Tumor Markers
Transcript of Tumor Markers
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