Tumor Markers

Definition

Tumor markers are measurable biochemicals that are associated with a malignancy. They are either produced by tumor cells (tumor-derived) or by the body in response to tumor cells (tumor-associated). They are typically substances that are released into the circulation and thus measured in the blood. There are a few exceptions to this, such as tissue-bound receptors that must be measured in a biopsy from the solid tumor or proteins that are secreted into the urine.

Purpose

Though tumor markers are rarely specific enough to be used alone to diagnose cancer, they do have a number of clinical uses. They can be used to stage cancer, to indicate a prognosis, to monitor treatment, or in follow-up to watch for cancer recurrence. Changes in some tumor markers have been sensitive enough to be used as targets in clinical trials. When used for diagnosis, tumor markers are used in conjunction with other clinical parameters such as biopsy and radiological findings. Although there are a multitude of tumor markers, very few of them have found their way into clinical practice because of their lack of specificity. However, some of these non-specific markers have found a place in monitoring cancer treatment rather than in diagnosis.

Description

As tumor cells grow and multiply, some of their substances can increase and leak into the bloodstream or other fluids. Depending upon the tumor marker, it can be measured in blood, urine, stool or tissue. Some widely used tumor markers include: AFP, beta-HCG, CA 15-3, CA 19-9, CA 27.29, CA 125, CEA, and PSA. Some tumor markers are associated with many types of cancer; others, with as few as one. Some tumor markers are always elevated in specific cancers; most are less predictable. However, no tumor marker is specific for cancer and most are found in low levels in healthy persons, or can be associated with non-neoplastic diseases as well as cancer. Also, no tumor marker test is free of false negatives or false positives.

Once cancer is diagnosed, tumor marker levels sometimes help to determine the extent of cancer. Higher levels can indicate more advanced cancer and a worse prognosis in some cases. The patient and their physician may use this information to choose between more or less aggressive treatments.

Monitoring cancer treatment is the most common use of tumor markers. As cancer is reduced, levels often decrease. Stable or increasing levels often indicate that the cancer is not responding to treatment. The choice of tumor marker to use for monitoring is important. Only a marker elevated before treatment should be used to monitor a person during or after treatment. Timing of the tests is also important. Each tumor marker has a unique life span in the blood. To monitor a treatment's success, enough time must have passed for the initial marker to be cleared from the blood. Tests done too soon may be falsely elevated because the marker produced by the untreated cancer is still present.

Watching for cancer recurrence after treatment is another reason for tumor marker testing. Periodic testing can sometimes detect a recurrence often months earlier than could an ultrasound, x ray, or physical examination.

Tumor marker tests are performed in a lab using immunological techniques. A sample of blood or other tissue is mixed with a substance containing specific antibodies to each tumor marker. If that tumor marker is present, these very specific antibodies bind to the markers. Some type of label, often a radioactive substance, is then used to measure the amount of bound marker and antibody. From this measurement, the amount of tumor marker is calculated. The results are usually available within a few days.

Conclusions based on tumor marker tests are seldom based on one test result but on a series of test results, called serial measurements. A series of increasing or decreasing values is more significant than a single value.

Tumor marker testing is currently the object of much research and attention. Their use is directed by approval from the Food and Drug Administration (FDA) and guidelines established by organizations such as the American Society of Clinical Oncology and the American Cancer Society. Not all tumor receptor marker tests are widely available nor are they widely accepted.

Oncofetal antigens

There are two common oncofetal antigens, alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA). Carcinoembryonic antigen CA 72-4 is a more recently discovered oncofetal antigen just coming into usage. The oncofetal antigens are so named because they are normally produced during embryonic development and decrease soon after birth. Cancer cells tend to dedifferentiate, or revert to a more immature tissue and begin to produce fetal antigens again. Oncofetal antigens are very non-specific and expressed by a wide number of cancer types. However, they are used both to monitor a patient's progress and their response to treatment over time.

ALPHA-FETOPROTEIN (AFP).

Elevated AFP typically indicates a primary liver tumor or a germ cell tumor of the ovary or testicle. AFP is a glycoprotein produced in high amounts by fetal tissue and is elevated during pregnancy. It is most widely used as a marker for hepatocellular carcinoma and testicular cancer but is also associated with ovarian cancer. Seventy percent of people with liver cancer have increased AFP levels. In China, where liver cancer rates are high, AFP is used as a screening test for that disease. AFP levels indicate the extent of cancer, and serial measurements are used to monitor treatment response. Non-cancerous liver conditions such as cirrhosis and hepatitis have moderately increased levels of AFP.

CARCINOEMBRYONIC ANTIGEN (CEA).

CEA is a glycoprotein most often associated with colorectal cancer, and used to monitor patients with this type of cancer. Its most popular use is in early detection of relapse in individuals already treated for colorectal cancer. After surgery, serial measurements indicate the surgery's success and are used to detect early signs of recurrence. It has recently been found to be useful when measured during surgery for colorectal cancer to help determine prognosis and who will benefit from adjuvant treatment.

CEA is measured in the blood plasma. It is very non-specific and can be increased in many types of cancer: gastrointestinal, colorectal, ovarian, bladder, cervical, stomach, kidney, lung, pancreatic, liver, prostate, thyroid, melanoma, lymphoma, and breast. People with non-cancerous conditions, such as cirrhosis or peptic disease, or inflammatory intestinal conditions such as colitis or diverticulitis, may also have increased levels. CEA levels can be elevated in elderly patients and in those who smoke.

CANCER ANTIGEN 72-4 (CA 72-4).

The more recently identified carcinoembryonic protein is CA 72-4. Although it is slightly elevated with most carcinomas, it is mostly associated with stomach carcinoma. CA 74-2 is finding a role in the management of patients with stomach (gastric) carcinoma.

Cancer antigen 15-3 (CA 15-3)

CA 15-3 is produced by cells in the breast and increased levels can be associated with breast cancer. Rarely increased in women with early breast cancer, it may be used to detect recurrence of cancer in women following treatment or mastectomy and to monitor treatment for women with advanced breast cancer. However, adenocarcinomas of the ovary, lung, colon, and pancreas also express elevated CA 15-3 levels. Non-cancerous conditions sometimes associated with elevated CA 15-3 include benign breast or ovarian disease, endometriosis, pelvic inflammatory disease, and hepatitis. Pregnancy and lactation are also related to high CA 15-3 levels.

Cancer antigen 27-29 (CA 27-29)

CA 27-29, also called breast carcinoma-associated antigen, is used as a marker for breast cancer. Eighty percent of women with breast cancer have an increased CA 27-29 level. This marker may be used with other procedures and tumor marker levels such as CA 15-3 to check for recurrences of cancer in previously treated women. Serial measurements monitor treatment response and identify recurrence.

Levels of CA 27-29 may also be increased in cancers of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver. Noncancerous conditions associated with elevated CA 27-29 include first trimester pregnancy, endometriosis, ovarian cysts, non-cancerous breast disease, kidney disease, and liver disease.

HER-2/neu

HER-2/neu is an oncogenic growth factor receptor also known as c-erbB-2. It is measured in the tissue from a biopsy either by immunological assays of the protein or polymerase chain reaction (PCR) to identify the DNA. The presence of HER-2/neu is generally associated with a poorer prognosis for breast cancer. It can also help to determine treatment options, since newer drugs can block this protein and decrease cancer growth. The most widely known of these drugs is trastuzumab (brand name Herceptin).

Estrogen Receptor

Measurement of the estrogen receptor (ER) is used specifically to evaluate breast cancers. It gives an indication of prognosis and responsiveness to therapy. Tissue from a biopsy is used to measure the estrogen receptor. Most breast cancers in post-menopausal women are ER-positive, meaning that they require estrogen to grow. These ER-positive breast cancers are less aggressive than ER-negative breast cancers, which are found generally in pre-menopausal women.

Cancer antigen 125 (CA 125)

Although produced by a number of cell types, CA 125 is primarily produced by ovarian cancer cells. Eighty percent of women with ovarian cancer have increased CA 125 levels. Although the test is not sensitive or specific enough to be used for screening, it contributes to a diagnosis when combined with an ultrasound and pelvic examination. Blood levels of CA 125 are used primarily to monitor the treatment of ovarian cancer. A falling CA 125 level usually indicates that cancer is responding to the treatment. After diagnosis and treatment, serial measurements help detect remaining or recurrent cancer. A negative or normal result, however, does not guarantee the absence of cancer.

Women may have increased CA 125 levels during menstruation and pregnancy. Increased levels are also found in pelvic inflammatory disease, endometriosis, pancreatitis, and liver disease. Elevated levels are also associated with non-ovarian cancers including cancers of the uterus, cervix, pancreas, liver, colon, breast, lung, or digestive tract.

Prostate Specific Antigen (PSA)

Prostate specific antigen (PSA) levels, along with the digital rectal examination, are used to screen for prostate cancer. PSA is a protein produced by the prostate gland and can be overproduced in prostate cancer. It is perhaps the best tumor marker in use because of its tissue specificity, meaning that it is produced only by the prostate. Men over the age of 50 years are advised to consider annual screening for prostate cancer. Men at high risk for prostate cancer, such as African-Americans or those with a family history of the disease, should begin screening at age 40. Once a diagnosis of prostate cancer is made, PSA levels can help determine the stage of the cancer, monitor the response to treatment, and watch for recurrence.

Measurements of PSA following prostatectomy are useful in determining the success of surgery. Any PSA level following surgery would indicate residual prostate tissue, possibly from metastasis. PSA levels can also be used to detect a recurrence of prostate cancer. PSA is also increased in benign prostatic hyperplasia (BPH), an enlarged prostate condition common in older men.

PSA can be found in the serum in two states, bound and free. Measuring both PSA levels can provide more specificity to the test and reduce unnecessary biopsies. The percentage of free PSA is greater in BPH than prostate cancer. If the total PSA level is higher than 4.0 nanogram/milliliter (ng/mL) and the free PSA level is less than 25%, a prostate biopsy is indicated.

PSA levels may increase after ejaculation. Men are recommended to abstain from sexual intercourse or masturbation for 48 hours before the test. PSA levels may also increase after prostate manipulation following the digital rectal exam.

Prostatic acid phosphatase (PAP) originally found to be produced by the prostate and thought to be a marker for prostate cancer. It is now found to be elevated with testicular cancer, leukemia, non-Hodgkin's lymphoma and several noncancerous conditions.

Cancer antigen 19-9 (CA 19-9)

CA 19-9 has been identified in patients with digestive tract or intra-abdominal carcinomas such as colorectal cancer, pancreatic cancer, stomach cancer and bile duct cancer. In pancreatic cancer, higher levels are associated with more advanced disease. After diagnosis, levels help predict the success of surgery and monitor the course of the cancer. Not all people with pancreatic cancer have increased CA 19-9 levels. This antigen is related to the Lewis blood group and so only patients positive for the Lewis blood group antigen will test positive for CA 19-9. It is also increased in liver and gastrointestinal cancers and in noncancerous diseases, including pancreatitis, gallstones and jaundice.

Human chorionic gonadotropin (hCG)

Human chorionic gonadotropin is normally produced by the placenta during pregnancy. There are two protein subunits that make up HCG, beta and alpha. It is the beta subunit that is increased in women's serum during early pregnancy. It is also the beta subunit that is increased in some malignant tumors. Tumors that secrete beta-hCG are typically germ cell tumors such as teratocarcinomas. These are tumors found in the ovaries and testes that contain embryonal tissue. Rarely, these types of tumors are found in the pineal region of the brain where beta-hCG can serve as a marker. Levels of hCG rise with choriocarcinoma and with trophoblastic disease, a rare cancer that develops from an abnormally fertilized egg. Gestational trophoblastic tumors also secrete AFP and this test is often used in combination.

HCG is most often used to screen for cancer of the testis or ovary. Serial measurements monitor the progress and treatment of these cancers. This marker can be elevated in individuals who use marijuana.

Squamous cell carcinoma (SCC) antigen

Squamous cell carcinoma (SCC) antigen was first identified in cervical cancer. It is a marker for squamous cell cancers, which can occur in the cervix, head and neck, lung, and skin. Levels of SCC can be used as an aid to stage the carcinoma and to determine the response to treatment.

Bence-Jones protein

Patients with plasmacytomas such as myeloma overproduce monoclonal immunoglobulins, also called M proteins. The Bence-Jones protein refers to the immunoglobulin light chain, a portion of these immunoglobulins. The Bence-Jones protein is secreted into the urine where it can be measured. It was the first tumor marker identified.

Neuron-Specific Enolase (NSE)

NSE is a protein found mainly in neurons and neuroendocrine cells. It is elevated in tumors derived from these tissues, including neuroblastoma and small cell lung cancer. It can give information about the extent of the disease, the patient's prognosis and the patient's response to treatment. NSE can also be elevated in medullary thyroid cancers, carcinoid tumors, pancreatic endocrine tumors, and melanoma.

Hormone Assays

Tumors of the endocrine glands oversecrete their corresponding hormones. By measuring particular hormones, clues can be obtained regarding certain cancers. For instance, breast cancer cells may secrete prolactin and estrogen. Medullary carcinoma can secrete calcitonin. Pheochromocytomas secrete catecholamines. Tumors of the pituitary gland may secrete growth hormone or cortisol. Carcinoid tumors secrete serotonin. Some tumors of the pancreas secrete insulin. Serial measurements can also monitor treatment for these tumors.

Enzymes

Several serum enzymes can be measured to help detect metastases in cancer patients. Tumors that metastasize to the liver cause increases in serum alkaline phosphatase, gamma-glutamyltransferase, and transaminases. Although these are not necessarily tumor markers, they indicate liver damage that may be caused by metastatic cancer. Tumors that metastasize to the bone sometimes secrete elevated alkaline phosphatase. Lactate dehydrogenase is an enzyme found throughout the body. Because of this it cannot be used as a marker for cancer. It can, however, be used to monitor the treatment of some types of cancer including germ cell tumors, testicular cancer, Ewing's sarcoma, non-Hodgkins lymphoma and some types of leukemia.

Precautions

There is not a good consensus in the medical community about the value of most tumor markers. Because they lack specificity and accuracy, their use is limited. False positives can cause emotional distress and fear. It is not yet determined if there is a savings of life or money with testing. Currently, much controversy surrounds the issue of mass screening for cancer using tumor markers.

Preparation

Tumor marker tests usually require 5-10 mL of blood. A healthcare worker ties a tourniquet on the patient's upper arm, locates a vein in the inner elbow region, and inserts a needle into that vein. Vacuum action draws the blood through the needle into an attached tube. Collection of the sample takes a few minutes and results are available within a few days.

Some markers, such as those for bladder cancer, multiple myeloma, and plasmacytomas, are measured in the urine. Typically this requires a 24-hour urine sample, which means that the individual must collect all of his or her urine for 24 hours. This is usually about 1.5 quarts or more. These results are then available within a few days.

Other tumor markers require tissue samples for analysis. These include receptor analysis such as estrogen receptor and Her-2/neu. Tissue samples are obtained by biopsy. This is usually done by inserting a needle through the skin and into the tumor. The area is typically numbed prior to the procedure. These results are also available within two to three days.

Aftercare

Discomfort or bruising may occur at the puncture site or the person may feel dizzy or faint. Pressure to the puncture site until the bleeding stops reduces bruising. Warm packs to the puncture site relieve discomfort. There is a rare chance of infection occurring especially after biopsy. Any sign of infections should be watched for such as pain and redness.

Normal results

• AFP: 99% of (nonpregnant) people have less than 15 ng/mL; 95% have less than 6 ng/mL. Serum AFP levels higher than 400 micrograms/L are associated with cancer or some other pathology.
• Beta-HCG: in males, less than 2.5 IU/L; in females, less than 5.0 IU/L; in postmenopausal females, less than 9.0 IU/L.
• CA 15-3: less than 40 U/mL.
• CA 19-9: less than 40 U/mL.
• CA 27.29: less than or equal to 38 U/mL.
• CA 125: less than 35 U/L.
• CEA: less than or equal to 5 ng/mL.
• PSA: less than 4 ng/mL; PSA levels increase with age. Age-specific values range from 2.0 micrograms/L at age 40 to 7.2 micrograms/L at age 80. Typically, levels below 4.0 micrograms/L rule out prostate cancer.

Abnormal results

The meaning of an increased tumor marker level depends on the specific marker, the person's medical history, and why the test was done. Knowledge of the patient's history and additional tests and physical examinations are needed to correctly interpret tumor marker test results.

Resources

BOOKS

Eissa, S. Tumor Markers. Philadelphia: Lippincott Williamsand Wilkins, 1999.

Henry, John B. Clinical Diagnosis and Management by Labo ratory Methods, 20th ed. Philadelphia: W. B. Saunders Company, 2001.

Wu, James T., and Robert M. Makamura. Human Circulating Tumor Markers: Current Concepts and Clinical Applica tions. Chicago: American Society of Clinical Pathologists Press (ASCP) Press, 1997.

PERIODICALS

Bast, R.C., P. Ravdin, D.F. Hayes, and others. "2000 Update Recommendations for the Use of Tumor Markers in Breast and Colorectal Cancer." Journal of Clinical Oncol ogy 19, no. 6 (2001).

Daugaard, G. "The Clinical Use of Tumor Markers in Germ Cell Cancer." Journal of Tumor Marker Oncology 16, no.1 (2001).

Eriksson, B., K. Oberg, M. Stridsberg. "Tumor Markers in Neuroendocrine Tumors." Digestion 62, no. 1 (2000).

Lindblom, Annika, and Annelie Liljegren. "Tumor Markers in Malignancies." British Medical Journal 320 (2000): 424.

Pamies, Rubens J., and Deborah R. Crawford. "Tumor Markers. An Update." Medical Clinics of North America (January, 1996): 185-99.

Ruckdeschel, John C. "Update in Oncology." Annals of Inter nal Medicine 131 (1999): 760-7.

Salgia, R., D. Harpole, J.E. Herndon, and others. "Role of Serum Tumor Markers CA125 and CEA in Non-Small Cell Lung Cancer." Anticancer Research 21, no. 2 (2001).

ORGANIZATIONS

American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA, 30329. (800) 227-2345. <http://www.cancer.org>.

American Society of Clinical Oncology. 225 Reinekers Lane, Suite 650, Alexandria, VA 22314. (703) 299-0150. <http://www.asco.org>.

National Cancer Institute. 9000 Rockville Pike, Building 31, Bethesda, MD 20892. (800) 4-CANCER. <http://www.nci.nih.gov>.

OTHER

National Cancer Institute. "Screening for Ovarian Cancer."May 1998. 11 June 1998. 17 July 2001 <http://cancernet.nci.nih.gov/clinpdq/screening/Screening_for_ovarian_cancer_Physician.html>.

National Cancer Institute. "Screening for Prostate Cancer."May 1998. 11 June 1998. 17 July 2001 <http://cancernet.nci.nih.gov/clinpdq/screening/Screening_for_prostate_cancer_Physician.html>.

National Cancer Institute. "NCI Fact Sheet: Tumor Markers."April 1998. 17 July 2001 <http://www.oncolink.upenn.edu/pdq_html/6/engl/600518.html>.

Nancy J. Nordenson

Cindy L. A. Jones, Ph.D.

AFP (Alpha-fetoprotein)

—A tumor marker associated with liver, testicular, and ovarian cancer.

Beta-HCG (Beta-human chorionic gonadotropin)

—A tumor marker associated with testicular cancer and tumors, such as choriocarcinoma and molar pregnancies, that begin in placental cells called trophoblasts.

Biopsy

—The process of taking a sample of tumor tissue through a needle.

CA 15-3 (Cancer antigen 15-3)

—A tumor marker associated with breast cancer.

CA 19-9 (Cancer antigen 19-9)

—A tumor marker associated with pancreatic cancer.

CA 27-29 (Breast carcinoma-associated antigen)

— A tumor marker associated with breast cancer.

CA 125 (Cancer antigen 125)

—A tumor marker associated with ovarian cancer.

CEA (Carcinoembryonic antigen)

—A tumor marker associated with many cancers, especially liver, intestinal, and pancreatic.

Prognosis

—The predicted outcome of a disease.

PSA (Prostate specific antigen)

—A tumor marker associated with prostate cancer.

Sensitivity

—A test's ability to detect all cases of a disease.

Serial measurements

—A series of measurements looking for an increase or decrease over time.

Specificity

—A test's ability to detect only the disease in question.

Tumor markers

—Biochemicals produced by tumor cells or by the body in response to tumor cells. Their levels in the blood help evaluate people for certain kinds of cancer.