What are Tumor Markers with Cancer?

Tumor markers are substances that are released by cancer cells or produced by the body in reaction to a malignant tumor or benign condition. By measuring these biomarkers in blood, urine, or other fluids, they may be used to monitor the progress of a cancer, check for recurrence, or sometimes to help screen for, diagnose, or stage cancer.

Most tumor markers are proteins, but DNA changes such as mutations and other alterations may also be used as biomarkers or tumor markers. A biomarker can be found circulating in bodily fluids or in a tumor tissue sample to help your healthcare provider learn more about your cancer and determine treatment options. Tumor marker results aren't usually used alone for diagnosis but can provide clues when combined with clinical symptoms and imaging studies.

Purpose of Tumor Marker Tests

There are a number of reasons why a tumor marker test may be ordered:

• To monitor progress of a cancer: The most common use of tumor markers is to follow a known cancer. In this setting, a decrease in the level of a tumor marker may be a sign that a tumor is decreasing in size (in other words, that the treatment is working) whereas an increase in the level could mean a tumor is progressing.
• To monitor for cancer recurrence: With some cancers, an increase in a particular tumor marker may indicate a recurrence of the cancer after surgery.
• To help diagnose cancer: Tumor markers are not used alone to diagnose cancer but may provide clues as part of the workup.
• To screen for cancer: An example of a tumor marker used for screening is the PSA test for prostate cancer. PSA can be used as both a screening test and to monitor a cancer. In some cases, a tumor marker may be used to to screen people who have a high risk of developing a particular cancer but not the general population.
• To help stage a tumor: In some cases, tumor markers may be helpful in determining the stage of a cancer, which is important in choosing the best treatment options.
• To help diagnose metastases: If a particular tumor marker level is very high, it may suggest that a tumor is not only growing, but has spread (metastasized) to other regions of the body.
• To estimate prognosis: In some cases, higher levels of a particular tumor marker may indicate a poorer prognosis.
• To determine treatment choice: Gene mutations and other genomic alterations may be used to determine if targeted therapy is indicated, to learn if resistance to targeted therapy has developed, and to predict prognosis. When genetic biomarkers are used to determine treatment, it is referred to as precision medicine.
• To predict complications of cancer: A 2018 study found that high tumor markers (CEA, CA 19-9, and CA 125) in people with colon, pancreatic, and ovarian cancers were associated with a high risk of blood clots (deep vein thrombosis), a complication that already affects roughly 20% of people with cancer at some time.

Tumor Marker Measurements

Your healthcare provider will take a sample of your bodily fluid or tumor tissue and send it to the laboratory to measure the level of the tumor marker. With protein tumor markers, tests are most often done on blood, but they may also be performed on urine, stool, cerebrospinal fluid, peritoneal fluid (abdominal fluid), or pleural fluid. With genetic biomarkers, tests may be done on tumor tissues or via a blood test that looks for circulating tumor cell DNA (liquid biopsy).

Your healthcare provider will then look at the measurement to see if it falls in the normal range. Normal cells make many of these tumor marker substances, but they may be produced in much higher amounts by cancer cells (or in response to cancer cells). When tumor markers are present in higher amounts, healthcare providers refer to the marker as being "overexpressed."

These tests are often most valuable when repeated to look at the progress of a tumor over time. If your lab test is abnormal, your healthcare provider may recommend more tests or treatments. Tumor markers should always be used along with other findings, such as biopsies and imaging studies, to evaluate the progress of a cancer.

Limitations

There are a number of limitations in using tumor markers to monitor cancer. Some of these include:

• Absence of tumor markers for some cancers: Some cancers do not produce or result in the production of any tumor markers.
• False negatives: In some cancers, particularly early-stage cancers, tumor markers may not be elevated.
• False positives: With some tumor markers, there are a number of benign conditions that can cause increases as well. For example, CA-125 may be increased with ovarian cancer, but also with uterine fibroids, pregnancy, and liver disease.
• Timing: The level of a tumor marker at one point in time may not necessarily reflect the status of the cancer. For example, if a tumor is responding to treatment it may take time for tumor marker levels to decrease, and if a lot of cancer cells are dying, levels may even increase for a period of time.

Risks and Contraindications

The risk of tumor marker tests are primarily that of the procedure used to obtain fluid or tissue to test, whether a blood draw, thoracentesis to obtain pleural fluid, or biopsy to obtain a tissue sample.

If used without considering other findings, tumor markers could provide inaccurate information, either false positives or false negatives, leading to less than optimal treatment.

Interpreting Results

Interpreting the results of a tumor marker will depend on the specific tumor marker and setting in which it is used. The following graph lists some tumor markers followed by a brief discussion of common protein and genetic biomarkers.

Common Tumor Markers

Tumor biomarkers can include proteins and other substances made by normal cells and cancer cells. They can also include genomic markers, such as changes in tumor DNA or gene mutations. Some tumor markers are associated with one cancer while others are associated with multiple cancers. Often, elevated biomarkers can be a sign of noncancerous conditions as well.

Some common tumor biomarkers include:

• Alpha-Fetoprotein (AFP): Used to test for recurrence, help diagnose, or monitor treatment with liver cancer or germ cell tumors of the ovaries or testicles. False positives may occur with cirrhosis and hepatitis.
• Beta-2 Microglobulin (B2M): Used to monitor treatment, check for recurrence, and estimate prognosis for some leukemias, lymphomas, and myelomas. False negatives may occur with kidney disease.
• Beta human chorionic gonadotropin (Beta hCG): Used to monitor choriocarcinoma and germ cell tumors. It’s also often tested to confirm pregnancy. It may be elevated in both seminoma and non-seminoma testicular cancers.
• BRAF mutations: A change in the BRAF gene that may be found in some cancers, including melanoma and colorectal cancer.
• BRCA mutations: Looks for a mutation in the genes BRCA1 and BRCA2 that may lead to breast, ovarian or prostate cancer.
• Calcitonin: Hormone that is used to monitor medullary thyroid cancer.
• Carcinoembryonic antigen (CEA): May be used to look for recurrence, spread, or progression of colorectal cancer. It is also used with some other cancers.
• CA 15-3 and CA 27-29: Checked to monitor for recurrence or progression of breast cancer, stomach cancer, lung cancer, and others. False positives may occur, and levels can be elevated with benign breast conditions.
• CA 19-9: May be checked to monitor treatment or screen for recurrence of pancreatic, gallbladder, bile duct, stomach, or colon cancer. False positives may occur with bile duct obstruction, pancreatitis, thyroid disease, inflammatory bowel disease, and more.
• CA-125: May be used to monitor progress with ovarian cancer. While it has sometimes been used to screen for the disease, there are many false positives.
• Cluster of Differentiation 20 (CD20): Found in higher amounts in patients with certain B-cell lymphomas and leukemias. It can help diagnose cancer or help determine treatment.
• Estrogen and Progesterone Receptors: May be studied with breast cancer cases to determine who is a candidate for hormonal therapy.
• Gastrin: May be found in higher levels with gastrinomas. It can help with diagnosis, treatment, and predicting recurrence. Elevated results may also occur with Zollinger-Ellison syndrome.
• Human epidermal growth factor receptor 2 (HER2): Found in some breast cancers, lung cancers, stomach cancers and more rarely in other types of cancers, like some cancers of the salivary glands for example. People who have tumors with increased HER2 expression may respond to HER2 targeted therapies.
• Lactate dehydrogenase (LDH): May be ordered during the work-up or management of many cancers. Levels tend to increase when a cancer is progressing or has metastasized, but there are many other noncancerous conditions that can cause elevations as well, such as anemia, kidney disease, and many infections.
• Neuron-Specific Enolase (NSE): Used to monitor carcinoids, islet cell tumors, neuroblastomas, and small cell lung cancer.
• Philadelphia chromosome (BCR-ABL fusion gene): Found in chronic myelogenous leukemia and acute lymphocytic leukemia.
• Programmed death ligand 1 (PD-L1): Can help determine who is most likely to respond to the immunotherapy, which boosts your immune system to recognize and fight cancer cells.
• Prostate-specific antigen (PSA): Widely used to screen for prostate cancer, though the risk of overdiagnosis has called this into question. It is still used to monitor response to treatment.
• Thyroglobulin: Used to monitor some types of thyroid cancer.