Specific tumor markers

This section focuses on some of the tumor markers often used today.

Tests for many other tumor markers are available through commercial testing labs, but these are seldom used. Some of these tests may even be advertised as being better than the more common markers, but this hasn’t yet been shown in scientific studies. In some of these cases, the tests have been taken off the market at the request of the Food and Drug Administration (FDA). Still, there are tests available for many types of cancer, but they have not yet been proven to work.

There are also other tumor 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 tumor markers listed here 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 tested. These marker levels may be increased in other kinds of cancer, too. And though we list the other, less common cancer types that may affect certain tumor marker levels, in many cases it is not yet clear how helpful those tumor markers may be for those cancers.

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 here are average values. Most labs will list their own “reference ranges” along with any test results you get. If you are tested for a tumor marker, be sure to ask the doctor what your test 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). 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 a person with chronic hepatitis often has high AFP levels. For them, AFP levels 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 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 when treatment works. 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.

Anaplastic lymphoma kinase (ALK)

Some lung cancers have changes in the ALK gene that cause the cancer cell to make a protein that leads to out of control growth. Tumor tissues can be tested for this gene change. If it’s found, the patient can be treated with a drug that targets the abnormal protein, like crizotinib (Xalkori^®).

BCR-ABL

Chronic myeloid leukemia (CML) cancer 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 changes that look like those seen 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 (including Waldenstrom macroglobulinemia). 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 in helping 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 and Waldenstrom macroglobulinemia 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’s sometimes used along with NMP22 (see below) to test patients for the return (recurrence) of bladder cancer.

This test is not used often. It’s 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. At this time, most experts still consider cystoscopy the best way to diagnose and follow-up bladder cancer.

BRAF

Defects (mutations) in the BRAF gene can be found in melanoma, thyroid cancer, and colorectal cancer. About half of melanomas have a BRAF mutation, most often the one called BRAF V600. This mutation causes the gene to make an altered BRAF protein that signals melanoma cells to grow and divide. This mutation can be tested for in tumor tissue. If it’s found, the patient can be treated with a drug that targets the altered BRAF protein, such as vemurafenib (Zelboraf^®).

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 be seen in women who do not have cancer. Levels of this marker can also be higher in other cancers, like lung, colon, pancreas, and ovarian, and in some non-cancerous conditions, like benign breast conditions, ovarian disease, endometriosis, and hepatitis.

CA 19-9

The CA 19-9 test was first developed to detect colorectal cancer, but it’s most often used in people with pancreatic cancer. In very early disease the level is often normal, so it’s not good as a screening test. Still, it’s the best tumor marker for following patients who have 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 be used to watch bladder cancer and see how aggressive it is. It may also be used to watch colorectal cancer, but the CEA test is preferred for this type of cancer..

CA 19-9 can 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, rheumatoid arthritis, inflammatory bowel disease, and pancreatitis (inflammation of the pancreas).

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’s not any better in detecting either early or advanced disease. And it’s not elevated in all people with breast cancer.

The normal level is usually less than 40 U/mL (units/milliliter), depending on the testing lab. This marker can be elevated in other cancers, too, such as cancers in the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver. It may also be higher than normal in some non-cancerous conditions, for instance, in women in the first trimester of pregnancy; and in people with endometriosis, ovarian cysts, non-cancerous breast disease, kidney stones, and liver disease.

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 with advanced ovarian cancer have high levels of CA 125. 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. Because of this, CA 125 has been studied as a screening test. But 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’s often higher in women with uterine fibroids or endometriosis. It may also be higher in men and women with lung, pancreatic, breast, liver, 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.

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). 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 elevate calcitonin levels, but calcitonin blood tests are not usually used for detecting these cancers.

Carcinoembryonic antigen (CEA)

CEA is not used to diagnose or screen for colorectal cancer, but it’s the preferred tumor marker to help predict outlook in patients with colorectal cancer.

The normal range of blood levels varies from lab to lab, and smokers often have higher levels. But even in smokers, levels higher than 5.5 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 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 melanoma, lymphoma, thyroid, pancreas, liver, stomach, kidney, 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, chronic obstructive pulmonary disease (COPD), colitis, rheumatoid arthritis, 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’s probably the most sensitive tumor marker for carcinoid tumors. It’s 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. It’s hard to define the normal level for CgA because there are different ways to test for this marker and each has its own normal value.

Taking drugs called proton-pump inhibitors (such as omeprazole and lansoprazole) to reduce stomach acid can raise CgA levels in healthy people, so be sure your doctor know what drugs you are taking before this lab test is done.

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 quickly, and be harder to treat. 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.

Some lung cancers have certain 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.

HE-4

Some ovarian cancers have too much of a gene called HE-4, and make more of a protein called HE-4 (or HE4). Levels of this protein can be measured in the blood and can be used like CA 125 to guide treatment. This test is most often used in patients who have normal CA 125 levels. HE-4 levels can go up in some benign conditions as well as with some other cancers, so it’s not used as a screening test.

HER2 (or HER2/neu, erbB-2, or EGFR2)

HER2 is a protein that tells some cancer cells to grow. It’s present in larger than normal amounts on the surface of breast cancer cells in about 1 out of 5 people with breast cancer. Higher than normal levels can be found in some other cancers, too, such as some stomach and esophageal cancers. HER2 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 drugs that work against the HER2 receptor on cancer cells.

Hormone receptors

Breast tumor samples – not blood samples – from all people with 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 called 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 may 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.

Some gynecologic tumors, such as endometrial cancers and endometrial stromal sarcomas, are also checked for hormone receptors to see if they can be treated with hormone therapy drugs.

Human chorionic gonadotropin (HCG)

HCG (also known as beta-HCG or β-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 watched 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 might 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’s 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.

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. 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 can be used to help guide treatment.

KRAS

Cetuximab (Erbitux^®) and panitumumab (Vectibix^®) are two drugs that target the EGFR protein and can be useful in the treatment of advanced colorectal cancer. But these drugs don’t work in colorectal cancers that have mutations (defects) in the KRAS 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.

KRAS mutations can also help guide treatment for some types of lung cancer. For instance, tumors with the mutations do not respond to treatment with drugs erlotinib (Tarceva^®) or gefitinib (Iressa^®). Doctors are looking at how KRAS may be used in many other types of cancer, too.

Lactate dehydrogenase (LDH)

LDH is used as a tumor marker for testicular cancer and other germ cell tumors. It’s not as useful as AFP and HCG for diagnosis because it goes 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.

LDH may be used in other cancers, too, including lymphoma, melanoma, and neuroblastoma.

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’s not used as a screening test.

It’s 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 medullary thyroid cancer, melanoma, and pancreatic endocrine tumors. Abnormal levels are usually higher than 9 ug/L (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’s 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 might allow doctors to do this procedure less often. NMP22 levels can also be higher than normal with some non-cancerous conditions or in people who have had recent chemo treatment.

Prostate-specific antigen (PSA)

PSA is a tumor marker for prostate cancer. PSA is a protein made by cells of the prostate gland, which is found only in men. It’s 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. (The American Cancer Society recommends that men talk to a doctor and make informed decisions about testing.)

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 higher 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. A doctor may recommend a prostate biopsy (getting samples of prostate tissue to look for cancer) for a man with a PSA level above 4 ng/mL.

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’s more useful to follow the PSA level over time because an increase from one year to the next might 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. Still, it’s not clear if measuring PSA velocity is any more helpful than looking at PSA levels alone.

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 measurement of the free PSA (also percent-free PSA or fPSA). PSA is in the blood in 2 forms—some is bound to a protein and some is free. The fPSA is the ratio of how much PSA circulates free compared to the total PSA level. A lower fPSA means that the likelihood of having prostate cancer is higher and a biopsy should probably be done. Many doctors recommend biopsies for men whose fPSA is 10% or less, and advise men to consider having a biopsy if it’s between 10% and 25%. Using these cutoffs detects most cancers and helps some men avoid unnecessary prostate biopsies. This test is widely used, but not all doctors agree that 25% is the best cutoff point to decide on a biopsy, and the cutoff may change depending on PSA level.

The PSA test is very valuable in monitoring the response to treatment and in the follow-up of men with prostate cancer. In men who have been treated with surgery meant to cure the disease, the PSA should fall to an undetectable level. The PSA should also go down after treatment with radiation therapy (although it doesn’t go away completely). A rise in the PSA level may be a sign the cancer is coming back.

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. It may also be used to help diagnose multiple myeloma and lung cancer.

S-100

S-100 is a protein found in most melanoma cells. Tissue samples of suspected melanomas may be 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 (melanoma that has spread to other parts of the body). So, this test is sometimes used to look for melanoma spread before, during, or after treatment.

Soluble mesothelin-related peptides (SMRP)

This test is sometimes used along with imaging tests to watch a rare type of lung cancer called mesothelioma. It may also be used to see if mesothelioma has come back (recurred) after treatment.

Researchers are looking at whether SMRP can be used as a screening tool in people at high risk for mesothelioma.

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.

Thyroglobulin levels in the blood should fall to undetectable levels after treatment for thyroid cancer. A rise in the thyroglobulin level after treatment can mean the cancer has come back (recurred). In people with thyroid cancer that has spread, thyroglobulin levels can be followed over time to watch the results of treatment.

Some people’s immune systems make antibodies against thyroglobulin, which can affect test results. Because of this, levels of anti-thyroglobulin antibodies are often measured at the same time.