|What Are Tumor Markers?
go here for another good review article)
Tumor markers are substances produced by cancer cells and sometimes normal cells. They can be found in large amounts in the blood or urine of some patients with cancer. Less often, they can also be found in large amounts in the blood or urine of people who do not have cancer.
There are many different kinds of tumor markers. Some are produced only by a single type of cancer. Others can be produced by several types of cancer. Most tumor markers used today are proteins or parts of proteins. They are detected by combining the patient's blood or urine with antibodies made to react with that specific protein. To test for the presence of a tumor marker, the doctor will send a sample of blood or urine to a laboratory. Because many people normally have low levels of these markers in their blood or urine, the doctor will need to interpret the results carefully. The results of any tumor marker test should be considered with other laboratory test results and a thorough medical history and physical examination.
How Were Tumor Markers Discovered?
The first modern tumor marker used to detect cancer is called human chorionic gonadotropin (HCG). The newly forming placenta, in pregnancy, makes HCG and releases it into blood and urine. Doctors look for this substance in pregnancy tests. Women whose pregnancy has ended but whose uterus continues to be enlarged, will be tested for the presence of HCG. A high level of HCG in the blood indicates that a cancer of the placenta called gestational trophoblastic neoplasia (GTN) may be present. This cancer continues to produce HCG. Some testicular and ovarian cancers resemble GTN because they both arise from reproductive cells called germ cells. These cancers also make HCG and this marker is used in their diagnosis and in monitoring their response to therapy.
The hope in the search for tumor markers was that all cancers could be detected by a single blood test. Both GTN and germ cell tumors of the ovaries and testicles are too rare to look for these cancers by testing everyone. But cancers such as colon, breast, and lung are more common. A simple blood test that would be able to detect these cancers in their earliest stages could prevent the death of millions of people. Many scientists began working toward this goal. The first success in developing a blood test for a common cancer was announced in 1965 by Dr. Joseph Gold. He found a substance in the blood of patients with colon cancer that was normally found in other tissues and called carcinoembryonic antigen (CEA).
By the end of the 1970's blood tests had been developed for several cancers. The new markers were given numeric labels. There was CA19-9 for colorectal and pancreatic cancer, CA15-3 for breast cancer, and CA 125 for ovarian cancer. Many others were also discovered, but because they did not show an advantage over the already discovered markers, they were not further developed for use. Unfortunately, none of these markers, including CEA, met the original goal of discovering cancer at an early stage. Almost everyone has a small amount of these markers in their blood and it is very difficult to spot early cancers by using these tests. Only when there is a significant amount of cancer present are the levels of these markers substantially higher. Not only did these markers fail to indicate many early cancers, even when they were high they were not specific enough. For example, patients with lung cancer or breast cancer can often have an elevated CEA, even though this marker was originally discovered in people with colon cancer. CA 125 can be high in women with other non-cancerous gynecologic conditions.
Only one marker has been discovered that allow doctors to detect early disease and is useful in testing for early cancer. That marker is the prostate-specific antigen (PSA). It was discovered around the same time as the others, but turned out to be a specific marker for prostate disease, especially, cancer. Even in early cancers, the PSA level will rise so that most prostate cancers can be detected in their earliest stage. PSA has become the only tumor marker that is specifically used for testing in contrast to the others, which are used mainly in patients with more advanced disease, to monitor their response to treatment or detect the return of cancer after treatment.
Many other markers have been developed. Below, we will discuss all those markers that are commonly used.
How Are Tumor Markers Used?
Diagnosing and screening for cancer
Tumor markers are usually not used to diagnose cancer. Cancer can only be diagnosed by a biopsy procedure. Although tumor markers were originally developed to test for cancer in people without symptoms, only the PSA has filled that role. But markers can help diagnose the source of widespread cancer in a patient without a previous history. A typical example is found in women who appear for examination with cancer throughout the pelvis and abdomen. The presence of a high level of CA 125 will strongly suggest ovarian cancer, even if the surgeon only sees a mass of tumor, and cannot locate the ovaries inside the mass.
Detecting recurrent cancer
Markers are also used to detect recurrent cancer. Many women with breast cancer, for example, have yearly blood tests for levels of CA-15-3. This can detect cancer recurrence before the woman has symptoms. Many doctors question the test's value, however, because no one has shown a real advantage in detecting recurrent breast cancer early. Usually the cancer produces symptoms or can be found by the doctor around the time the CA 15-3 level rises. The same is true for CEA and colorectal cancer. Because of this, the American Society of Clinical Oncology (ASCO) has recommended against using these markers to follow patients after curative treatment of these diseases but does recommend CEA for measuring treatment response of patients with advanced colorectal cancer. Not all doctors or even all medical organizations agree on the use of these and other tumor markers. For example the National Comprehensive Cancer Network, an organization of 19 US cancer centers agrees with the ASCO on CA 15-3, but also recommends CEA for follow-up of some patients with colorectal cancer.
It may be useful to test for some markers after the patient has received curative treatment. This may be true for prostate cancer, gestational trophoblastic tumors, germ cell cancers of the ovaries and testicles, and perhaps epithelial ovarian cancers.
The use of markers in advanced cancer
Most doctors find that the most important use for tumor markers is to monitor patients being treated for advanced cancer. It is much easier to measure the marker to see if the treatment is working than to repeat chest x-rays, computed tomography (CT) scans, bone scans, or other complicated tests. It is also cheaper. If the marker level in the blood goes down, that is almost always a sign that the treatment is effective. On the other hand, if it goes up, then the treatment probably should be changed. One exception is if the cancer is very sensitive to a particular chemotherapy treatment. The chemotherapy can cause many cancer cells to rapidly die and release large amounts of the marker, which will cause the level of the marker in the blood to temporarily rise.
Specific Tumor Markers
In this section we will list and describe the commonly used tumor markers. There are many markers being produced by commercial testing laboratories that are not commonly used. They have often been advertised as being better than the commonly used markers only to disappear from use when they have shown no advantage over the others. There are also markers that are used by researchers and these are often not available in commercial laboratories. If the research shows they are useful, then they will be made available to practicing doctors and their patients. This list will be confined to those available to most doctors and for which there is reliable scientific information that they are useful.
Note: The cancers described in these brief summaries are those for which the marker is usually used. These markers can be increased in other kinds of cancer so they are not used to diagnose the type of cancer a person has.
Alpha-fetoprotein (AFP) -- AFP levels are higher in two-thirds of patients with hepatocellular cancer (cancer starting in the liver). Normal levels are less than 20 ng/ml (nanogram/ml). A nanogram is one-billionth of a gram. The level increases with the size of the tumor. In small tumors, levels may be less than 20. AFP is also elevated in acute and chronic hepatitis but seldom above 100 ng/ml. It is also higher in testicular cancers of the embryonal cell and endodermal sinus types and is used for follow-up of these cancers. Elevated AFP levels are also seen in a certain type of ovarian and testicular cancer called yolk sac tumor or mixed germ cell cancer. These account for about 5% of all ovarian cancers.
Beta-2-microglobulin (B2M) -- B2M levels are elevated in multiple myeloma and some lymphomas. It is very useful in determining prognosis (long-term outlook for survival). Patients with levels over 3 ng/ml have a poorer prognosis.
Bladder tumor antigen (BTA) -- BTA is present in the urine of many patients with bladder cancer. It is being used along with NMP22 (see below) to test patients for recurrent cancer. It is not widely used, but is still being studied. It is still not certain whether it is as sensitive as cystoscopy (looking into the bladder through a lighted tube). Most experts recommend cystoscopy as the best procedure for diagnosis and follow-up of bladder cancer.
CA 15-3 -- CA 15-3 is used primarily in patients with breast cancer. It is elevated in less than 10% of patients with early disease and in about 75% of patients with disease through their body. The normal level is around 25 U/ml (units/milliliter). Levels as high as 100 U/ml can sometimes be seen in women who do not have cancer. This marker can also be higher in other cancers.
CA 27.29 -- CA 27.29 is also used for patients with breast cancer. Although a newer test than CA 15-3, it does not appear to be 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 38-40 U/ml, depnding on the testing laboratory. Also this test measures the same marker as the CA 15-3 test, but in a different way. This marker can also be elevated in other cancers.
CA 125 -- CA 125 is the standard tumor marker for epithelial ovarian cancer (the most common type of ovarian cancer). More than 90% of patients have levels above 30 U/ml when the cancer is advanced. Levels are often elevated when the disease is confined to the ovary. Because of this, CA 125 is being studied as a screening test. The problem with using it as a screening test is that many women can have levels above 30 U/ml without having ovarian cancer. It is also higher when there is fluid in the abdomen or chest. High levels of CA 125 are also found in women with endometriosis (uterine lining cells that occur in abnormal locations such as the ovaries), in men and women with lung cancer, and in people who have had cancer in the past.
CA 72-4 -- CA 72-4 is a newer test being used for ovarian cancer and cancers arising in the gastrointestinal tract. There is no evidence that it is better than the CA 125 test for ovarian cancer, but may be valuable as an added test. Studies are still in progress of this marker in ovarian cancer as well as other cancers.
CA 19-9 -- Although the CA 19-9 test was first developed for use in detecting colorectal cancer, it is more sensitive to pancreatic cancer. It is now considered the best tumor marker for patients with cancer of the pancreas. It will not usually detect very early disease but is used to observe patients being treated for advanced disease. If the CA 19-9 blood level is high in newly diagnosed patients this usually means the disease is advanced. Abnormal levels are above 37 U/ml. Because CA 19-9 is less sensitive than the CEA test for colorectal cancer, ASCO recommends against its use in colorectal cancer and recommends CEA testing instead. CA 19-9 can also be elevated in other forms of intestinal cancer, especially cancer of the bile ducts.
Calcitonin -- Calcitonin is a hormone produced by certain cells (parafollicular C cells) in the thyroid gland. It helps regulate blood calcium levels. In cancers of the parafollicular C cells, called medullary carcinoma of the thyroid, levels of this hormone are elevated. This is one of the rare tumor markers that can be used to help diagnose early cancer. Because medullary carcinoma of the thyroid is often inherited, blood calcitonin can be measured to detect the cancer in its very earliest stages in family members who are at risk. Other cancers, particularly lung cancers can produce calcitonin, but measurement of its level in the blood is not usually used to follow these cancers.
Carcinoembryonic antigen (CEA) -- CEA is the preferred tumor marker in patients with colorectal cancer. Levels above 5 U/ml are considered abnormal. Many doctors use this marker to follow other cancers such as lung cancer and breast cancer. CEA levels are also elevated in many other cancers such as thyroid, pancreas, liver, cervix, and bladder. It is also elevated in other diseases and in otherwise healthy smokers. It is not useful to screen for or to diagnose colorectal cancer. If it is elevated when colorectal cancer is detected, this may mean the cancer is more advanced.
Chromogranin A -- Chromogranin A is produced by neuroendocrine tumors. The most common are carcinoid tumors. Its level is very often elevated in the blood of people with carcinoid tumors as well as those people with other, rarer neuroendocrine tumors. It is probably the most sensitive tumor marker for these cancers, being abnormal in one-third of people with localized disease and two-thirds of those with metastatic cancer. Levels can be elevated in other cancers such as lung and prostate. Abnormal levels vary between testing centers, but are generally above 76 ng/ml in men, above 51 ng/ml in women.
Serum gamma globulin -- Bone marrow cancers such as multiple myeloma and Waldenstrom's macroglobulinemia often produce gamma globulins in the blood. A high level indicates the presence of one of these diseases. There are many different gamma globulins, each molecule differing very slightly from the other. The classic sign in patients with myeloma or macroglobulinemia is that all the globulins are alike. This can be seen on a test called serum protein electrophoresis where the globulins are separated by electrical current. With myeloma or macroglobulinemia, the globulins stick together and form a "spike" on the readout of the test. The level of the "spike" is important, because older people tend to show low levels of this spike of gamma globulin without having myeloma or macroglobulinemia. A level greater than 2 to 3 gm/ 100 ml is suspicious for myeloma or macroglobulinemia. The diagnosis, however, must be made by a biopsy of the bone marrow.
Serum Her-2/neu -- Her-2/neu is a marker found primarily in some breast cancer cells, and can be released into the bloodstream. It is sometimes also found in some other cancers. Its only use is as a predictor of prognosis (survival outlook). Women with breast cancer with this marker don't respond as well to chemotherapy and have a less favorable outlook. Most of the time the marker level is determined by testing the cancer, not the blood. The usefulness of this marker is still being studied. Normal levels in the blood are below 450 fmol/ml.
Human chorionic gonadotropin (HCG) -- HCG is elevated in patients with testicular cancer and gestational trophoblastic neoplasms, primarily choriocarcinoma. It is also higher in some men with cancers in the middle of their chest (mediastinum), which come from the same cells as testicular cancer (mediastinal germ cell neoplasms). An elevated level of this marker will raise suspicions of cancer in certain situations. For example, in women who continue to have large uteruses after pregnancy has ended, elevation of this marker is a sign of a cancer. This is also true of men with an enlarged testicle or with a mass in their chest. The definition of a normal level is difficult because there are different methods of testing for this marker and each has its own normal value.
Lipid Associated Sialic Acid in Plasma (LASA-P) -- LASA-P has been studied as a marker for ovarian cancer as well as a host of other cancers. It has not proved valuable, however, and has been replaced by more specific marker tests. It is not often used and there is little information on its value.
NMP22 -- NMP22 is a protein found in the urine of people with bladder cancer. It is being used for patient follow-up to avoid repeated cystoscopy (looking into the bladder). So far it hasn't been found to be sensitive enough to be used instead of cystoscopy and is not in widespread use.
Neuron-specific enolase (NSE) -- NSE is sometimes used as a marker for lung cancer, particularly the variety called small cell lung cancer. It may be somewhat better than CEA for follow-up of patients with this disease. It has also been used for other forms of lung cancer, but is probably no better than CEA. This marker is also seen in people with neuroendocrine tumors other than small cell cancer. The most common neuroendocrine tumor is carcinoid.
Prostate-specific antigen (PSA) -- PSA is the only marker used for detecting a cancer early. It is specific for prostate disease. The American Cancer Society recommends that you discuss with your doctor the decision to use this test for prostate cancer. When it is used for screening, most doctors feel that a level below 4 ng/ml means cancer is unlikely and levels greater than 10 ng/ml mean cancer is likely. The area between 4 and 10 is a gray zone. Most doctors will recommend a prostate biopsy for a person with a level above 4. Levels above 20 often suggest the cancer has spread out of the prostate and is no longer curable. This is not true for all patients, however.
Other factors affect the PSA level besides cancer. Older men tend to have a higher PSA normally. Also men with benign prostatic hypertrophy (BPH) have higher levels. One helpful test when the values are above 4 and below 10, is to measure the free PSA. Some of the PSA in the blood is bound to a circulating protein and some is free. As the amount of free PSA goes up, it is less likely that there is prostate cancer. Levels of free PSA higher than 25% of the total PSA (Free PSA/Total PSA) are seldom associated with prostate cancer. Below 15%, the chance of cancer goes above 20% and if the free PSA is below 10%, the chance of prostate cancer is much higher, anywhere from 30% to 60%.
The PSA test is very valuable in follow-up of patients with prostate cancer. For patients who have been treated with curative surgery or radiation therapy, a rise in the PSA level is a sign the cancer is coming back. After these treatments, the PSA should be 0. If the cancer does come back and spread, or if it has already spread at the time of diagnosis, then PSA is used to check the effectiveness of treatment. It should go down with effective treatment and will rise if the cancer grows. For more information about the PSA test, see our Prostate Cancer document.
Prostatic acid phosphatase (PAP) -- PAP (not to be confused with the Pap test for women) is another test for prostate cancer that was used before the PSA test was developed. It is rarely used now because the PSA is much more sensitive.
Prostate- specific membrane antigen (PSMA) -- PSMA is a substance found in all prostate cells. Levels increase with age and with cancer. So far it has not proved to be better than the PSA. Its usefulness is still being studied. It is not used much in medicine.
S-100 -- S-100 is associated with malignant melanoma. Early studies show that its level is elevated in most patients with metastatic melanoma. It is still being studied and new blood tests are being developed.
TA-90 -- Like the S-100, TA-90 can detect metastatic melanoma. It is also not widely used and is still being studied. It is also being studied for use in other cancers such as breast cancer.
Thyroglobulin -- Thyroglobulin is produced by the thyroid gland and is elevated in many thyroid diseases. However, when thyroid cancer is surgically removed, the whole thyroid gland is usually also removed. Any elevation of the thyroglobulin level above 10 ng/ml suggests the cancer has returned. Thyroglobulin levels can also be followed to evaluate the results of treatment for metastatic thyroid cancer.
Tissue polypeptide antigen (TPA) -- TPA is another test, similar to NSE, for lung cancer. It has not been any more useful than CEA.
Common Cancers And Associated Tumor Markers
Bladder Cancer (For more information refer to the ACS document on Bladder Cancer.) Urinary tumor markers are being used to follow some patients after their first treatment and any further treatment. These are the bladder tumor antigen (BTA) and the NMP22. Other tests are being studied. None of these are recommended for screening. It is too early to tell if these tests will take the place of urine cytology (looking for cancer cells in the urine) and cystoscopy (looking in the bladder for cancer) for diagnosis and follow-up. Periodic cystoscopy augmented by cytology is still recommended as the standard test for diagnosis and follow-up. For advanced cancer some of the markers used for other cancers such as CEA, CA 125, CA 19-9 may be elevated and can be used to assess response to treatment.
Breast Cancer (For more information refer to the ACS document on Breast Cancer.) No tumor marker is useful for diagnosis of early stage breast cancer. The two markers most commonly used to follow patients with advanced cancer or to detect recurrence are the CA15-3 and the CEA. The CA 27.29 test has recently been approved and is also used by some doctors. The CA 15-3 and CA 27.29 are probably equally sensitive while the CEA is less sensitive. They are most useful in measuring the results of treatment for patients with advanced disease. Generally speaking, their levels in the blood go down if the cancer responds to treatment and rise if the cancer progresses. Many doctors use these tests in follow-up of women who have no symptoms of recurrent cancer after their first treatment (surgery with or without radiation therapy). The ASCO has questioned this and has written a guideline that recommends against using these markers for follow-up of asymptomatic women who have completed treatment for localized breast cancer.
Colorectal Cancer (For more information refer to the ACS document on Colorectal Cancer.) The markers most often elevated in advanced colorectal cancer are CEA and CA 19-9. Neither of these is useful as a screening test for colorectal cancer. For screening for colorectal cancer, the ACS recommends that beginning at age 50, people who are not at high risk have:
Double-contrast barium enema every 5 years
How often will I be tested?