Tumor Marker Tests

Tumor Marker Tests

Reviewed By:
Martin E. Liebling, M.D., FACP
Mark Oren, M.D., FACP

Summary

Tumor markers, also called biomarkers, are measurable substances found in the body that may indicate the presence of cancer when present in large amounts. These substances may include proteins and other biochemicals that can be produced by either tumor cells or by the body in response to tumor cells. In some cases, normal cells also can produce tumor markers, and infrequently they can be found in large amounts in people who do not have cancer.

Tumor markers alone are rarely specific enough to diagnose cancer. Physicians had hoped to use tumor markers to help diagnose cancer in its early stages. However, to date only one marker – prostate-specific antigen (PSA) – has fulfilled that role. Instead, most tumor markers are used to determine the stage of cancer, monitor treatment of advanced cases of cancer, or to detect cancer recurrence after treatment of the disease.  

To determine the presence of a tumor marker, a physician obtains a sample of blood, urine or other tissue from a patient. The sample is sent to a laboratory to determine the presence or level of tumor marker. Tumor markers alone are not used to diagnose cancer. The presence of a tumor marker in higher or lower levels of the substance also can indicate a noncancerous condition, such as inflammation.  

Depending on the type of cancer, additional tests such as blood tests, CAT scans and biopsies must be used to definitively diagnose and stage the disease. Tumor marker tests may be just one component in diagnosing and treating cancer in certain individuals.

Tumor marker testing is continually being studied in many areas of research. The use of tumor marker tests is directed by the U.S. Food and Drug Administration (FDA) and guidelines established by organizations such as the American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO). The reliability and acceptance of tumor marker tests is not uniform among medical professionals. In recent years, research has focused more on identifying changes in DNA that may indicate cancer or may suggest the best methods to treat certain cancers.

About tumor marker tests

Tumor markers are certain antigens, proteins and biochemicals that might indicate the presence of cancer when found at high levels in a patient’s blood, urine or body tissues. They may be produced by the tumor itself or by the body’s response to cancer or some noncancerous (benign) conditions.

When cancer cells grow and multiply, certain substances can leak into the bloodstream or other fluids. Depending on the type of tumor marker, it can be measured in blood, urine, stool or tissue. Tumor markers appear in many different varieties and can be produced by one or several types of cancer. Most tumor markers are whole or partial proteins detected when a patient’s blood or urine is combined with antibodies made to react with that specific protein. To test for levels of a certain tumor marker, a physician performs blood tests, urine tests or a tissue biopsy and sends the sample to a laboratory for analysis.

The sample of blood or tissue is mixed with a substance containing antibodies specific to each tumor marker. If that tumor marker is present, the specific antibodies bind to the markers. Using a substance, typically a radioactive element, the amount of bound marker and antibody is measured. From this measurement, the level of tumor marker is calculated for the individual.

The presence of tumor markers does not necessarily mean the presence of cancer. Some noncancerous conditions can cause higher or lower than normal levels of a tumor marker. The test results need to be interpreted carefully by trained healthcare professionals, and to be confirmed by other tests. Tumor marker testing cannot be used solely for cancer diagnosis for the following reasons:

  • Noncancerous conditions can cause abnormal results.
  • Tumor marker levels are not elevated in everyone who has cancer, particularly in the disease’s early stages.

  • Tumor markers are not always specific to a particular type of cancer.

  • No tumor marker test is free of false negatives or false positives.

Originally, tumor markers were intended to help diagnose cancer in its early stages before the appearance of symptoms. However, in general, tumor markers have not proved to be reliable in diagnosing cancer at an early stage. Because most people have a small amount of these markers in their blood, it is very difficult to detect early cancers using these tests. Marker levels only become substantially higher after the cancer has established a significant presence.

Physicians generally use tumor markers for the following purposes:

  • To screen for cancer. Although this was the initial purpose for tumor marker tests, most tumor markers have not been successful in cancer screening. To date, the prostate-specific antigen (PSA) blood test is the only tumor marker test used to screen for a common type of cancer (prostate).

  • To diagnose cancer in an advanced stage. Markers can be used to help diagnose the source of widespread cancer that has been found in a patient without a previous history of the disease. For example, a high level of a certain tumor marker may indicate that the source of the cancer is an organ associated with that marker. Tumor markers are also used to help predict how well the type of cancer might respond to treatment.

  • To diagnose cancer that has returned after treatment. Certain tumor markers may indicate the return of cancer after the patient has received definitive treatment, including:

    • Gestational trophoblastic tumors (cancer in the uterus that begins following pregnancy, miscarriage or abortion)

    • Prostate cancer

    • Colon cancer

    • Germ cell cancers of the ovaries and testicles

    • Epithelial ovarian cancers

  • To monitor treatment of advanced cases of cancer. Many physicians find tumor marker testing easier and less expensive to monitor treatment by measuring marker levels than to repeat complicated tests such as computed axial tomography (CAT) scans. When marker levels drop, it is a reliable indication that the cancer treatment has been effective.

If tumor marker levels increase, it may be an indication that a change in treatment is necessary. However, in some cases chemotherapy will cause many cancer cells to rapidly die and release large amounts of the marker. This causes the level of the marker to temporarily rise, even though the treatment is working very effectively. Prostate-specific antigen (PSA) is the only marker used to detect early prostate cancer and other diseases of the prostate. Even in its early stages, prostate cancer will be indicated by a significant rise in PSA levels.

Types and differences of tumor marker tests

There are many different tumor markers used to detect and monitor cancer. The most commonly used markers include the following:

DiseaseMarkers
Bladder cancerBTA, NMP22, CEA, CA 125, CA 19-9
Breast cancerCA 15-3, CEA, CA 27.29
Colorectal cancerCEA, CA 19-9
Gestational trophoblastic diseaseHCG
Liver cancerAFP
Lung cancerCEA, NSE
Melanoma skin cancerTA-90, S100
Multiple myelomaB2M
Ovarian cancerCA 125, CA 72-4, LASA-P, HCG, AFP
Pancreatic cancerCA 19-9, CEA
Prostate cancerPSA, PAP, PSMA
Stomach (gastric) cancerCEA
Testicular cancerHCG, AFP, PAP
  • Alpha-fetoprotein (AFP).  AFP is normally found in fetal development. In adults, it may indicate liver cancer. The larger the tumor, the higher the level of this marker, which is elevated in two-thirds of patients with cancers that start in the liver (hepatocellular cancer), according to the American Cancer Society. AFP levels are also higher in some testicular and ovarian cancers. Noncancerous conditions such as cirrhosis or hepatitis may result in moderately increased levels of AFP.

  • Beta-2-microglobulin (B2M). Levels are elevated in multiple myeloma, chronic lymphocytic leukemia (CLL) and some lymphomas.

  • Bladder tumor antigen (BTA). Elevated in urine tests of many patients with bladder cancer. It is sometimes used along with the tumor marker NMP22 to detect bladder cancer that has returned in a patient after the disease was initially treated.

  • CA 15-3. Produced by the cells in the breast. Elevated levels of this marker can be associated with breast cancer. Adenocarcinomas of the ovary, lung, colon and pancreas also produce elevated levels of CA 15-3.  This tumor marker test may be used to detect the recurrence of breast cancer in women who have undergone treatment. Benign breast disease, endometriosis and pelvic inflammatory disease (PID) are also related to high levels of this tumor marker.

  • CA 27.29. Also called breast carcinoma-antigen, it is used to detect breast cancer. It is often used in conjunction with levels of CA 15-3 to monitor patients for recurrence after treatment.  Levels of this marker may be elevated in cancers of other internal organs and women’s reproductive system. Non-cancerous conditions associated with elevated levels of this marker include endometriosis, ovarian cysts and breast disease.

  • CA 125.  The standard tumor marker for ovarian cancer. The test is not sensitive enough to be used for ovarian cancer screening but it often contributes to a diagnosis when combined with an ultrasound and pelvic examination. Blood levels of CA 125 are used to monitor treatment effectiveness. High levels of CA 125 are also found in women with endometriosis (presence of endometrial tissue outside the lining of the uterus), pelvic inflammatory disease (PID), pancreatitis and liver disease. It may be associated with other cancers including liver, colon, lung and breast.

  • CA 72-4. A newer test being studied for use in ovarian cancer and cancers of the gastrointestinal tract.

  • CA 19-9. First developed to detect colorectal cancer, it is now considered the best tumor marker for patients with cancer of the pancreas. It is not often used as a screening tool for pancreatic cancer, but is considered valuable for monitoring patients with the disease. CA 19-9 can also be elevated in other forms of intestinal cancer, especially cancer of the bile ducts and stomach. It can be increased in non-cancerous diseases such as pancreatitis, gallstones and jaundice.

  • Calcitonin. A hormone produced by cells in the thyroid gland that helps regulate blood calcium levels. When these cells become cancerous, levels of this hormone are elevated.

  • Carcinoembryonic antigen (CEA). Elevated in patients with colorectal cancer, it is also used to monitor lung cancer and breast cancer. It is most commonly used for detection of recurrence of colorectal cancer in patients treated for the disease. CEA levels are also elevated in many other cancers such as those of the thyroid, pancreas, liver, cervix and bladder. Individuals with cirrhosis and various intestinal disorders may have increased CEA levels.

  • Chromogranin A (CgA). This is the most sensitive marker for detecting neuroendocrine tumors such as carcinoid tumors. Levels can be elevated in other cancers such as lung and prostate.

  • Estrogen/progesterone receptors. Tissue samples from breast cancer tumors are commonly tested for these two markers. The cancer is categorized as ER positive or PR positive if the marker is present. The receptor status is important for breast cancer treatment planning and prognosis. These cancers are more likely to respond to hormonal therapy, such as tamoxifen and aromatase inhibitors.

  • HER2/neu. A marker found primarily in some breast cancer cells that can be released into the bloodstream. It is sometimes also found in some other cancers. Recent research has found that HER2/neu status can be used to determine a treatment course for breast cancer. Tumors with this marker are less responsive to conventional chemotherapy, but more responsive to newer therapies that use monoclonal antibodies such as trastuzumab (Herceptin).

  • Human chorionic gonadotropin (HCG). When a woman becomes pregnant, the forming placenta produces HCG and releases it into blood and urine. High levels of HCG in the blood may indicate germ cell tumors found in the ovaries (in women) and testes (in men). It also may indicate a cancer of the placenta called gestational trophoblastic neoplasia (GTN). HCG also may be used to monitor the effectiveness of cancer treatment and signs of recurrence after treatment.

  • Lactate dehydrogenase. A protein found throughout the body that is elevated in every type of cancer, as well as many other diseases. As a result, this marker cannot be used to diagnose a particular type of cancer.

  • NMP22.  A protein found in the urine of people with bladder cancer that is used for patient follow-up to avoid repeated cystoscopy (looking into the bladder).

  • Neuron-specific enolase (NSE). Sometimes used as a marker for lung cancer, particularly a type called small cell lung cancer. This marker is also seen in people with neuroendocrine tumors (such as carcinoid) other than small cell cancer.

  • Prostate-specific antigen (PSA). PSA is a protein produced by the prostate gland and can be overproduced in prostate cancer. It is probably the best tumor marker in use and is typically used for screening and early detection of prostate cancer. If prostate cancer is diagnosed, PSA levels can help determine the stage of cancer, the effectiveness of treatment and monitor for recurrence. In addition, other factors aside from cancer can affect PSA levels including an enlarged prostate common in older men. Healthcare professionals recommend that PSA should be used along with a digital rectal exam for prostate cancer screening. In addition, there is some controversy about PSA levels and their relationship to prostate cancer. PSA continues to be a valuable tool for monitoring patients who have been treated for prostate cancer.

  • Prostate-specific membrane antigen (PSMA). A substance found in all prostate cells, levels increase with age and with cancer. It has not proven to be better than the PSA for detection of prostate cancer. Its usefulness is still being studied.

  • Prostatic acid phosphatase (PAP). May be found at higher levels in some patients with prostate cancer, especially if the cancer has spread beyond the prostate. May also be elevated in patients with certain benign prostate conditions or early stage cancer. Other cancers that can cause a rise in PAP levels include testicular cancer, leukemia and non-Hodgkin’s lymphoma. PAP is used less often since the advent of the more reliable PSA test.

  • S-100. Early studies show that its level is elevated in most patients with metastatic melanoma. It is still being studied in patients with this form of cancer.

  • Serum gamma globulin. High levels in the blood may indicate bone marrow cancers (including multiple myeloma and Waldenstrom’s macroglobulinemia). However, a biopsy of the bone marrow is necessary for a definitive diagnosis.

  • TA-90. Also used to detect metastatic melanoma, it is still being studied. It is also being examined for its effectiveness with other cancers, particularly colon and breast cancer.

  • Thyroglobulin. Produced by the thyroid gland and elevated in many thyroid diseases.

  • Tissue polypeptide antigen (TPA). Similar to NSE, it is used to monitor patients with several types of cancer, including lung and bladder cancer.

Ongoing research for tumor marker tests

A considerable amount of research is devoted to studying and developing tumor marker tests. Recent research has identified a protein in patients undergoing treatment for lung cancer.  Study of earlier samples indicated the presence of the protein in some patients one or more years before diagnosis. Such a marker would be especially useful because lung cancer has few symptoms and is difficult to diagnose in its early stages.

Many laboratories are looking past standard protein markers and concentrating on developing genetic markers to detect cancer. Most cancers have abnormalities of DNA, and scientists are looking for these abnormalities in blood, stool or urine to detect cancers early. Researchers have detected changes in genes, such as APC and p53, that may be linked to certain cancers. Much current research focuses on analysis of DNA changes in cells and how that may help predict treatment outcomes.

Experts are also working toward breakthroughs in an approach called proteomics, which examines the pattern of proteins in the blood of patients. These techniques are being tested in clinical trials. Advances in tumor marker tests may contribute to earlier detection of cancer, improved treatment methods and better monitoring of the disease.

Questions for your doctor

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions about tumor marker tests:

  1. Which tumor marker tests should I consider?
  2. What type of sample (blood, urine or tissue) will you need from me for the test?
  3. How and where will the test be conducted?
  4. What conditions can be detected with the recommended tumor marker tests?
  5. How quickly will I receive the results and from whom?
  6. What are the chances of receiving unreliable results with my test?
  7. What other tests might I need with a tumor marker test?
  8. If I have cancer, can a tumor marker test help with treatment planning?
  9. Will the tests monitor my treatment and indicate a recurrence of the cancer?
  10. How often should I have the tests repeated?
  11. If I have one type of cancer, will tumor marker tests indicate my risk for other cancers?
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