Tumor Markers

Francis Ian L. Salaver, RMT Channey 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
The process is transient and regulated e.g. Wound healing, Pregnancy, Menestruation, development

Pathological
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)

Causes of cancer (1)

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 (2)

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

 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)

Screening

Early Detection

Diagnosis Prognosis

Monitor

Antigens

Hormones

TUMOR Enzymes Tissue Specific

Ideal Tumour Marker should be.

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 .

Correlate with the tumour stage or tumour mass correlate with the prognosis have a reliable prediction value

but ideal tumour marker doesnt exists

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 carcinogens 3. 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

PSA LDH ALP 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 ageadjusted 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/mL Or
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 protein Serum 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/dL Polyclonal 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

Monoclonal gammopathy
Albumin decreased Sharp peak in gamma region

Albumin 1

Carbohydrate Antigen
CA 19-9 CA 15-3 Ca 27-29 CA 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
AFP CEA

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 markers

HVA VMA Metanephrine Cathecolamines 5-HIAA Serotonin Calcitonin PTH GH PRL ACTH ADH Chromogranin A C-Peptide

Homovanilic Acid, Vanillylmandelic acid Metanephrine, 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, Cushings syndrome

 Cushings syndrome

Cushings 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 receptor Progesterone receptor Her-2-neu EGRF

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)
2. Cancer ovary 3. Breast Cancer

AFP
CA-125 CA15-3 CEA Her-2/neu Estrogen and progesterone receptors

Suggested Recommended Markers for diagnosis/prognosis, continued

Tumor 4. Cancer head of the pancreas 5. Colorectal carcinoma 6. Pheochromocytoma 7. Nonseminomatous testicular cancer Tumor markers CA 19-9 CEA CA 19-9 CEA Vanillylmandelic Acid (VMA) in urine AFP -hCG CEA PSA

8. Vesicular mole and Choriocarcinoma -hCG 9. Prostate cancer

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