Tumor Marker Tests Health Article

Definition

Tumor markers are proteins, hormones, enzymes, receptors and other cellular products that are overexpressed 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 produced by the tumor, the substance will be increased either in the blood or in the tissue of origin.

Purpose

The majority of tumor markers are used to monitor the patient for recurrence of the tumor 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 those found in healthy persons. Most are elevated in conditions other than malignancy, and therefore, are not useful for the purpose or establishing a diagnosis.

Precautions

Tumor markers may be elevated in nonmalignant conditions. Not every tumor will cause an elevation 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 using imaging, biopsy, and other procedures. False positive results may occur in immunoassays when the patient has heterophile antibodies that interfere with the test. Tumor markers at very high concentrations may give erroneously low results caused by the "hook effect." This occurs when the concentration of antigen is so great that all of it cannot be bound by the antibody used in the test system.

Description

Physicians use changes in tumor marker levels to follow the course of the 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 cancer. 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 about the stage of the cancer, and some help predict the response to treatment. A decrease in the amount 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 favorably to the therapy.

There are five types of tumor markers. Many enzymes that are rich in certain tissues are found in plasma at higher levels when the cancer involves that tissue. Enzymes are usually measured by determining the rate at which they convert substrate to product, while most tumor markers of other types are measured by immunoassay. Some examples of enzymes increase in cases of malignant diseases are acid phosphatase, alkaline phosphatase, amylase, creatine kinase, gamma glutamyl transferase, lactate dehydrogenase, and terminal deoxynucleotidyl transferase.

Tissue receptors, proteins associated with the cell membrane, are another type of tumor marker. These bind to hormones and growth factors, and therefore, affect the rate of tumor growth. Some tissue receptors must be measured in biopsied tissue, while others are secreted into the extracellular fluid 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.

Oncofetal antigens are proteins made by genes that are very active during fetal development, but which function at a very low level after birth. The genes become activated in malignancy and produce large amounts of protein. This is the largest class of tumor marker and includes the tumor associated glycoprotein antigens (designated by the letters CA). Important tumor markers of 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.

Some tumor markers are the product of oncogenes. These are genes that are active in fetal development and induce tumor growth when they become active in mature cells. Some important oncogenes are BRAC-1, myc, p53, RB (retinoblastoma) gene (RB), and Ph¹ (Philadelphia chromosome).

The fifth type of tumor marker consists of hormones. This includes hormones that are normally secreted by the tissue in which the malignancy arises and those which are 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.

Currently, there are over 60 analytes that are measured as tumor markers. All of the enzymes and hormones mentioned above are FDA approved as tumor markers, but most of the others are not. These are designated for investigational purposes only. The following list describes the most common tumor markers approved by the Food and Drug Administration for screening, diagnosis, or monitoring of cancer.

• Alpha-fetoprotein (AFP): AFP is a glycoprotein produced by the developing fetus, but levels decline after birth. Healthy non-pregnant adults rarely have detectable levels of AFP in their blood. The AFP test is primarily used for the diagnosis of spina bifida and other abnormalities associated with cerebrospinal fluid leakage during embryonic development. In adult males and non-pregnant 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 1,000 ng/L are almost always associated with cancer. AFP is FDA-approved for the diagnosis and monitoring of patients with non-seminoma testicular cancer. It is elevated in approximately 100% of yolk sac tumors and 80% of hepatomas.
• CA125: This test 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 levels. This includes approximately 50% of persons with Stage I disease and 90% with Stage II or higher. It is also found in approximately 20% of persons with pancreatic cancer. Other cancers detected by this marker include liver, colon, breast, lung, and digestive. Pregnancy and menstruation affect test results. 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, and therefore, this test is used to determine whether recurrence of the cancer has occurred following chemotherapy. However, in some patients, recurrence occurs without an increase in the level of CA-125.
• Carcinoembryonic antigen (CEA): A glycoprotein that is part of the normal cell membrane. CEA is shed into 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 CEA secreting tumors to determine if second-look surgery should be performed. CEA levels may also be elevated in inflammatory bowel disease, pancreatitis, and liver diease. CEA is also elevated in smokers, and about 5% of healthy persons have an elevated plasma level.
• Prostate specific antigen (PSA): A small glycoprotein with protease activity that is specific for prostate tissue. The antigen is present in low levels in all adult males. Therefore an elevated level may require additional testing to confirm that cancer is the cause of the elevated result. 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 and 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): 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. Tissues levels are measured using one of two methods. The tissue can be homogenized into a cytosol, and a sandwich 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): 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 which 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): 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 by a large number of other tumors, but at a lower frequency. Some malignancies cause an increase in alpha and/or beta hCG subunits in the absence of significant increases in intact hCG. For this reason, tests have evolved for alpha and beta hCG, and most labs use these assays as tumor marker tests. Most EIA sandwich 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. Urine is tested using an immunochemical method. 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.