Tumor markers are a group of proteins, hormones, enzymes, receptors, and other cellular products that are overexpressed (produced in higher than normal amounts) by malignant cells. Tumor markers are usually normal cellular constituents that are present at normal or very low levels in the blood of healthy persons. If the substance in question is produced by the tumor, its levels will be increased either in the blood or in the tissue of origin.
Purpose
The majority of tumor markers are used to monitor patients for recurrence of tumors following treatment. In addition, some markers are associated with a more aggressive course and higher relapse rate and have value in staging and prognosis of the cancer. Most tumor markers are not useful for screening because levels found in early malignancy overlap the range of levels found in healthy persons. The levels of most tumor markers are elevated in conditions other than malignancy, and are therefore not useful in establishing a diagnosis.
Precautions
Tumor markers are sometimes elevated in nonmalignant conditions. Not every tumor will cause a rise in the level of its associated marker, especially in the early stages of some cancers. When a marker is used for cancer screening or diagnosis, the physician must confirm a positive test result by using imaging studies, tissue biopsies, and other procedures. False positive results may occur in laboratory tests when the patient has cross-reacting antibodies that interfere with the test.
Description
Physicians use changes in tumor marker levels to follow the course of a patient's disease, to measure the effect of treatment, and to check for recurrence of certain cancers. Tumor markers have been identified in several types of cancer, including malignant melanoma; multiple myeloma; and bone, breast, colon, gastric, liver, lung, ovarian, pancreatic, prostate, renal, and uterine cancers. Serial measurements of a tumor marker are often an effective means to monitor the course of therapy. Some tumor markers can provide physicians with information used in staging cancers, and some help predict the response to treatment. A decrease in the levels of the tumor marker during treatment indicates that the therapy is having a positive effect on the cancer, while an increase indicates that the cancer is growing and not responding to the therapy.
ENZYMES. Many enzymes that occur in certain tissues are found in blood plasma at higher levels when the cancer involves that tissue. Enzymes are usually measured by determining the rate at which they convert a substrate to an end product, while most tumor markers of other types are measured by a test called an immunoassay. Some examples of enzymes whose levels rise in cases of malignant diseases are acid phosphatase, alkaline phosphatase, amylase, creatine kinase, gamma glutamyl transferase, lactate dehydrogenase, and terminal deoxynucleotidyl transferase.
TISSUE RECEPTORS. Tissue receptors, which are proteins associated with the cell membrane, are another type of tumor marker. These substances bind to hormones and growth factors, and therefore affect the rate of tumor growth. Some tissue receptors must be measured in tissue samples removed for a biopsy, while others are secreted into the extracellular fluid (fluid outside the cells) and may be measured in the blood. Some important receptor tumor markers are estrogen receptor, progesterone receptor, interleukin-2 receptor, and epidermal growth factor receptor.
ANTIGENS. Oncofetal antigens are proteins made by genes that are very active during fetal development but function at a very low level after birth. The genes become activated when a malignant tumor arises and produce large amounts of protein. Antigens comprise the largest class of tumor marker and include the tumor-associated glycoprotein antigens. Important tumor markers in this class are alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), prostate specific antigen (PSA), cathespin-D, HER-2/neu, CA-125, CA-19-9, CA-15-3, nuclear matrix protein, and bladder tumor-associated antigen.
ONCOGENES. Some tumor markers are the product of oncogenes, which are genes that are active in fetal development and trigger the growth of tumors when they are activated in mature cells. Some important oncogenes are BRAC-1, myc, p53, RB (retinoblastoma) gene (RB), and Ph1 (Philadelphia chromosome).
HORMONES. The fifth type of tumor marker consists of hormones. This group includes hormones that are normally secreted by the tissue in which the malignancy arises as well as those produced by tissues that do not normally make the hormone (ectopic production). Some hormones associated with malignancy are adrenal corticotropic hormone (ACTH), calcitonin, catecholamines, gastrin, human chorionic gonadogropin (hCG), and prolactin.
Tumor markers in clinical use
Currently, there are over 60 analytes that are used as tumor markers. All of the enzymes and hormones mentioned above have been approved as tumor markers by the Food and Drug Administration (FDA), but most of the others are not; they have been designated for investigation purposes only. The following list describes the most commonly used tumor markers approved by the FDA for screening, diagnosis, or monitoring of cancer.
Alpha-fetoprotein (AFP): AFP is a glycoprotein produced by the developing fetus, but its blood levels decline after birth. Healthy adults who are not pregnant rarely have detectable levels of AFP in their blood. The AFP test is primarily used for prenatal diagnoses of spina bifida and other abnormalities associated with cerebrospinal fluid leakage during embryonic development. In adult males and nonpregnant females, an AFP above 300 ng/L is often associated with cancer, although levels in this range may be seen in nonmalignant liver diseases. Levels above 1000 ng/L are almost always associated with cancer. AFP has been approved by the FDA for the diagnosis and monitoring of patients with non-seminoma testicular cancer. It is elevated in almost all yolk sac tumors and 80% of malignant liver tumors.
CA-125: Measurement of this tumor marker is FDA-approved for the diagnosis and monitoring of women with ovarian cancer. Approximately 75% of persons with ovarian cancer shed CA-125 into the blood and have elevated serum levels. This figure includes approximately 50% of persons with Stage I disease and 90% with Stage II or higher. Elevated levels of CA-125 are also found in approximately 20% of persons with pancreatic cancer. Other cancers detected by this marker include malignancies of the liver, colon, breast, lung, and digestive tract. Test results, however, are affected by pregnancy and menstruation. Benign diseases detected by the test include endometriosis, ovarian cysts, fibroids, inflammatory bowel disease, cirrhosis, peritonitis, and pancreatitis. CA-125 levels correlate with tumor mass; consequently, this test is used to determine whether recurrence of the cancer has occurred following chemotherapy. Some patients, however, have a recurrence of their cancer without a corresponding increase in the level of CA-125.
Carcinoembryonic antigen (CEA): CEA is a glycoprotein that is part of the normal cell membrane. It is shed into blood serum and reaches very high levels in colorectal cancer. Over 50% of persons with breast, colon, lung, gastric, ovarian, pancreatic, and uterine cancer have elevated levels of CEA. CEA levels in plasma are monitored in patients with tumors that secrete this antigen to determine if second-look surgery should be performed. CEA levels may also be elevated in inflammatory bowel disease (IBD), pancreatitis, and liver disease. Heavy smokers and about 5% of healthy persons have elevated plasma levels of CEA.
Prostate specific antigen (PSA): PSA is a small glycoprotein with protease activity that is specific for prostate tissue. The antigen is present in low levels in all adult males, which means that an elevated level may require additional testing to confirm that cancer is the cause. High levels are seen in prostate cancer, benign prostatic hypertrophy, and inflammation of the prostate. PSA is approved as a screening test for prostatic carcinoma. PSA has been found to be elevated in more than 60% of persons with Stage A and more than 70% with Stage B cancer of the prostate. It has replaced the use of prostatic acid phosphatase for prostate cancer screening because it is far more sensitive. Most PSA is bound to antitrypsins in plasma but some PSA circulates unbound to protein (free PSA). Persons with a borderline total PSA (between 4–10 ng/L), but who have a low free PSA are more likely to have malignant prostate disease.
Estrogen receptor (ER): ER is a protein found in the nucleus of breast and uterine tissues. The level of ER in the tissue is used to determine whether a person with breast cancer is likely to respond to estrogen therapy with tamoxifen, which binds to the receptors blocking the action of estrogen. Women who are ER-negative have a greater risk of recurrence than women who are
ER-positive. Tissue levels are measured using one of two methods. The tissue can be homogenized into a cytosol, and an immunoassay used to measure the concentration of ER receptor protein. Alternatively, the tissue is frozen and thin-sectioned. An immunoperoxidase stain is used to detect and measure the estrogen receptors in the tissue.
Progesterone receptor (PR): PR consists of two proteins, like the estrogen receptor, which are located in the nuclei of both breast and uterine tissues. PR has the same prognostic value as ER, and is measured by similar methods. Tissue that does not express the PR receptors is less likely to bind estrogen analogs used to treat the tumor. Persons who test negative for both ER and PR have less than a 5% chance of responding to endocrine therapy. Those who test positive for both markers have greater than a 60% chance of tumor shrinkage when treated with hormone therapy.
Human chorionic gonadotropin (hCG): hCG is a glycoprotein produced by cells of the trophoblast and developing placenta. Very high levels are produced by trophoblastic tumors and choriocarcinoma. About 60% of testicular cancers secrete hCG. hCG is also produced less frequently by a number of other tumors. Some malignancies cause an increase in alpha and/or beta hCG subunits in the absence of significant increases in intact hCG. For this reason, separate tests have been developed for alpha and beta hCG, and most laboratories use these assays as tumor marker tests. Most EIA tests for pregnancy are specific for hCG, but detect the whole molecule and are called intact hCG assays.
Nuclear matrix protein (NMP22) and bladder tumor-associated analytes (BTA): NMP22 is a structural nuclear protein that is released into the urine when bladder carcinoma cells die. Approximately 70% of bladder carcinomas are positive for NMP22. BTA is comprised of type IV collagen, fibronectin, laminin, and proteoglycan, which are components of the basement membrane that are released into the urine when bladder tumor cells attach to the basement membrane of the bladder wall. These products can be detected in urine using a mixture of antibodies to the four components. BTA is elevated in about 30% of persons with low-grade bladder tumors and over 60% of persons with high-grade tumors.
Preparation
Determination of the circulating level of tumor markers requires a blood test performed by a laboratory scientist. A nurse or phlebotomist usually draws the patient's blood; he or she ties a tourniquet above the patient's elbow, locates a vein near the inner elbow, cleanses the skin overlying the vein with an antiseptic solution, and inserts a sterile needle into that vein. The blood is drawn through the needle into an attached vacuum tube. Collection of a blood sample takes only a few minutes.
Tissue samples are collected by a physician at the time of surgical or needle biopsy. A urine sample is collected by the patient, using the midstream void technique.
Aftercare
Aftercare following a blood test consists of routine care of the area around the puncture site. Pressure is applied for a few seconds and the wound is covered with a bandage. If a bruise or swelling develops around the puncture site, the area is treated with a moist warm compress.
Risks
The risks associated with drawing blood include dizziness, bruising, swelling, or excessive bleeding from the puncture site. As previously mentioned, the results of blood tests should be interpreted with caution. A single test result may not yield clinically useful information. Several laboratory reports over a period of months may be needed to evaluate treatment and identify recurrence. Positive results must be interpreted cautiously because some tumor markers are increased in nonmalignant diseases and in a small number of apparently healthy persons. In addition false negative results may occur because the tumor does not produce the marker, and because levels seen in healthy persons may overlap those seen in the early stages of cancer. A false positive result occurs when the value is elevated even though cancer is not present. A false negative result occurs when the value is normal but cancer is present.
Normal results
Reference ranges for tumor markers will vary from one laboratory to another because different antibodies and calibrators are used by various test systems. The values below are representative of normal values or cutoffs for commonly measured tumor markers.
Alpha-fetoprotein (AFP): Less than 15 ng/L in men and nonpregnant women. Levels greater than 1,000 ng/L indicate malignant disease (except in pregnancy).
CA125: Less than 35 U/mL.
Carcinoembryonic antigen (CEA): Less than 3 μg/L for nonsmokers and less than 5 μg/L for smokers.
Estrogen receptor: Less than 6 fmol/mg protein is negative; greater than 10 fmol/mg protein is positive.
Human chorionic gonadotropin (HCG): Less than 20 IU/L for males and non-pregnant females. Greater than 100,00 IU/L indicates trophoblastic tumor.
Progesterone receptor: Less than 6 fmol/mg protein is negative. Greater than 10 fmol/mg protein is positive.
Henry, J.B., ed. Clinical Diagnosis and Management by Laboratory Methods, 20th ed. Philadelphia, PA: Saunders, 2001.
"Tumor Immunology." Section 11, Chapter 143 in The MerckManual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.
Wallach, Jacques. Interpretation of Diagnostic Tests, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkens, 2000.
ORGANIZATIONS
American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329-4251. (800) 227-2345. <www.cancer.org>.
American Society of Clinical Oncology (ASCO). 1900 Duke Street, Suite 200, Alexandria, VA 22314. (703) 299-0150. <www.asco.org>.
National Cancer Institute (NCI). NCI Public Inquiries Office, Suite 3036A, 6116 Executive Boulevard, MSC8332, Bethesda, MD 20892-8322. (800) 4-CANCER or (800) 332-8615 (TTY). <www.nci.nih.gov>.
United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFO-FDA. <www.fda.gov>.
