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Chapter 19
Tumor Markers
Zou Xiong
DEFINITIONS-1
Tumor markers originally were
defined as substances that can be measured
quantitatively by immunochemical means in tissue
or body fluids to identify the presence of a cancer
and possibly the organ where it resides, to
establish the extent of tumor burden before
treatment, to predict prognosis, and to monitor the
response to therapy.
DEFINITIONS-2
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tumor markers
tumor-associated antigens
nuclear and specific proteins
enzymes
isoenzymes
genes
oncogenes and their products
DEFINITIONS-3
• Epidemiological sensitivity is the percentage of true
positives.
• Specificity is the percentage of true normals.
• The positive predictive value is a percentage of the
true positives compared to positive values.
• The negative predictive value is the true negatives
compared to all negatives.
• The efficiency of the test is the true negatives and
true positives divided by the number of tested
individuals.
DEFINITIONS-4
• Analytical sensitivity can be defined as the lowest
detectable amount of marker measured by the method
in use, while
• Analytical specificity reflects the extent of exogenous
material interferences in the assay.
APPLICATION
1. Carcinoembryonic Antigen (CEA)
APPLICATION-1
• When first described, CEA apparently was
elevated in almost all patients with colorectal
cancer, but was normal after successful
removal of the tumor.
• 30 years later, it now is well-understood that
CEA is elevated in all solid-tissue tumors,
not only those of the colon or rectum and is
elevated in the cancer of the breast, ovary,
and pancreas.
APPLICATION-2
• Following successful therapy, elevations of CEA may
fall and subsequent elevations suggest recurrence.
• These elevations may be seen months, if not years,
before there is clinical evidence of disease.
• It is important to understand that elevations will not
be seen in about 30% of individuals with recurrent
metastasis disease.
APPLICATION-3
American Society of Clinical Oncology (ASCO)
concluded that
• CEA cannot be used for screening for colon-rectal
cancer, but preoperative CEA may assist staging and
surgical treatment planning.
• CEA elevations detect recurrence earlier than other
techniques and CEA monitoring should be done at the
start of treatment and then every 2 to 3 months
thereafter.
2.
CA19-9
APPLICATION
• CA19-9 is the marker most useful in adenocarcinoma
of the pancreas. It is more sensitive (70% to 95%)
and specific (72%) than CEA (40% to 60% and 70%
respectively).
• CA19-9 is not elevated in islet cell carcinoma of the
pancreas.
• Benign conditions such as acute or chronic
pancreatitis or cholelithiasis may cause elevations.
3.
CA72-4
APPLICATION
• CA72-4 elevated in patients with many different
gastrointestinal cancers and only rarely in benign
gastrointestinal diseases.
• It is more sensitive and specific than any other marker
in gastric cancer. It identified 59% of the patients
compared to 52% with CA19-9 and 25% with CEA.
• When combined with CA19-9, 70% of the gastric
cancer patients were identified.
4.
Alpha Feto Protein (AFP)
APPLICATION
• AFP has been used for more than 30 years in
screening for hepatocellular cancer (HCC) and in
diagnosis and monitoring of patients with germ-cell
tumors.
• AFP screening is not useful in detecting cirrhotic
patients who will develop HCC .
• AFP is of use in monitoring patients with HCC. The
concentrations rise and fall, reflecting the course of
the disease, and may be reflective of recurrence
before any other clinical or diagnostic indication.
5. Human Chorionic Gonadotropin
(hCG) and its BetaSubunit (β-hCG)
APPLICATION
• hCG and β-hCG has been used for more than 50 years
in the diagnosis and monitoring of trophoblastic
cancers such as choriocarcinoma and hydatidiform
mole.
• AFP and β-hCG have been used to predict therapeutic
response and to evaluate prognosis of testicular
cancer.
6. CA-125
APPLICATION-1
• CA-125 has been observed in the patients with
ovarian cancer but also is elevated in a variety of
cancers (uterus, pancreas, liver, lung).
• Elevations of CA-125 may be seen in many
nonmalignant conditions including pregnancy,
menstruation, ovarian cysts, endometriosis, and
peritoneal or pleural inflammation.
• CA-125 cannot be used for early diagnosis.
•
APPLICATION-2
• CA-125 is an important marker because elevations
after treatment suggest presence of residual tumor,
and second-look exploratory surgery probably is
unwarranted.
• CA-125 may be a prognostic predictor.
• Use of an algorithm and sequential CA-125 results
may make it possible to use CA-125 for early
detection ( sensitivity 83%, specificity 99.8%, and
positive predictive value 16%) .
7. Prostate-Specific Antigen (PSA)
APPLICATION-1

PSA is prostate tissue specific but not prostate cancer
specific.
 Elevations (PSA >4.0 μg /L) are seen in about 40% of
men with early prostate cancer, 70% of men with
more advanced cancer, and in 20% of men with
benign prostatic hypertrophy (BPH).
 After surgical removal of the prostate, the PSA in
serum falls with a half-life of 3.2 ± 0.6 days.A
subsequent elevation to very low levels suggests
recurrence.
APPLICATION-2
• Preoperative PSA values may be important
prognostic markers.
• The FDA recently has approved the use of PSA for
screening. 60% to 70% of men with PSA values > 10
μg /L will have biopsy-proven cancer.
8. Free and Complexed PSA
APPLICATION-1
 PSA exists in serum primarily as three forms.
• One form is complexed to the protease inhibitor α1antichymotrypsin,
• A second is complexed to α-2 macroglobulin
• The remainder is noncomplexed (free PSA).
 The total PSA is presumably the free and the
antichymotrypsin bound form because the α-2
macroglobulin form is not immunoreactive.
APPLICATION-2
• If the ratio between free and total PSA was greater
than 0.154, benign disease was present, and if it was
lower, the patient suffered from cancer.
• With this cut-off, 93% of men with BPH were
identified.
9.
Acid Phosphatase
APPLICATION
• Acid phosphatase is one of the oldest cancer markers
and has been used for more than 50 years in
monitoring patients with prostate cancer.
• Elevations are seen in about 80% of men with bone
metastases but in 20% or less of men with localized
cancer.
• PSA is more sensitive and more useful than acid
phosphatase and will be elevated in patients with
smaller tumors.
10. Breast Antigen (CA15-3)
APPLICATION-1
Elevations are directly related to stage.
In one study of CA15-3 elevation,
* 9% of women with stage I disease
* 19% of those with stage II disease
* 38% in women with stage III cancer
* 75% with stage IV.
APPLICATION-2
• The ASCO panel, recommended hormone receptor
assays be used in management, but concluded that
present data are insufficient to recommend CA15-3
for screening, diagnosis, staging, or surveillance
following primary treatment.
• CA15-3 is not useful in screening because its
presence in the serum is related to the extent of tumor
burden and the stage of the cancer nor is it useful
prognostic marker.
11.
HER-2/neu
APPLICATION-1
• The neu oncogene in rats was reported to encode an
epidermal growth factor receptor-related protein with
a molecular weight of 185Kd (p185).
• The human homologue of the rat neu oncogene has
been referred to as C-erb-B-2 or HER-2/neu.
• The HER-2/neu gene is amplified in a variety of
epithelial-cell tumors.
• Most attention has been paid to this amplification in
breast cancer and the increases in the protein product.
APPLICATION-2
• Breast cancer patients with HER-2/neu positive
primary tumors have a poor prognosis with shorter
disease free and overall survival.
• Many reports suggest that patients with HER-2/neupositive primary tumors should be monitored for
elevated serum HER-2/neu levels as a means of
detecting early recurrence.
• Elevated levels of serum HER-2/neu correlate with
the presence of metastatic disease and poor prognosis
and may be valuable in predicting response to various
forms of therapy.
APPLICATION-3
 In normal women the specificity of HER-2/neu was
100% and those with benign disease was 95%.
 In women with breast cancer, the sensitivity was
* 1.7% in stage I disease,
* 3.0% in stage II disease
* 35.5% in stage V.
 A combination of serum HER-2/neu, CA15-3 and
CEA allowed a more precise evaluation of response
to therapy
APPLICATION-4
• Serum concentrations were correlated to tumor size
and node involvement.
• Elevated HER-2/neu levels indicated a lack of
response to hormonal therapy.
• Serum HER-2/neu levels before chemotherapy were
found to correlate with the number of positive nodes,
but there was no correlation to age, receptor, or
disease status.
12. Enzymes as Tumor Markers
APPLICATION
• Many of the markers already discussed are enzymes
(acid phophatase, prostate specific antigen).
• However, many other enzymes are valid markers,
some of which have been used for decades and are
still of clinical relevance.
13. Alkaline Phosphatase (ALP)
APPLICATION-1
• Serum ALP is elevated in patients with primary bone
cancer as well as in individuals with cancer metastatic
to bone.
• Elevations are greater in persons with osteoblastic
bone lesions than in patients with osteolytic disease.
• In osteoblastic disease, serum levels can be as much
as 40-fold the upper reference level.
• Because the majority of metastatic bone lesions in
breast cancer are osteolytic and in prostate cancer
osteoblastic, elevations of ALP in prostate cancer
usually are much higher than in breast cancer.
APPLICATION-2
• Serum levels reflect regression and progression, but there
may be a paradoxical rise in ALP during the early phase
of disease regression, presumably reflecting an attempt to
repair the damaged bone.
• Alkaline phosphatase exists in forms that are organ
related; primarily bone, liver, and placenta.
• The bone-ALP measured immunochemically with
monoclonal antibodies has been successfully used to
monitor metastases to bone and differentiate bone verses
liver-elevated serum ALP levels.
14. Lactate Dehydrogenase (LDH)
APPLICATION
• The role of LDH in algorithms already has been
discussed.
• Serum levels of total LDH have been found useful in
hematologic cancers.
• Patients with lymphoma have been stratified based on
LDH levels and remission rates are related to this
level.
15. Neuron-Specific Enolase (NSE)
APPLICATION-1
• Enolase exists as three dimeric subunits γ, β, α, which
give rise to five isoenzymes: αα, ββ, γγ, αβ, and αγ.
• The γγ isomer (NSE) is the predominant form in brain.
• In serum, it is a specific marker for the family or
neuroendocrine tumors referred to as the amine precursor
uptake decarboxylase (APUD) tumors including
neuroblastoma, medullary carcinoma of the thyroid, and
small-cell carcinoma of the lung (SCCL).
APPLICATION-2
• Elevations initially were observed in 90% of patients
with neuroblastoma, primarily those with extensive
disease, and in 70% of patients with SCCL.
• NSE is useful in monitoring patients. Falls reflect
response to successful therapy and subsequent
elevations reflect an exacerbation.
CONCLUSION-1
Circulating and tissue-tumor markers have been
proposed as clinically useful in screening, diagnosis,
prediction of prognosis, and patient management.
CONCLUSION-2
• In screening, the marker should merely answer
the question as to whether a cancer is present
or not.
• In diagnosis, the markers should aid in
confirmation of the cancer and also provide
information on how severe or extensive the
malignancy is (staging).
• In prognosis, the marker should assist in
predicting the aggressiveness of the tumor.
CONCLUSION-3
• The most significant and accepted use of markers is
in assistance in the therapeutic management of the
cancer patient.
• In this case, there are two questions the marker can
help to answer:
⑴ what is the prognosis before therapeutic
intervention;
⑵ what is the probability of success of specific
therapy.
CONCLUSION-4
• Marker levels may suggest a need for a change in
therapy or for additional therapy and provide leadtime for initiation of new or more aggressive therapy.
• It must be emphasized that markers may not be
elevated in some patients with extensive and
progressive tumors.
• The important point is that a positive marker may be
very meaningful from a clinical point of view, but a
negative marker should never create a false sense of
security that tumor is not present or is not
progressing.
CONCLUSION-5
• Although tumor markers can provide information on
regression or progression of disease, the question
arises whether the costs of the assay, and more
importantly, the cost of other diagnostic procedures
triggered by positive marker results, are justifiable in
the treatment of ultimately incurable disease and what
level of intervention is acceptable among false
positives.
• The acceptance or rejection of these costs is related to
the individual’s definition of cost effectiveness.
AFP
CA125
cholangiocarcinoma
breast carcinoma
CA153
CA199
CA72-4
CEA
CYFRA
21-1
CONCLUSION
★
★
★
uterine cervix
cancer
★
chorionic carcinoma
★
Total
PSA
★
★
★
esophageal
carcinoma
★
germinocarcinoma
★
hepatoma
★
★
SCLC
★
NSCLC
prostatic carcinoma
Free
PSA
★
intestinal carcinoma
pancreatic
carcinoma
NSE
★
Islet cell carcinoma
ovarian cancer
HCG
★
★
★
★
★
★