Tumor Markers

Universiti Kuala Lumpur (UniKL) | Where Knowledge Is Applied and Dreams Realized
OBJECTIVES
 To briefly enumerate the commonly used methods for
tumor markers detection.
 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. 
INTRODUCTION

 The four most common cancers occurring worldwide are lung, female breast,
bowel and prostate cancer. These four account for around 4 in 10 of all cancers
diagnosed worldwide.
 Lung cancer causes the most cancer deaths worldwide. Almost a fifth of all cancer
deaths worldwide are lung cancers.
 Although it is often specified as a single disorder, cancer is a broad term used to
describe > 200 different diseases that affect ? 50 tissues.
INTRODUCTION
 Cancer
 Uncontrolled growth of cells that can develop into a solid
mass or tumor and spread to other areas of the body
 Severity is classified by tumor size, histology, regional lymph
node involvement and presence of metastasis
 Detected and monitored by tumor markers
 Tumor markers is used to detect the presence of certain types
of cancer in the body, and to monitor the progress of cancer
treatment.
TERMS
 Tumorigenesis
 Formation of tumors
 Occur due to mutation of growth factors and oncogenes

 Metastasis
 Spreading of tumors
 Oncofetal
 Expressed during the development of the fetus, then
reexpressed in tumors
 Angiogenesis
 Development of new blood vessels to supply oxygen and
nutrients to cells
TUMOR MARKERS
 Tumorigenesis & metastasis of tumors are caused by a
complex combination of inherited and acquired genetic
mutations
 During tumorigenesis, these mutations include activation
of growth factors & oncogenes in combination of
inhibition of apoptosis, tumor suppressor, and cell cycle
regulation genes
TUMOR MARKERS
 Produced directly by the tumor or as an effect of the
tumor on healthy tissue
 Include diverse molecules such as serum proteins,
oncofetal antigens, hormones, metabolites, receptors and
enzymes
 Concentration increases with tumor progression, highest
levels when tumors metastasis
TUMOR MARKER DETECTION
 Ideally, a tumor marker would be:
 tumor specific
 absent in healthy individuals
 readily detectable in body fluids.
 Unfortunately, all of the presently available tumor markers do not fit this ideal
model.
 However, a host of tumor markers have been identified that have a high enough
specificity & sensitivity to be used in:
 screening populations at risk
 Diagnosis
 Prognosis
 Detection of recurrence
 Monitoring response to treatment.
METHODS FOR DETECTION
 Immunoassay
 Most common measurement method
 Challenges
 Markers often above linearity
 Hook effect: excessive high marker concentrations result in false lows

 Heterophile Antibodies

 Interfere with testing due to the presence of circulating antibodies

against animal immunoglobulin

 Lipemia, hemolysis and antibody cross reactivity cause interferences
METHODS FOR DETECTION
 High Performance Liquid Chromatography (HPLC)
 Used to detect catecholamines in the plasma and urine

 Immunohistochemistry
 Direct detection in solid tissue
EXAMPLES OF FREQUENTLY ORDERED
TUMOR MARKERS
 Alpha-fetoprotein  BrCa1
 CA-125  BrCa2
 CEA
 hCG  CA-15.3
 PSA  CS-19.9
 Her-2/neu  Estrogen and progesterone
 P53 receptor
 VMA
CLINICAL APPLICATIONS
Role in Screening
 Tumor markers play a limited role for tumor screening,
just because of its relatively low sensitivity, lack of
specificity, not elevated in early stage, inappropriate for
the detection of small in situ cancer
 Examples
 AFP in liver cancer in China
 Urinary VMA and homovanillic acid for neuroblastoma in
Japanese children
 PSA along with DRE for prostate cancer in >50 yr aged men
CLINICAL APPLICATIONS
Role in Diagnosis
 Most tumor marker levels alone are often insufficient to diagnose
cancer for the following reasons:
 TM levels can be elevated in people with benign conditions;
 TM levels are not elevated in every person with cancer, especially
in the early stages of the disease;  Many TM are not specific to a
particular type of cancer;
 The level of a TM can be elevated by more than one type of cancer
 Tumor marker is not the key diagnostic tool, but can be a
complementary sign to clinical finding & medical imaging  
Role in staging/prognosis
 The pre-therapeutic level of certain tumor marker can
contributes a prognostic factor because of links with:
 Metabolic activity
 Tumor size
 Invasion Eg: -High PSA preoperatively associated with high
gleason score, positive surgical margins, + lymph node status -
ER +ve breast tumors have good prognosis - C-erb-2-gene(HER-
2/neu) is prognostic for ovarian & breast cancer
 Allow doctors to refine therapeutic strategy by selecting groups
with risk of failure response to treatment
CLINICAL APPLICATIONS
Monitoring & recurrence
 One of the most useful application

 The serum level of tumor markers reflects the success of

surgery or the efficacy of chemotherapy.
 If the marker level in the blood goes down, that is almost
always a sign that the treatment is effective
 If marker level after surgery remain elevated would
indicate either incomplete removal of the tumor,
recurrence, or the presence of metastases.
CLINICAL APPLICATIONS
Monitoring & recurrence (Cont.)
 The measurement of serum tumor markers during
chemotherapy also gives an indication of the
effectiveness of the antitumor drug used and a guide for
the selection of the most effective drug for each
individual case.
 Eg: PSA for prostate cancer, HCG for gestational
trophoblastic tumours & germ cell tumours of ovaries &
testicles CA 125 for epithelial ovarian cancer
CLASSIFICATION EXAMPLES
 Oncofetal antigens: AFP, CEA
 Tumor associated antigens : CA125, CA19-9, CA15-3,
CA72-4, CA50
 Hormones: β-hCG, Calcitonin

 Receptors : ER, PR, EGFR

 Enzymes and Isoenzymes : PSA, PAP, NSE, PALP,

 Serum and tissue proteins : -β2 microglobulin, monoclonal

immunoglobulin/para proteins, GFAP, protein S-100,
ferritin, fibrinogen
 Other biomolecules: polyamines

 Oncogenes: Ras, myc ,abl-bcr

 Tumour supressor genes: BRCA1 , P53, Rb

FREQUENTLY ORDERED TUMOR
MARKERS
 (α) – Fetoprotein (AFP)
 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) 
 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 is also used as a tumor marker for classification and monitoring
therapy for nonseminomatous testicular cancer.
 This is in combination with another tumor marker: β -human

chorionic gonadotropin (β -hCG) 

FREQUENTLY ORDERED TUMOR
MARKERS
 Cancer Antigen 125 (CA-125)
 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 is the only clinically accepted serologic marker of
ovarian cancer. 
 CA-125 is predominantly used to monitor therapy and to
distinguish benign masses from ovarian cancer. 
FREQUENTLY ORDERED TUMOR
MARKERS
 Carcinoembryonic Antigen (CEA)
 Immunoglobulin family
 Used to detect colorectal, lung, breast and GI cancers
 CEA is not specific for colorectal cancer but it is the most
widely used tumor marker for colorectal cancer. 
 CEA is an example of an oncofetal antigen It is expressed
druing development and then reexpressed in tumors.
 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. 
FREQUENTLY ORDERED TUMOR
MARKERS
 Prostate Specific Antigen (PSA)
 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. 
 There are 2 major forms of PSA that are found circulating in the blood:
 Free

 Complexed: Complexed to α1 -antichymotrypsin or α2

-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. 
OTHER TUMOR MARKERS
 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
 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
OTHER TUMOR MARKERS
 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
RECOMMENDED MARKERS FOR
DIAGNOSIS/PROGNOSIS
 Hepatoma (HCC)
 AFP

 Cancer ovary
 CA-125
 Inherited ovarian cancer: BrCa1(on chromosome 17, which is
the same chromosome having the p53 & Her-2/Neu)
 Breast Cancer
 CA15-3
 CEA
 Her-2/neu
 Estrogen and progesterone receptors
 If inherited: BrCa1, and BrCa2 (on chromosome 13)
RECOMMENDED MARKERS FOR
DIAGNOSIS/PROGNOSIS
 Cancer head of the pancreas
 CA 19-9
 CEA
 Colorectal carcinoma
 CA 19-9 CEA
 Pheochromocytoma
 Vanillylmandelic Acid (VMA) in urine
 Nonseminomatous testicular cancer
 AFP
 β-hCG
 CEA
RECOMMENDED MARKERS FOR
DIAGNOSIS/PROGNOSIS
 Vesicular mole and Choriocarcinoma
 β -hCG
 Prostate cancer
 PSA
STRATEGY
 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

SUMMARY
 Tumor markers may be used to help diagnose cancer,
predict and monitor response to treatment and determine
whether cancer has recurred after treatment.
 In general, tumor markers alone cannot be used to
diagnose cancer, they must be combined with other tests.
Studies are being done to determine if tumor markers
can be used in early detection and diagnosis of cancer
THANK YOU

UNIVERS ITI KUALA LUMP UR

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