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TUMOR MARKERS

What are tumor markers? 

Tumor markers are substances that can be found in the body when cancer is present. The classic tumor marker is a protein that can be found in the blood in at increased levels when a certain type of cancer is present, but not all tumor markers are like that. Some are found in urine or other body fluid, and others are 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, but some newer markers are genes or other substances.

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.

Tumor markers alone are rarely enough to show that 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.

This is why 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. It's been hard to identify single substances that provide useful information, but 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?

Tumor markers can be used in a number of ways.

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. Tumor markers were first developed to test for cancer in people without symptoms, but 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 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 always mean that no cancer is present. At this time, not all doctors agree that PSA screening is right for all men.

So far, no other tumor marker has been shown to help screen 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 if a cancer is already widespread when it is found, tumor markers can help figure out where it 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 find the source. This can be important because treatment can then be aimed at this type of cancer.

Alpha fetoprotein (AFP) is an example of a tumor marker that can be used to help diagnose cancer. This tumor marker 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 in someone with a liver tumor, doctors can be fairly sure that liver cancer is present (even without a biopsy).

Determining the outlook (prognosis) for certain cancers

Some types of cancer grow and spread faster than others. But even within a cancer type (such as testicular cancer), some cancers will grow and spread more quickly or may be more or less responsive to certain treatments. Sometimes the level of a tumor marker can help predict the behavior and outlook for certain cancers. For example, in testicular cancer, very high levels of a tumor marker like HCG or AFP predicts for a more aggressive cancer and a poorer outlook for survival. Patients with these high levels may be given more aggressive treatment to start.

Seeing if certain treatments are likely to work

Certain markers found on cancer cells can be used to help predict if a certain treatment is likely to work or not. For example, in breast and stomach cancer, if the cells have too much of a protein called HER2, drugs such as trastuzumab (Herceptin®) can be helpful in treatment. If the cancer cells have a normal amount of HER2, the drugs won't help, so tumor tissue is checked for HER2 before treatment is started.

Determining how well treatment is working

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 certain type of cancer, the level of the marker may be able to be used to see if the treatment is working, instead of doing other tests like x-rays, CT scans, bone scans, or other tests.

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 chemo 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 have come back (recur) after treatment. Certain tumor markers may be useful once treatment is complete and there is no sign 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 and liver cancer

  • CA 125 for 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.

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 over time. The changes are important, which is why a series of levels often has more meaning than a single result. If at all possible it is best to compare results from tests done at 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).

The drawbacks of tumor markers

Early on  in the search for tumor markers, the hope was that someday all cancers could be detected early with a blood test. A simple blood test that could find cancers in their

earliest stages could prevent the deaths of millions of people. But very few tumor markers are useful for finding cancer at a very early stage. There are a few reasons for this:

Almost everyone has a small amount of these markers in their blood, so 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, it doesn't always mean that cancer is present. 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 why, today, 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.

Many other tumor markers have been found in recent years, and this remains an active area of cancer research.

Specific tumor markers

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 they 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 types of cancer.

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. The list below is limited to those tumor markers that are available to most doctors and have 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.

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 help diagnose and guide the 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 can mean 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 germ cell tumors, such as some testicular cancers (those containing embryonal cell and endodermal sinus types), certain rare types of ovarian cancer (yolk sac tumor or mixed germ cell cancer), and germ cell tumors that start in the chest (mediastinal germ cell tumors). AFP is used to monitor the response to treatment, since high levels should go down with successful treatment. If the cancer has gone away with treatment the level should go back to normal. After that, any increase can be a sign that the cancer has come back.

Bcr-abl

In chronic myeloid leukemia (CML), the cancer (leukemia) cells contain a new, abnormal gene called bcr-abl. A test called PCR can find this gene in very small amounts in blood or bone marrow. In someone with blood and bone marrow findings consistent with CML, finding the gene confirms the diagnosis. Also, the level of the gene can be measured and used to guide treatment.

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 and hepatitis. 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 poorer outcomes. 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 gaining  acceptance. 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 best way to diagnose and follow-up 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 if treatment is working, 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, like lung and ovarian, and in some non-cancerous conditions, like 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, and 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. If the CA-125 level is increased at the time of diagnosis, changes in the CA 125 level can be used 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 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, inflammatory bowel 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 known to be at risk. Other cancers, like 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.

CEA may be used for lung and breast cancer. This marker can be high in some other cancers, too like thyroid, pancreas, liver, stomach, prostate, ovary, cervix, and bladder cancer. If the CEA level is high at diagnosis, it can be used to follow the response to treatment. CEA can also be elevated in some non-cancerous diseases, like hepatitis, COPD, colitis, and pancreatitis, and in otherwise healthy smokers.

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).

Epidermal growth factor receptor (EGFR)

This protein, also known as HER1, is a receptor found on cells that helps them grow. Tests done on a piece of the cancer tissue can look for increased amounts of these receptors, which is a sign that the cancer may grow fast, spread, and be harder to treat. This means patients with elevated EGFR may have poorer outcomes and need more aggressive treatment, particularly with drugs that block (or inhibit) the EGFR receptors.

EGFR may be used to guide treatment and predict outcomes of non-small cell lung, head and neck, colon, pancreas, or breast cancers. The results are reported as a percentage based on the number of cells tested. This test is not yet widely available.

Some lung cancers have defects (mutations) in the EGFR gene that make it more likely that certain drugs will work against the cancer. These gene changes are more common in lung cancer patients who are women, non-smokers, or Asian.

Hormone receptors

Breast tumor samples – not blood samples – from all cases of breast cancer are tested for estrogen and progesterone receptors. These 2 hormones often fuel the growth of breast cancer cells. 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. Hormone receptor-positive breast 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 some cancer cells to grow. It is elevated in about 1 out of 5 breast cancers. Higher than normal levels can be found in some other cancers, too, such as some stomach cancers. The HER2 level is usually found by testing a sample of the cancer tissue itself, not the blood. Cancers that are HER2-positive tend to grow and spread faster than other cancers.

All newly diagnosed breast cancers and advanced stomach cancers should be tested for HER2. HER2-positive cancers are more likely to respond to treatments which work against the HER2 receptor on 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 may be a 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 classic tumor markers but instead are 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 one 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.

here 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. 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.

Free light chains

Immunoglobulins are made up of protein chains: 2 long (heavy) chains and 2 shorter (light) chains. Sometimes in multiple myeloma an M protein can't be found but the level of the light chain part the blood is high, instead. This level can be measured with a test called free light chains, and be used to help guide treatment.

KRAS

Cetuximab (Erbitux®) and panitumumab (Vectibix®) are drugs targeting the EGFR protein that can be useful in the treatment of advanced colorectal cancer. These drugs don't work in colorectal cancers that have mutations (defects) in the K-ras gene. Doctors now commonly test the tumor for this gene change and only use these drugs in people whose cancers do not have the mutation.

K-ras mutations can also help guide treatment for some types of lung cancer. Tumors with the mutations do not respond to treatment with erlotinib (Tarceva®) or gefitinib (Iressa®).

Lactate dehydrogenase (LDH)

LDH is used as a tumor marker for testicular cancer and other germ cell tumors. It is not as useful as AFP and HCG for diagnosis because its level can be up with many other things besides cancer, including blood and liver problems. Still, high levels of LDH predict a poorer outlook for survival. LDH levels are also used to monitor the effect of treatment and to watch for recurrent disease.

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. This test is not widely used at this time. 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 bladder 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 may allow doctors to do this procedure less often. NMP22 levels can also be higher than normal with some non-cancerous conditions or due to recent chemo treatment.

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, but most medical groups do not recommend using it routinely to screen all men (instead recommending that men make informed decisions for themselves about testing). PSA is a protein made by cells of the prostate gland, which is found only in men. The prostate gland 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 things, 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.

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