|
What are tumor markers?
Tumor markers are substances that can be found in the body
when cancer is present. They are most often found in the blood or
urine, but they can also be found in tumors and other tissue. They can
be products of the cancer cells themselves, or made by the body in
response to cancer or other conditions. Most tumor markers are
proteins.
There are many different tumor markers. Some are seen only in
a single type of cancer, while others can be found in many types of
cancer.
To test for a tumor marker, the doctor most often sends a
sample of the patient's blood or urine to a lab. The marker is usually
found by combining the blood or urine with man-made antibodies that
react with the tumor marker protein. Sometimes a piece of the tumor
itself is tested for tumor markers.
For many reasons, tumor markers alone are usually not enough
to know if cancer is present. Most tumor markers can be made by normal
cells as well as by cancer cells. Sometimes, non-cancerous diseases can
also cause levels of certain tumor markers to be higher than normal.
And not every person with cancer may have higher levels of a tumor
marker.
For these reasons, only a few tumor markers are commonly used
by most doctors. When a doctor looks at the level of a certain tumor
marker, he or she will consider it along with the patient's history and
physical exam and other lab tests or imaging tests.
In recent years, doctors have begun to develop newer types of
tumor markers. With advances in technology, levels of certain genetic
materials (DNA or RNA) can now be measured. And while it has been hard
to identify single substances that provide useful information, doctors
are now beginning to look at patterns of genes or proteins in the
blood. These new fields of genomics and proteomics are discussed in the
section, "What's
new in tumor marker research?"
How are tumor markers used?
Screening and early detection of cancer
Screening
refers to looking for cancer in people who have no symptoms of the
disease. Early detection
is finding cancer at an early stage, when it is less likely to have
spread and is easier to treat. Although tumor markers were first
developed to test for cancer in people without symptoms, very few
markers have been shown to be helpful in this way.
A perfect tumor marker could be used as a cancer screening
blood test for all people. The tumor marker would only be found in
people with cancer. It would tell doctors the type of cancer, how much
cancer there is, and which treatment would work best. At this time
there are no tumor marker tests that work like this.
Today the most widely used tumor marker is the
prostate-specific antigen (PSA) blood test. The PSA test is used along
with the digital rectal exam to screen men for prostate cancer. People
with prostate cancer usually have high PSA levels. But it's not always
clear what the test results mean -- high PSA levels can be seen in men
without cancer, and a normal PSA does not mean that no cancer is
present. At this time, not all doctors agree that PSA screening is
right for all men. Newer versions of the PSA test may prove to be more
accurate.
So far, no other tumor marker has been shown to be helpful in
screening for cancer in the general population. A few of the markers
that are now available can help find cancer at an early stage when only
patients at high risk are tested.
Diagnosing cancer
Tumor markers are usually not used to diagnose cancer. In most
cases, cancer can only be diagnosed by a biopsy (taking out some tumor
cells so they can be looked at under a microscope). Still, markers can
help figure out if a cancer is likely. And when a cancer is already
widespread at diagnosis, tumor markers can help the doctor figure out
where the cancer started.
An example is a woman who has cancer throughout her pelvis and
belly (abdomen). A high level of the tumor marker CA 125 will strongly
suggest ovarian cancer, even if surgery can't identify the source. This
can be important because treatment can then be tailored to this type of
cancer.
Another example is the tumor marker alpha fetoprotein (AFP).
It can sometimes be used to help diagnose liver cancer. The level of
AFP can go up with some liver diseases, but when it reaches a certain
high level, doctors can be sure that liver cancer is present (even
without a biopsy).
Determining the prognosis (outlook) for
certain cancers
Some types of cancer grow and spread faster than other types.
But even within a cancer type (such as breast cancer), some cancers
will grow and spread more quickly or may be more or less responsive to
certain treatments. Some newer tumor markers help show how aggressive a
cancer is likely to be, or even how well it might respond to certain
drugs.
Determining the effectiveness of cancer
treatment
One of the most important uses for tumor markers is to watch
patients being treated for cancer, especially advanced cancer. If a
tumor marker is available for a specific type of cancer, it is much
easier to measure and track it to see if the treatment is working
rather than often repeat chest x-rays, CT scans, bone scans, or other
tests. It also tends to be less expensive.
If the tumor marker level in the blood goes down, it is almost
always a sign that the treatment is working. On the other hand, if the
marker level goes up, then the cancer is not responding and the
treatment may need to be changed. (One exception is if the cancer is
very sensitive to a certain chemotherapy treatment. In this case, the
chemotherapy can cause many cancer cells to die and release large
amounts of the marker into the blood, which will cause the level of the
tumor marker to rise for a short time.)
Detecting recurrent cancer
Tumor markers are also used to look for cancer that may come
back (recur) after initial treatment. Some tumor markers may be useful
once treatment is complete and there is no evidence of cancer in the
body. These include
- prostate specific antigen (PSA) for prostate cancer
- human chorionic gonadotropin (HCG) for gestational
trophoblastic tumors and some germ cell cancers
- alpha fetoprotein (AFP) for certain germ cell cancers
- CA 125 for epithelial ovarian cancer
- carcinoembryonic antigen (CEA) for colon and rectal cancers
Some women who have been treated for breast cancer have blood
tests for levels of the tumor marker CA 15-3. This can sometimes show
that cancer has come back (recurred) before the woman has symptoms or
the cancer can be seen on imaging tests. Many doctors question the
test's value, though, because it isn't clear that it is better to treat
recurrent breast cancer before it is causing symptoms. In studies done
so far, starting treatment earlier has not helped women live longer or
feel better. Breast cancer recurrence can usually be found because of
symptoms or a change on exam about 6 months after the CA 15-3 level
rises.
Findings like this are why many experts do not recommend
checking tumor markers after treatment aimed at curing most cancers.
These markers are more likely to be used to keep an eye on advanced
cancer during treatment.
When are tumor markers checked?
Whether or not tumor markers are followed depends on the type
of cancer a person has. Tumor markers may be checked at the time of
diagnosis; before, during, and after treatment; and then regularly for
many years to see if the cancer has come back. During treatment,
changes in tumor marker levels can be a sign of whether treatment is
working.
Tumor marker levels can change a lot over time. The changes
are important; this is why a series of levels is more meaningful than a
single result. If at all possible it is best to compare results from
the same lab, and always be sure that the results are of the same
value, such as ng/mL (nanograms per milliliter) or U/mL
(units/milliliter).
History of tumor markers
The first modern tumor marker used to detect cancer was human
chorionic gonadotropin (HCG) the substance doctors look for in
pregnancy tests. Women who have ended a pregnancy but still have an
enlarged uterus are tested for HCG. A high level of HCG in the blood
may be a sign of a cancer of the placenta called gestational
trophoblastic disease (GTD). This cancer continues to produce HCG. Some
testicular and ovarian cancers look a lot like GTD because they start
in reproductive cells called germ cells. These cancers also make HCG,
so this marker is also used to help diagnose them and watch their
response to treatment.
The hope in the search for tumor markers was that all cancers
could someday be detected by a single blood test. Both GTD and germ
cell tumors of the ovaries and testicles are too rare to look for these
cancers by testing everyone. But other cancers, such as colon, breast,
and lung are much more common. A simple blood test that could detect
these cancers in their earliest stages could prevent the deaths of
millions of people. And so, many scientists began working toward this
goal.
The first success in developing a blood test for a common
cancer was in 1965, when carcinoembryonic antigen (CEA) was found in
the blood of some patients with colon cancer. By the end of the 1970s
several other blood tests had been developed for different cancers. The
new markers were often given numeric labels. There was CA 19-9 for
colorectal and pancreatic cancer, CA15-3 for breast cancer, and CA 125
for ovarian cancer. Many others were also found, but because they did
not show an advantage over the already discovered markers, they were
not studied any further.
None of these tumor markers, including CEA, met the original
goal of being able to find cancer at a very early stage. There were a
few reasons for this:
- Almost everyone has a small amount of these markers in
their blood, and it is very hard to spot early cancers by using these
tests.
- The levels of these markers tend to get higher than normal
only when there is a large amount of cancer present.
- Some people with cancer never have higher levels of these
markers.
- Even when levels of these markers are high, they are often
not specific enough. For example, the level of the tumor marker CA 125
can be high in women with gynecologic conditions other than ovarian
cancer.
These reasons are way tumor markers are used mainly in
patients who have already been diagnosed with cancer to watch their
response to treatment or look for the return of cancer after treatment.
The only tumor marker widely used in screening today is the
prostate-specific antigen (PSA) test. It was discovered around the same
time as the others, but it's been in widespread use for screening since
the early 1990s because it has certain advantages. First, it is made
only by prostate cells, so a rise in PSA is most likely a sign of a
prostate problem. Also, the PSA level usually rises even in early
cancers, so most prostate cancers can be found at an early stage, when
they are most likely to be curable. But the test is not perfect. Some
men may have an elevated PSA because of other prostate conditions. In
others, the high PSA is from a prostate cancer that would never have
needed treatment. Also, some men with prostate cancer may not have an
elevated PSA. This is why doctors and medical organizations do not
agree about whether all men should be tested.
Many other tumor markers have been found in recent years and
are now under study. Some of these are different from traditional
markers, which were proteins found in the blood.
Specific tumor markers
This section focuses on some of the tumor markers most often
used today.
Tests for many other markers are available through commercial
testing labs, but these are not commonly used. They may even be
advertised as being better than the more common markers, but haven't
yet been shown to have an advantage over the others. In some cases like
this, the tests have been taken off the market at the request of the
Food and Drug Administration. Still, there are tests with unproven
value available for many tumor markers.
There are also other markers that are used by researchers.
These are often not available to doctors or hospital labs. If research
does show that they are useful, they are then made available to doctors
and their patients. This list is limited to those tumor markers
available to most doctors and for which there is reliable scientific
information showing that they are useful.
The cancers described in these brief summaries are those for
which the marker is usually used. These marker levels may be increased
in other kinds of cancer, too. This is why tumor markers are not often
used to figure out what type of cancer a person has.
As with other kinds of lab tests, different labs may consider
slightly different marker levels to be normal or abnormal. This can
depend on a number of factors, including a person's age and gender,
which test kit the lab uses, and how the test is done. The values
listed below are average values, but most labs will list their own
"reference ranges" along with any test results you get. If you are
being tested for a tumor marker, be sure to ask your doctor about what
your results mean.
Alpha-fetoprotein (AFP)
AFP can be helpful in the diagnosis and treatment of liver
cancer (hepatocellular carcinoma). Normal levels of AFP are usually
less than 10 ng/mL (nanograms per milliliter). (A nanogram is
one-billionth of a gram.) AFP levels are increased in most patients
with liver cancer. AFP is also elevated in acute and chronic hepatitis,
but it seldom gets above 100 ng/mL in these diseases.
In someone with a liver tumor, an AFP level over a certain
value means that the person has liver cancer. In people without liver
problems, that value is 400 ng/mL. But in a person with chronic
hepatitis who has a liver tumor, AFP levels of over 4,000 ng/mL are a
sign of liver cancer. AFP is also useful in following the response to
treatment for liver cancer. If the cancer is completely removed with
surgery, the AFP level should go down to normal. If the level goes back
up again, it often means that the cancer has come back.
AFP is also higher in certain testicular cancers (those
containing embryonal cell and endodermal sinus types) and is used for
follow-up of these cancers. Elevated AFP levels are also seen in
certain rare types of ovarian cancer called yolk sac tumor or mixed
germ cell cancer.
Beta-2-microglobulin (B2M)
B2M blood levels are elevated in multiple myeloma, chronic
lymphocytic leukemia (CLL), and some lymphomas. Levels may also be
higher in some non-cancerous conditions, such as kidney disease. Normal
levels are usually below 2.5 mg/L (milligrams per liter). B2M is useful
to help predict the long-term outlook (prognosis) in some of these
cancers. Patients with higher levels of B2M usually have a poorer
prognosis. B2M is also checked during treatment of multiple myeloma to
see how well the treatment is working.
Beta-HCG
See human chorionic gonadotropin (HCG) below
Bladder tumor antigen (BTA)
BTA is found in the urine of many patients with bladder
cancer. It may be a sign of some non-cancerous conditions, too, such as
kidney stones or urinary tract infections. The results of the test are
reported as either positive (BTA is present) or negative (BTA is not
present). It is sometimes used along with NMP22 (see below) to test
patients for the return (recurrence) of bladder cancer. This test is
not often used but is still being studied. It is not as good as
cystoscopy (looking into the bladder through a thin, lighted tube) for
finding bladder cancer, but it may be helpful in allowing cystoscopy to
be done less often during bladder cancer follow-up. Most experts still
consider cystoscopy the standard for diagnosis and follow-up of bladder
cancer.
CA 15-3
CA 15-3 is mainly used to watch patients with breast cancer.
Elevated blood levels are found in less than 10% of patients with early
disease and in about 70% of patients with advanced disease. Levels
usually drop after effective treatment, but they may go up in the first
few weeks after treatment is started. This rise is caused when dying
cancer cells spill their contents into the bloodstream.
The normal level is usually less than 30 U/mL
(units/milliliter), depending on the lab. But levels as high as 100
U/mL can sometimes be seen in women who do not have cancer. Levels of
this marker can also be higher in other cancers and in some
non-cancerous conditions, such as benign breast conditions and
hepatitis.
CA 27.29
CA 27.29 is another marker that can be used to follow patients
with breast cancer during or after treatment. This test measures the
same marker as the CA 15-3 test, but in a different way. Although it is
a newer test than CA 15-3, it is not any better in detecting either
early or advanced disease. It may be less likely to be positive in
people without cancer. The normal level is usually less than 40 U/mL
(units/milliliter), depending on the testing lab. This marker can also
be elevated in other cancers and in some non-cancerous conditions, but
it is not elevated in all patients with breast cancer.
CA 125
CA 125 is the standard tumor marker used to follow women
during or after treatment for epithelial ovarian cancer (the most
common type of ovarian cancer). Normal blood levels are usually less
than 35 U/mL (units/milliliter). More than 90% of women have high
levels of CA 125 when the cancer is advanced. And changes in CA 125
levels are often watched during treatment to get an idea of how well
it's working.
Levels are also elevated in about half of women whose cancer
has not spread outside of the ovary. This is why CA 125 has been
studied as a screening test. The trouble with using it as a screening
test is that it would still miss many early cancers, and problems other
than ovarian cancer can cause an elevated CA 125 level. For example, it
is also often higher in women with uterine fibroids or endometriosis
(having uterine cells in abnormal locations). It may also be higher in
men and women with lung, pancreatic, breast, and colon cancer, and in
people who have had cancer in the past. Because ovarian cancer is a
rather rare disease, an increased CA 125 level is more likely to be
caused by something other than ovarian cancer.
CA 72-4
CA 72-4 is a newer test being studied in ovarian and
pancreatic cancer and cancers starting in the digestive tract,
especially stomach cancer. There is no evidence that it is better than
the tumor markers currently in use, but it may be valuable when used
along with other tests. Studies of this marker are still in progress.
CA 19-9
The CA 19-9 test was first developed to detect colorectal
cancer, but it is more often used in patients with pancreatic cancer.
In very early disease the level is often normal, so it is not good as a
screening test. Still, it is the best tumor marker for following
patients with cancer of the pancreas.
Normal blood levels of CA 19-9 are below 37 U/mL
(units/milliliter). A high CA 19-9 level in a newly diagnosed patient
usually means the disease is advanced.
CA 19-9 can also be used to watch colorectal cancer, but the
CEA test is preferred for this type of cancer.
CA 19-9 can also be elevated in other forms of digestive tract
cancer, especially cancers of the stomach and bile ducts, and in some
non-cancerous conditions such as thyroid disease and pancreatitis
(inflammation of the pancreas).
Calcitonin
Calcitonin is a hormone produced by cells called
parafollicular C cells in the thyroid gland. It normally helps regulate
blood calcium levels. Normal calcitonin levels are below 5 to 12 pg/ml
(picograms per milliliter). (A picogram is one trillionth of a gram.)
In medullary thyroid carcinoma (MTC), a rare cancer that starts in the
parafollicular C cells, blood levels of this hormone are often greater
than 100 pg/ml.
This is one of the rare tumor markers that can be used to help
detect early cancer. Because MTC is often inherited, blood calcitonin
can be measured to detect the cancer in its very earliest stages in
family members who known to be at risk. Other cancers, such as lung
cancers and leukemias, can also cause calcitonin levels to be elevated,
but calcitonin blood levels are not usually used to follow these
cancers.
Carcinoembryonic antigen (CEA)
CEA is not used to diagnose or screen for colorectal cancer,
but it is the preferred tumor marker to help predict outlook in
patients with colorectal cancer. The normal range of blood levels
varies from lab to lab, but levels higher than 3 ng/mL (nanograms per
milliliter) are not normal. The higher the CEA level at the time
colorectal cancer is detected, the more likely it is that the cancer is
advanced.
CEA is also the standard marker used to follow patients with
colorectal cancer during and after treatment. In this way CEA levels
are used to see if the cancer is responding to treatment or to see if
it has come back (recurred) after treatment.
This marker can be high in some other cancers, too. If the CEA
level is high at diagnosis, it can be used to follow the response to
treatment. It is often used for cancers of the lung and breast. CEA
levels are also elevated in many other cancers such as those of the
thyroid, pancreas, liver, stomach, prostate, ovary, and bladder. They
are elevated in some non-cancerous diseases and in otherwise healthy
smokers, too.
Chromogranin A
Chromogranin A (CgA) is made by neuroendocrine tumors, which
include carcinoid tumors, neuroblastoma, and small cell lung cancer.
The blood level of CgA is often elevated in people with these diseases.
It is probably the most sensitive tumor marker for carcinoid tumors. It
is abnormal in 1 out of 3 people with localized disease and 2 out of 3
of those with cancer that has spread (metastatic cancer). Levels can
also be elevated in some advanced forms of prostate cancer that have
neuroendocrine features. The range of normal blood levels varies
between testing centers, but is commonly less than 50 ng/mL (nanograms
per milliliter).
Hormone receptors
Breast tumor samples -- not blood samples -- from all cases of
breast cancer are tested for estrogen and progesterone receptors.
Breast cancers that contain estrogen receptors are often referred to as
"ER-positive;" those with progesterone receptors are "PR-positive."
About 2 out of 3 breast cancers test positive for at least one of these
markers. These cancers tend to grow more slowly and have a better
outlook than cancers without these receptors. Cancers that have these
receptors can be treated with hormone therapy such as tamoxifen or
aromatase inhibitors.
HER2 (also known as HER2/neu, erbB-2, or
EGFR2)
HER2 is a protein that tells breast cancer cells to grow. It
is elevated in some breast cancers. Higher than normal levels can be
found in some other cancers, too. The HER2 level is usually found by
testing a sample of the cancer tissue itself, not the blood. About 1 in
5 breast cancers test positive for HER2. These cancers tend to grow and
spread more aggressively than other breast cancers.
All newly diagnosed breast cancers should be tested for HER2.
HER2-positive cancers are more likely to respond to certain treatments
such as trastuzumab (Herceptin®) and
lapatinib
(Tykerb®), which work against the HER2
receptor on breast
cancer cells.
Human chorionic gonadotropin (HCG)
HCG (also known as beta-HCG) blood levels are elevated in
patients with some types of testicular and ovarian cancers (germ cell
tumors) and in gestational trophoblastic disease, mainly
choriocarcinoma. They are also higher in some people with mediastinal
germ cell tumors -- cancers in the middle of the chest (the
mediastinum) that start in the same cells as germ cell tumors of the
testicles and ovaries. Levels of HCG can be used to help diagnose these
conditions and can be followed over time to see how well treatment is
working. They can also be used to look for cancer that has come back
after treatment has ended (recurrence).
An elevated blood level of HCG will also raise suspicions of
cancer in certain situations. For example, in a woman who still has a
large uterus after pregnancy has ended, a high blood level of this
marker is a possible sign of a cancer. This is also true of men with an
enlarged testicle or anyone with a tumor in their chest.
It is hard to define the HCG normal level because there are
different ways to test for this marker and each has its own normal
value.
Immunoglobulins
Immunoglobulins are not really tumor markers but antibodies,
which are blood proteins normally made by immune system cells to help
fight germs. There are many types of immunoglobulins, including IgA,
IgG, IgD, and IgM. Bone marrow cancers such as multiple myeloma and
Waldenstrom macroglobulinemia often cause a person to have too much of
1 type of immunoglobulin in the blood. These cancers can also cause
pieces of immunoglobulin to be found in the urine. A high level of
immunoglobulins may be a sign of one of these diseases.
There are normally many different immunoglobulins in the
blood, with each one differing very slightly from the others. A classic
sign in patients with myeloma or macroglobulinemia is a very high level
of a certain monoclonal immunoglobulin. This can be seen on a test
called serum protein electrophoresis (also called SPEP). In this test,
the blood proteins are separated by an electrical current. With myeloma
or macroglobulinemia, the monoclonal immunoglobulin forms a monoclonal
"spike" on the SPEP. This is often called the M spike, monoclonal
protein, or M protein. The level of the spike is important, because
some people may show low levels of a spike without having myeloma or
macroglobulinemia. Still, the diagnosis of multiple myeloma or
Waldenstrom macroglobulinemia must be confirmed by a biopsy of the bone
marrow.
Immunoglobulin levels can also be followed over time to help
see how well treatment is working.
Lipid associated sialic acid in plasma
(LASA-P)
LASA-P has been studied as a marker for ovarian cancer as well
as some other cancers. For the most part it has not proven valuable,
and has been replaced by more specific marker tests. It is not specific
for any one cancer or even for cancer in general, as it can also be
elevated in some non-cancerous conditions. Still, it is sometimes used
along with other tumor markers to follow response to treatment.
Neuron-specific enolase (NSE)
NSE, like chromogranin A, is a marker for neuroendocrine
tumors such as small cell lung cancer, neuroblastoma, and carcinoid
tumors. It is not used as a screening test. It is most useful in the
follow-up of patients with small cell lung cancer or neuroblastoma.
(Chromogranin A seems to be a better marker for carcinoid tumors.)
Elevated levels of NSE may also be found in some non-neuroendocrine
cancers. Abnormal levels are usually higher than 9 ug/mL (micrograms
per milliliter).
NMP22
NMP22 is a protein found in the nucleus (control center) of
cells. Levels of NMP22 are often elevated (more than 10 U/mL or
units/milliliter) in the urine of people with bladder cancer. So far it
hasn't been found to be sensitive enough to be used as a screening
tool. It is most often used to look for cancer that has come back after
treatment. This is a less invasive way to look for cancer than
cystoscopy (looking into the bladder with a thin, lighted tube), but
it's not always as accurate. NMP22 testing can't take the place of
cystoscopy completely, but it can permit this procedure to be done less
often. NMP22 levels can also be higher than normal with some
non-cancerous conditions or due to recent treatment with chemotherapy.
Prostate-specific antigen (PSA):
PSA is a tumor marker for prostate cancer. It is the only
marker used to screen for a common type of cancer, although some
medical groups do not recommend its use. PSA is a protein made by cells
of the prostate gland. The prostate gland is found only in men. It
makes some of the liquid in semen.
The level of PSA in the blood can be elevated in prostate
cancer, but PSA levels can be affected by other factors, too. Men with
benign prostatic hyperplasia (BPH), a non-cancerous growth of the
prostate, often have higher levels. The PSA level also tends to be
higher in older men and those with infected or inflamed prostates. It
can also be elevated for a day or 2 after ejaculation.
When the PSA test is used for screening, it should be done
along with a digital rectal exam. For this test the doctor puts a
gloved, lubricated finger into the rectum to feel the prostate gland
for any bumps or hard areas.
PSA is measured in nanograms per milliliter (ng/mL). Most
doctors feel that a blood PSA level below 4 ng/mL means cancer is
unlikely. Levels greater than 10 ng/mL mean cancer is likely. The area
between 4 and 10 is a gray zone. Men with PSA levels in this borderline
range have about a 1 in 4 chance of having prostate cancer. Doctors
often recommend a prostate biopsy (getting samples of prostate tissue
to look for cancer) for men with a PSA level above 4 ng/mL.
But not all doctors agree with these cutoff points. This is
because some men with prostate cancer do not have an elevated PSA
level, while some others with a borderline or elevated level will not
have cancer. Some doctors believe it is more useful to follow the PSA
level over time because an increase from one year to the next may mean
prostate cancer is more likely. This is called PSA velocity. Most
doctors believe that PSA levels should be measured at least 3 times
over a period of at least 18 months in order to get an accurate PSA
velocity. Doctors are also looking at the PSA level in other ways to
see if it might be more useful.
A helpful test when a PSA value is in the borderline range
(between 4 and 10 ng/mL) is to measure the free PSA (or percent-free
PSA). PSA is in the blood in 2 forms -- some is bound to a
protein and
some is free. The percent-free PSA (fPSA) is the ratio of how much PSA
circulates free compared to the total PSA level. As the amount of free
PSA goes up, the less likely it is that there is prostate cancer. When
the free PSA makes up more than 25% of the total PSA, prostate cancer
is unlikely. If the free PSA is below 10%, the chance of prostate
cancer is much higher and a biopsy should be done.
The PSA test is very valuable in the follow-up of men with
prostate cancer. For those who have been treated with surgery meant to
cure the disease, the PSA should fall to an undetectable level. Those
treated with radiation therapy should also have the PSA go down after
treatment. A rise in the PSA level may be a sign the cancer is coming
back. The PSA can also be used to follow the response to treatment.
Prostatic acid phosphatase (PAP)
PAP (not to be confused with the Pap test for women) is
another test for prostate cancer. It was used before the PSA test was
developed but is seldom used now because the PSA test is better.
Prostate-specific membrane antigen (PSMA)
PSMA is a substance found in all prostate cells. Blood levels
increase with age and with prostate cancer. PSMA is a very sensitive
marker, but so far it has not proven to be better than PSA. Its use in
finding or following cancer is still being studied. Its current use is
limited to being part of a nuclear scan (a type of imaging test) to
look for the spread of prostate cancer in the body. Some potential
immunotherapy treatments for prostate cancer based on PSMA are now
under study.
S-100
S-100 is a protein found in most melanoma cells. Tissue
samples of suspected melanomas are often tested for this marker to help
in diagnosis.
Some studies have shown that blood levels of S-100 are
elevated in most patients with metastatic melanoma. The test is
sometimes used to look for melanoma spread before, during, or after
treatment.
TA-90
TA-90 is a protein found on the outer surface of melanoma
cells. Like S-100, TA-90 can be used to look for the spread of
melanoma. Its value in following melanoma is still being studied, and
it is not widely used at this time. It is also being studied for use in
other cancers such as colon and breast cancer.
Thyroglobulin
Thyroglobulin is a protein made by the thyroid gland. Normal
blood levels depend on a person's age and gender. Thyroglobulin levels
are elevated in many thyroid diseases, including some common forms of
thyroid cancer.
Treatment for thyroid cancer often involves removal of the
entire thyroid gland, sometimes along with radiation therapy.
Thyroglobulin levels in the blood should fall to undetectable levels
after treatment. A rise in the thyroglobulin level may mean the cancer
has come back. In people with thyroid cancer that has spread,
thyroglobulin levels can be followed over time to evaluate the results
of treatment.
Some people's immune systems make antibodies against
thyroglobulin, which can affect test results. This is why levels of
anti-thyroglobulin antibodies are often measured at the same time.
Tissue polypeptide antigen (TPA)
TPA is a protein marker that is found in high levels when
there are many rapidly dividing cells (such as cancer cells). The TPA
blood test is sometimes used along with other tumor markers to help
follow patients being treated for lung, bladder, and many other
cancers. TPA levels are also elevated in some non-cancerous conditions.
Common cancers and the tumor markers linked
to them
Bladder cancer
No tumor markers in urine are recommended for bladder cancer
screening. But the bladder
tumor antigen (BTA) and the NMP22 tests can
be used along with cystoscopy (using a thin, lighted tube to look in
the bladder) in diagnosing it in patients with symptoms.
These tests are also being used to follow some patients after
treatment, though cystoscopy and urine cytology (using a microscope to
look for cancer cells in the urine) are still recommended as the
standard tests for diagnosis and follow-up. BTA and NMP22 tests are
often used between cystoscopies. Normal values may allow cystoscopy to
be done less often. These tests do not take the place of urine cytology
and cystoscopy. Other tumor markers are also being studied in this
setting.
For advanced bladder cancer, some of the markers used for
other cancers such as CEA, CA 125, CA 19-9, and TPA may be elevated and
can be used to follow patients during and after treatment.
(For more information refer to our document Bladder Cancer.)
Breast cancer
No tumor marker has been found to be useful for screening or
diagnosing early stage breast cancer.
At the time of diagnosis, breast cancer tissue should be
tested for estrogen
and progesterone
receptors, as well as the HER2/neu
antigen. These markers give information on how aggressive the cancer
may be and how likely it is to respond to certain treatments.
The markers most often used to follow patients with advanced
cancer or to look for the return of the cancer after treatment
(recurrence) are CA 15-3
and CEA.
The CA 27.29
test is also used by
some doctors. The CA 15-3 and CA 27.29 are probably equally sensitive,
while the CEA is less sensitive.
These markers are most useful in measuring the results of
treatment for patients with advanced disease. In most cases, blood
levels go down if the cancer responds to treatment and rise if the
cancer progresses.
Some doctors use these tests to look for signs of recurrence
in women who have no symptoms of cancer after their first treatment.
But most professional groups do not recommend using these markers to
follow women already treated for early stage disease.
(For more information refer to our document Breast Cancer.)
Colorectal cancer
The markers most often elevated in advanced colorectal cancer
are CEA
and CA 19-9,
but neither of these is useful as a screening test
for colorectal cancer.
An elevated CEA before surgery may be a sign of a poorer
outcome. If it is high before surgery, the CEA should go to normal
levels in about 4 to 6 weeks if all of the cancer has been removed.
Many doctors follow patients after surgery with CEA tests
every 3 to 6 months or so to look for the return of the cancer
(recurrence). Finding a recurrence early is good because it may then be
removed by surgery. But for most patients the recurrence is likely to
be too widespread to be removed.
CEA is also used to follow patients who are being treated for
advanced or recurrent disease. The CEA level will go down if the
treatment is working and will rise if the cancer progresses.
If the CEA is not elevated in patients with advanced or
recurrent cancer, sometimes the CA 19-9 can be used to follow the
disease.
(For more information refer to our document Colorectal
Cancer.)
Gestational trophoblastic disease
Trophoblastic tumors include molar pregnancies (a pregnancy
that results in a tumor of the placenta) and the more aggressive
choriocarcinoma. Human
chorionic gonadotropin (HCG) is elevated in
these tumors. HCG testing can be used to find these cancers in women
who are no longer pregnant but still have an enlarged uterus.
Measurements of HCG during treatment for trophoblastic disease
are very useful in looking at response to treatment.
(For more information refer to our document Gestational
Trophoblastic Disease.)
Liver cancer
Cancer that starts in the liver (known as hepatocellular
carcinoma) is linked with chronic infections caused by hepatitis B and
C viruses and with cirrhosis from various causes. This is a common type
of cancer in Southeast Asia.
Liver cancers can cause elevated levels of alpha fetoprotein
(AFP). Higher AFP levels occur in most patients with liver
cancer. An
elevated AFP in someone with chronic hepatitis may suggest the
diagnosis of this cancer and lead to testing to see if the liver
contains a tumor.
Liver cancer is not very common in the United States, so AFP
testing is not used to test the general population for this type of
cancer. Screening with AFP has been successful in parts of Asia where
liver cancer is common. Sometimes the cancer is found early enough so
that the patient can be cured with surgery. Because of this success,
some doctors in the United States may screen their patients with
cirrhosis of the liver due to hepatitis B or C. A rising AFP level
might be a sign of cancer.
AFP can be used to help figure out the best treatment for
liver cancer and to follow patients after curative surgery or other
treatment.
(For more information refer to our document Liver Cancer.)
Lung cancer
No tumor markers have proven useful as screening tests for
lung cancer.
Some of the tumor markers that may be elevated in lung cancer
are the carcinoembryonic
antigen (CEA) in non-small cell lung cancer
and the neuron-specific
enolase (NSE) in small cell lung cancer.
Sometimes doctors will follow these markers to evaluate treatment
results. There are many other markers that can also be followed. But
because lung cancer is fairly easily seen on chest x-rays or other
imaging tests, tumor markers play a less important role.
(For more information refer to our document Lung Cancer
(Non-Small Cell) or Lung Cancer (Small Cell).)
Melanoma skin cancer
No tumor marker is of value in finding this disease early.
The markers TA-90,
S-100, and
some other markers can be used
to test tissue samples to help see if a tumor is melanoma.
Blood levels of TA-90 have been used to help find out if the
melanoma has spread (metastasized). If the blood TA-90 level is high,
there is a good chance the melanoma is metastatic. But TA-90 can
sometimes be elevated in the absence of metastatic melanoma. Because of
this, it has not yet been used to plan treatment or predict prognosis.
S-100 is also elevated in the blood when the disease is
widespread. This marker can also be used to look for progression of the
melanoma.
(For more information refer to our document Melanoma Skin
Cancer.)
Multiple myeloma
There are no tumor markers commonly used to screen for this
disease, but tests for immunoglobulins
can be used to help detect it or
make a diagnosis. Protein electrophoresis and immunofixation can find
these immune system proteins in the blood or urine of most patients
with myeloma.
Pieces of immunoglobulins in the urine, called Bence Jones
proteins, are found in some patients with multiple
myeloma. Most people
with myeloma also have detectable levels of a certain immunoglobulin,
called a monoclonal
protein or M-protein,
in their blood. This protein
leads to a monoclonal spike, or M
spike, on a protein electrophoresis.
These proteins can help diagnose the disease, but a bone marrow biopsy
may be needed to confirm the diagnosis. These markers are also helpful
in tracking the course of the disease and its response to treatment.
Many patients with multiple myeloma also have higher blood
levels of beta-2-microglobulin,
which can also give information on
outlook and the response to treatment.
(For more information refer to our document Multiple Myeloma.)
Ovarian cancer
Epithelial ovarian cancer (the most common form of ovarian
cancer) is linked with elevated levels of CA 125. Other
markers that
are sometimes measured are CA
72-4 and
LASA-P. CA 125, which is
elevated in most women with advanced disease, is the standard marker
that most doctors use. Ovarian cancer, even when advanced, is often
confined to the abdomen and pelvis and hard to find through x-ray
testing. This is why the CA 125 is often the easiest and best way to
measure the response to treatment or to find a cancer that has come
back.
CA 125 has been studied as a screening tool in women who have
no family history of ovarian cancer. At the present time, most medical
groups do not recommend CA 125 testing for ovarian cancer screening
because it doesn't seem to find the cancer early enough to help women
live longer. Another problem with this test is that ovarian cancer is
not common, and the CA 125 level can be elevated in other cancers and
other conditions. So an elevated CA 125 is more likely to be due to
some other cause, and more tests, including surgery, are often needed
to rule out ovarian cancer.
CA 125 is used by some doctors to screen for ovarian cancer in
women with a strong family history of ovarian cancers. Such women
usually get regular ultrasounds for early detection along with CA 125
tests. Still, even in women with a high risk of ovarian cancer, this
testing has not yet been found to find the cancers early or help women
live longer.
The second most common group of ovarian cancers is the germ
cell tumors. Patients with these cancers often have elevated levels of
HCG and/or AFP, which are
useful in diagnosis and follow-up.
(For more information refer to our document Ovarian Cancer.)
Pancreatic cancer
No markers have been found to be helpful in screening for
pancreatic cancer.
The CA 19-9 marker
is the most useful marker for pancreatic
cancer. Most people with pancreatic cancer have elevated levels of CA
19-9 in their blood. The higher the level, the more likely the disease
has spread. CA 19-9 levels give information about the outlook for
people with pancreatic cancer but cannot be used to diagnose the
disease.
It can be useful in patient follow-up. Patients whose CA 19-9
levels drop to normal after surgery have a much better outlook than
those people whose CA 19-9 remains elevated after surgery. This marker
can also be used to follow the effects of treatment on more advanced
disease.
Some doctors also follow the level of CEA in the blood, but it
may not be as helpful as the CA 19-9 level.
(For more information refer to our document Pancreatic
Cancer.)
Prostate cancer
The marker most often used to detect prostate cancer is the
prostate-specific
antigen (PSA). Prostate cancer can often be found in
its early stages by measuring blood levels of PSA. Levels above 4
(ng/mL) suggest cancer may be present, while levels above 10 (ng/mL)
strongly suggest cancer. Doctors usually advise that men with elevated
PSA levels have their prostate gland biopsied to find out if there is
cancer. (This means small pieces of the gland are taken out to look for
cancer cells.)
Prostate cancer is often a slow growing cancer that is found
in older men. This is why it is not clear if screening with PSA really
saves lives or helps people live longer. Some doctors believe that
screening may cause more harm than good. It may lead some men to get
treated for cancers that would never have caused them problems, and the
treatment itself can have major side effects.
PSA is very useful in finding cancer that has come back after
treatment (recurrent disease). After surgery, the PSA level should be
undetectable or near undetectable (0 or very close to 0). Those treated
with radiation therapy should also have a huge drop in PSA after
treatment, but it can take years before it goes back to normal. A rise
in PSA after treatment could mean the disease is coming back and that
more treatment should be considered. The PSA can also be used to follow
the response to treatment for more advanced disease.
Another marker being studied for following prostate cancer is
the prostate-specific
membrane antigen (PSMA). It's not yet clear how
useful it will be.
A rare type of prostate cancer, small cell, has neuroendocrine
features. It often does not cause abnormal blood PSA levels or respond
well to hormone therapy. Men with these cancers may have higher than
normal levels of chromogranin
A. These cancers are more likely to
respond to certain chemotherapy drugs.
Prostatic acid
phosphatase (PAP) is an older, less sensitive
marker which is no longer used very much.
(For more information refer to our document Prostate Cancer.)
Stomach (gastric) cancer
No marker has been developed for this cancer. Some other
digestive cancer markers may be elevated, such as CEA, CA 72-4, and/or
CA 19-9. If
the levels of these markers are elevated at the time of
diagnosis, the levels can be followed while the cancer is being
treated.
(For more information refer to our document Stomach Cancer.)
Testicular cancer
Tumor markers are very important in this cancer and are used
by doctors to follow its course. Human
chorionic gonadotropin (HCG) and
alpha fetoprotein
(AFP) are usually elevated in the blood of men with
testicular cancer. There are different kinds of testicular cancers, and
they differ in the level and kind of marker that is elevated.
Seminoma: About
10% of men with seminoma, a type of testicular
cancer, will have elevated HCG. None will have elevated AFP.
Non-seminoma: More
than half of men with early stage disease
will have elevated HCG or AFP or both. The amount of the marker found
in the blood at the time of diagnosis does not often help in predicting
outcome. These markers are elevated in most men with advanced disease.
Very high levels of these markers can be a sign of a poorer outlook.
HCG is almost always elevated and AFP is never elevated in
choriocarcinoma, a subtype of non-seminoma. In contrast AFP, but not
HCG, is elevated in another subtype known as yolk sac tumor or
endodermal sinus tumor. Many tumors are made up of a mixture of
different types of non-seminoma.
(For more information refer to our document Testicular
Cancer.)
What should you ask your doctor about tumor
markers?
It is important to talk openly with your cancer care team.
Don't be afraid to ask any question that's on your mind, no matter how
small or silly it might seem to you. Here are some questions you might
ask. Be sure and add your own.
- Do I have any elevated tumor markers?
- Which tumor markers are elevated?
- What does this mean for me?
- Are there other health problems or medicines that
could affect my tumor marker levels?
- Does the elevation in my tumor marker(s) change my
treatment?
- Will you use these markers to evaluate my
treatment?
- How often will the tumor markers be tested?
What's
new in tumor marker research?
Because it's important to detect cancer early and to be able
to follow it during or after treatment, researchers are looking for new
and better tumor markers. But as doctors have learned more about
cancer, they've found that the level of a single protein or other
substance in the blood may not be the best marker for the disease.
Genomics
Researchers are starting to focus on genetic markers to detect
cancer. We know that most cancers have changes in their DNA, the
molecules that direct the functions of all cells. By looking for DNA
changes in blood, stool, or urine, scientists may be able to find
cancers very early. The study of patterns of DNA changes (known as
genomics)
is likely to prove more useful than looking for single DNA
changes.
Proteomics
Another newer approach is called proteomics. This
technology
looks at the patterns of all the proteins in the blood instead of
looking at individual protein levels. New testing equipment allows
doctors to look at thousands of proteins at one time. It's unlikely
that such a test would be used in a doctor's office, but it may help
researchers narrow down which protein levels are important in a certain
type of cancer. This information could then be used to develop a blood
test that might look only at these important proteins.
These new testing methods are still in the early stages of
development. Very few are in routine use at this time.
New developments and areas of research for
some common cancers
Bladder cancer
Doctors have been looking for ways to find bladder cancer that
has come back (recurrence) by testing the urine. Looking at DNA in the
urine has been very successful so far. In fact, the urine tests can
find cancer recurrence before doctors can see it by looking directly
into the bladder with cystoscopy.
Breast cancer
Breast cancer cells likely spill into the blood, even in early
stages of the disease. Researchers have found abnormal DNA from these
cells in the blood of patients with breast cancer. About half of
patients with even early stage breast cancer have cancer cells in their
blood. Researchers are still trying to figure out if the presence of
these cells can help predict a person's outlook.
New genetic tests may help find out if women are likely to
have cancer come back (recurrence) after initial treatment, and whether
they might benefit from additional (adjuvant) hormone therapy or
chemotherapy. Tests such as Oncotype DX™ and
MammaPrint®, which look at a number of
specific genes in a
breast tumor sample, are now being used by some doctors for this
purpose, and other tests are being studied.
Some other markers in the tumor tissue may also help to
predict outlook and help guide treatment decisions. The levels of 2
proteins, urokinase plasminogen activator (uPA) and plasminogen
activator inhibitor (PAI-1) may be helpful for this. Higher-than-normal
levels of these tumor markers in the cancer tissue may mean that the
cancer is more aggressive (faster growing). These tumor markers may be
used to guide the use of chemotherapy after surgery for patients with
node-negative breast cancer (meaning there is no cancer found in the
lymph nodes). The problem with these markers is that they have to be
checked on tumor tissue that is not preserved. (It must be fresh or
frozen) This makes these tests harder to do (and less available) than
other tumor marker tests for breast cancer.
Colorectal cancer
Most colorectal cancers contain changes in genes such as APC,
k-ras, and p53. New studies have found pieces of abnormal DNA in the
stools of people with early colorectal cancer. Testing stool samples
for these DNA changes can be used to screen for this disease.
Other studies have found changes in DNA in the blood of
patients with early colorectal cancer. Looking at the number of
repeated sequences in DNA (known as microsatellite instability) may
give doctors clues as to how well treatment might work.
Lung cancer
Studies have found elevated levels of DNA in the blood of
patients with lung cancer, while more sensitive tests have been able to
detect abnormal DNA in their blood. These abnormal DNA changes have
also been found in the sputum of patients with early lung cancer.
Doctors think that this may some day be a good way of finding lung
cancer early in patients who have a high risk of developing the
disease.
Liver cancer
The gene called p53 is often abnormal in liver cancers. Blood
tests can find this abnormality in DNA in the blood of some patients
with this cancer. It's not yet clear how useful this will be.
Melanoma
In patients with advanced melanoma, small numbers of melanoma
cells are found in the blood. This may prove to be a good way of
finding out how advanced a person's melanoma is and whether it is
responding to treatment. More study is needed.
Oral cavity cancers
Abnormal DNA can be found in saliva samples of people with
these cancers. It may be a good way to detect them early in people at
high risk or who have been treated for these cancers. Research on this
is under way.
Ovarian cancer
Several different blood tests are being studied for early
detection of this cancer. The most successful appears to be the use of
protein patterns in patients' blood. This method, called proteomics,
has shown some promising early results. This type of test still needs
to be studied to see if it can find this cancer at an early stage in
women with no symptoms.
The use of CA 125, along with imaging tests such as
ultrasound, as a screening test for ovarian cancer is still being
studied.
Prostate cancer
There is a major clinical trial in progress to determine the
value of PSA screening for prostate cancer. There are also newer
versions of this test that look at certain fractions of PSA, such as
free PSA or complexed PSA, which may give more useful information.
Doctors are also studying the usefulness of watching the change in PSA
levels over time, as opposed to focusing on a single test result (PSA
velocity).
There are also attempts to look at protein patterns in the
blood as a way of finding the disease in the early stages. Other new
tests are looking at certain proteins or genes to try to find out which
prostate cancers are likely to be aggressive (and need treatment) and
which are likely to grow more slowly (and can probably just be watched
carefully).
Most of these new methods of detecting cancer are still in the
experimental stage. Many studies are in progress to try to figure out
how useful they will be.
Additional resources
More information from your American Cancer
Society
The following related information may also be helpful to you.
These materials may be ordered from our toll-free number.
- After Diagnosis: A Guide for Patients and Families (also
available in Spanish)
- Understanding Your Lab Test Results
The following information may also be helpful to you. These
books may be ordered from our toll-free number.
National organizations and Web sites*
Along with the American Cancer Society, other sources of
information include:
National Cancer Institute
Toll-free number: 1-800-422-6237 (1-800-4-CANCER)
Web site: www.cancer.gov
*Inclusion on
this list does not imply endorsement by the
American Cancer Society.
No matter who you are, we can help. Contact us anytime, day or
night, for cancer-related information and support. Call us at
1-800-ACS-2345
(1-800-227-2345)
or visit www.cancer.org..
References
American Society of Clinical Oncology (ASCO). Understanding
Tumor Markers. Available at:
www.cancer.net/patient/Library/Cancer.Net+Features/Treatments%2C+Tests%2C+and+Procedures/Understanding+Tumor+Markers.
Accessed November 6, 2008.
Associated Regional and University Pathologists (ARUP)
Laboratories. ARUP's Laboratory Test Directory. Available at:
www.aruplab.com/TestDirectory/testdirectory.jsp. Accessed November 6,
2008.
Bigbee W, Herberman RB. Tumor markers and immunodiagnosis. In:
Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF,
Frei E III, eds. Cancer
Medicine. 6th ed. Hamilton, Ontario: BC Decker;
2003: 209-220.
Harris L, Fritsche H, Mennel R, et al. American Society of
Clinical Oncology 2007 Update of recommendations for the use of tumor
markers in breast cancer.
Journal of Clinical Oncology, 2007;25:
5287-5312.
Lab Tests Online. Tumor Markers. 2006. Available at:
http://labtestsonline.org/understanding/analytes/tumor_markers/glance.html.
Accessed November 10, 2008.
Lee P, Pincus MR, McPherson RA. Diagnosis and management of
cancer using serologic tumor markers. In: McPherson RA, Pincus MR, eds.
Henry's Clinical
Diagnosis and Management by Laboratory Methods. 21st
ed. Philadelphia, Pa: Saunders Elsevier; 2007: 1353-1366.
Locker GY, Hamilton S, Harris J, et al. ASCO 2006 Update of
Recommendations for the Use of Tumor Markers in Gastrointestinal
Cancer. Journal of
Clinical Oncology, 2006; 24: 5313-5327.
National Cancer Institute. Tumor Markers: Questions and
Answers. Available at:
www.cancer.gov/cancertopics/factsheet/Detection/tumor-markers. Accessed
November 6, 2008.
National Comprehensive Cancer Network Clinical Practice
Guidelines in Oncology. Hepatobiliary cancers. V.2.2008. Available at:
www.nccn.org. Accessed November 13, 2008.
Last Medical Review: 12/08/2008
Last Revised: 12/08/2008
|
