Tumor Markers

Lecture twoBy

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

Angiogenesis Development of new blood vessels to supply oxygen and nutrients to cells

Physiological Pathological

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. tumorogenesisExample 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

Tumor Tumor 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

Tumor Tumor markers

4. Cancer head of the pancreas CA 19-9CEA

5. Colorectal carcinoma CA 19-9CEA

6. Pheochromocytoma Vanillylmandelic Acid (VMA) in urine

7. Nonseminomatous testicular cancer AFP-hCGCEA

8. Vesicular mole and Choriocarcinoma

-hCG

9. Prostate cancer PSA

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

THANK YOU