Tumor Markers

Francis Ian L. Salaver, RMTChanney T. Salas, RMT

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.

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)

tumours not attributable to a single cause

factors involved can be biological, chemical, physical, or age-related

biological factors can be genetically linked or virus linked e.g. papilloma, hepatitis B, herpes or HIV virus

– chemical factors (e.g benzopyrene in tar, N-nitroso compounds in cigarette smoke,, aflatoxins in Aspergillus mould)

Causes of cancer (1)

physical factors (e.g UV, , x-rays)

age-related; increasing errors in DNA transcription and translation occur with ageing

immune system defects can predispose individuals to cancer

Causes of cancer (2)

Biological substances synthesized and released by cancer cells themselves or

Produced by the host in response to the presence of tumor

Most tumor markers are proteins

Detected in a solid tumor, in circulating tumor cells in peripheral blood, in serum, lymph nodes, in bone marrow, or in other body fluid (urine, stool, ascites)

Highly specific i.e. not detectable in benign disease and healthy subjects

Highly sensitive i.e. detectable when only a few cancer cells are present

specific to a particular organ

Ideal Tumour Marker should be….

Correlate with the tumour stage or tumour mass

correlate with the prognosis

have a reliable prediction value

but ideal tumour marker doesn´t exists

Ideal Tumour Marker should ….

Tumour-Associated Proteins (TAP) Cell membrane receptors Hormones Immunoglobulins / Cellular antigens Polyamines Protein clusters and fragments Chromosomal material Genes (single, clusters) Genetic material (DNA, RNA, mRNA) Cell modulators (transducers / suppressors)

1. Viral Antigen : a- Viral proteins and glycoproteins b- New antigens produced by virally infected host

cells under control of viral nucleic acid 2. Tumor specific antigens : - Tumor cells develop new antigens specific to their carcinogens3. Tumor specific transplantation antigens : - Tumor cells express new MHC antigens due to alteration of normally present MHC antigens

4. Oncofetal antigens:

a- Carcino-embryonic antigens (CEA) - Normally expressed during fetal life on fetal gut - Reappearance in adult life: GIT, pancreas, biliary system and cancer breast b- Alpha fetoprotein: - Normally expressed in fetal life - Reappearance in adult life; hepatoma

A. Hormones :

Human Chorionic Gonadotrophins (HCG) are secreted in Choriocarcinoma, Ovarian Ca;

Thyroxin is secreted in thyroid cancer

B. Enzymes :

Acid phosphatase in prostate cancer;

Alkaline phosphatase, lipase and amylase

enzymes in cases of cancer of pancreas

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

Enzyme Tumor Markers

PSALDHALP

Neuron-specific enolase

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

Digital Rectal examination 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)

Prostate Specific Antigen

< 4ng/mLOr

PSA velocity (for example rapid doubling time of PSA or a rise of 0.35 ng/mL or more per year) may signal a rapidly growing cancer regardless of how high the absolute PSA level is.

LDH

Hematologic malignancies

Elevated nonspecifically in numerous cancers

ALP

Metastatic carcinoma to the bone, hepatocellular cacinoma, osteosarcoma, lymphoma

Neuron-specific enolase

Neuroendocrine tumors

Serum Protein Markers

Serum M proteinSerum free light chains

B2-Microglobulin

Beta-2-Microglobulin Found on surface on all nucleated cells =

Class I MHC High cell turnover (Hematologic

malignancies)

Beta-2-Microglobulin in AUBF??

Serum M protein

MULTIPLE MYELOMA

- -Biochemical -

Serum monoclonal proteins >3.0 g/dLPolyclonal Immunoglobulin Decreased

Proteinuria, Bence-Jones Protein present in urine

ESR Increased

Serum M protein

MULTIPLE MYELOMA

- proliferation of a single clone of plasma cells that produces a monoclonal protein

Normal SPE

Albumin 1 2

Monoclonal gammopathy

Albumin 1 2

Albumin decreasedSharp peak in gamma region

Carbohydrate Antigen

CA 19-9CA 15-3Ca 27-29CA 125

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.

Ca 19-9

Monitoring pancreatic cancer and some GIT tumors

Ca 15-3 and 27-29

Monitoring breast cancers and therapy CA 15-3 is a protein that is a normal product of

your breast tissue, and it does not cause breast cancer. If a cancerous tumor (cells growing out of control) is present in your breast, though, your levels of CA 15-3 may increase as the number of cancer cells increase. Tumor cells will shed copies of the CA 15-3 protein

Oncofetal antigens

AFPCEA

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)

Please refer to page 642 of your book

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 every 2-3 months

CEA

Note: High in smokers, liver damage, lung, breast and GIT tumors

Endocrine Tumor markersHVAVMA

MetanephrineCathecolamines

5-HIAASerotoninCalcitonin

PTHGHPRL

ACTHADH

Chromogranin AC-Peptide

Homovanilic Acid, Vanillylmandelic acidMetanephrine, Cathecolamines

Pheochromocytoma Neuroblastoma Paraganglioma

Tumor of the sympathetic nervous system and adrenal gland

Serotonin, 5-HIAA

Carcinoid tumor

Parathyroid hormone

Parathyroid adenoma

Calcium??? Phosphate???

Growth hormone

Pituitary adenoma, acromegaly

ACTH and Cortisol

Pituitary adenoma, ectopic-ACTH producing tumor, Cushing’s syndrome

Cushing’s syndrome

Cushing’s disease

ADH

SIADH

Blood sodium? Blood osmolality? Urine output?

C-peptide

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.

Receptor Tumor Markers

Estrogen receptorProgesterone receptor

Her-2-neuEGRF

Her-2/neu It is a proto-oncogene that upon mutation (especially or

altered (over) expression will encode an Epidermal Factor Receptor (EGF-R) that mediate tumorigenesis

Marker for breast

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

Estrogen and Progesterone receptors

Examples of methods used to measure tumor markers

Immunoassays HPLC Immunohistochemistry Enzyme assays

Suggested Recommended Markers for diagnosis/prognosis

Tumor Tumor markers

1. Hepatoma (HCC)

AFP

2. Cancer ovary

CA-125

3. Breast Cancer

CA15-3 CEA Her-2/neu Estrogen and progesterone receptors

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

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