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 Alpha-fetoprotein CEA CA-19.9

PSA CA-125 -hCG 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 TermsAngiogenesis Development of new blood vessels to supply

oxygen and nutrients to cells

Physiological PathologicalThe process is transient and tightly regulated

e.g., Wound healing, Pregnancy, Menstruation, development

The process is persistent and out of control

e.g., tumorogenesis & MetastasisMarker for angiogenesis: e.g., Vascular Endothelial Growth Factor (VEGF)Follow-up & treatment of angiogenic cancerTreatment can target more than one tumor type

HER-2/NEU 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

Tumor suppressor gene

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

Tumor Tumor markers1. Hepatoma

(HCC)AFP

2. Ovarian Cancer

CA-125 Inherited ovarian cancer: BRCA1

3. Breast Cancer

CA15-3 CEA HER-2/NEU Estrogen and progesterone receptorsIf inherited: BRCA1, and BRCA2 (on chromosome 13)

Recommended Tumor Markers for Specific type of Cancers….continued

Tumor Tumor markers

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

5. Colorectal carcinoma CEACA 19-9

6. Pheochromocytoma Vanillylmandelic Acid (VMA) in urine

7. Nonseminomatous testicular cancer

AFP-hCGCEA

8. Vesicular mole & Choriocarcinoma -hCG9. 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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