen It is expressed druing development and then re-expressed in tumors It is the most widely used tumor marker for colorectal cancer

CEA, continued… Clinical Applications: 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: hCG is a hormone normally secreted by trophoblasts in the placenta during pregnancy It is a glycoprotein consisting of - and -subunits

hCG, continued… Clinical Applications: Detection and follow-up of gestational trophoblastic diseases (GTDs) GTDs include: Hydatiform mole (vesicular mole) Choriocarcinoma It is also elevated in nonseminomas testicular cancers

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

PSA, continued… There are 2 major circulating forms of PSA: Free Complexed: Complexed to 1-antichymotrypsin or 2-macroglobulin

PSA, continued… Annual PSA 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 Total PSA: Screening for and in monitoring of prostate cancer Free PSA: Differentiate levels of PSA that are in the grey zone Patient with cancer prostate have a lower % of free PSA

PSA, continued… To increase the accuracy of the PSA testing, age-adjusted cutoff values of PSA can be used Elevated PSA can be found also in: Prostate infection Pelvic congestion Benign prostatic hyperplasia (enlargement)

Common Cancer Terms Physiological Pathological Angiogenesis Development of new blood vessels to supply oxygen and nutrients to cells Physiological Pathological The process is transient and tightly regulated e.g., Wound healing, Pregnancy, Menstruation, development The process is persistent and out of control e.g., tumorogenesis & Metastasis Marker for angiogenesis: e.g., Vascular Endothelial Growth Factor (VEGF) Follow-up & treatment of angiogenic cancer Treatment can target more than one tumor type

HER-2/NEU Mutation (especially point mutation) or Encodes an Epidermal Growth Factor Receptor (EGF-R) A proto-oncogene that is converted to oncogene by: Mutation (especially point mutation) or Altered (over) expression Marker for breast and ovarian cancers It is now routinely measured in breast cancer (IHC and FISH) to determine the type of therapy: Breast cancer positive for HER-2/NEU is responsive to treatment (Herceptin)

Tumor suppressor genes, e.g., p53 Encodes a protein involved in protecting cells from unregulated growth The gene is located on chromosome 17 (Plus 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

Recommended Tumor Markers for Specific type of Cancers Hepatoma (HCC) AFP Ovarian Cancer CA-125 Inherited ovarian cancer: BRCA1 Breast Cancer CA15-3 CEA HER-2/NEU Estrogen and progesterone receptors If inherited: BRCA1, and BRCA2 (on chromosome 13)

Recommended Tumor Markers for Specific type of Cancers….continued Cancer head of the pancreas CA 19-9 CEA Colorectal carcinoma Pheochromocytoma Vanillylmandelic Acid (VMA) in urine Nonseminomatous testicular cancer AFP -hCG Vesicular mole & Choriocarcinoma Prostate cancer PSA

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, liver metastases were suspected. Which one of the following tumor markers is the best marker for follow-up 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, liver metastases were suspected. Which one of the following tumor markers is the best marker for follow-up 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,

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