UNDERSTANDING CANCER

Benefits and Limitations of Tumor Markers

Biomarkers help doctors know more about an individual person’s tumor, allowing them to make better, more informed decisions about treatment options. There are two types of biomarkers: protein and molecular.

Protein biomarkers include substances that are either produced by cancer cells themselves or by other cells in response to cancer. Protein biomarkers are primarily found in the blood and, sometimes, urine. Most protein biomarkers related to cancer are used to monitor response and/or detect recurrence or progression during follow-up after treatment (Table 1).

Molecular biomarkers are changes or alterations in genes, cellular receptors, or enzymes that have been found to identify a subtype of cancer. Identifying subtypes is important for determining prognosis and also for guiding treatment. Testing for molecular biomarkers is usually done on samples of tissue taken from the tumor.

Limitations of Biomarkers

Although biomarkers are becoming increasingly valuable in treating cancer, they have limitations. For example, many protein biomarkers are not cancer specific; that is, conditions other than cancer may cause a protein biomarker to be present or be at an elevated level. In addition, the levels of some protein biomarkers are not elevated in all patients with a particular cancer. Because of these limitations, your doctor must consider other clinical information (such as results of blood tests and imaging studies) when interpreting the results of biomarker testing.

Molecular biomarkers are usually more reliable than many protein biomarkers, but these biomarkers have not yet been identified for every type of cancer. Also, testing for some molecular and genetic biomarkers is limited by the availability of laboratories that have the equipment necessary to perform the testing.

Because the treatment of your cancer often depends on the results of biomarker testing, it is imperative that the tests be carried out by approved methods at accredited facilities. You should talk to your doctor about the accuracy of your biomarker testing results and whether testing should be repeated for verification.

How Tumor Markers Are Used

Screening	Most tumor markers are not useful for screening; only 1 tumor marker (prostate-specific antigen) is used for screening
Diagnostic Aid	Tumor markers can help identify the type of cancer when considered along with other clinical factors, such as symptoms and findings on imaging studies
Determine Prognosis	Some tumor markers are factors considered when determining prognosis, or a prediction of the outcome
Guide Treatment	Some tumor markers can provide information about what types of treatment are more likely to produce a response
Monitor Response to Treatment	Tumor markers can monitor the effectiveness of treatment, especially for advanced cancers
Detect Recurrence or Progression	One of the primary uses of tumor markers; if the level of a tumor marker is elevated before treatment, is low after treatment, and then begins to increase after treatment, it is likely that cancer is recurring or progressing

Table 1. Biomarkers According to the Type of Cancer

Biomarker	Type of Sample	Function	Use
Breast Cancer
ER/PR (estrogen receptor)/ (progesterone receptor)	Tumor tissue	Guide treatment	Routine testing at time of diagnosis highly recommended, as presence of receptors is associated with response to hormone therapy.
HER2	Tumor tissue	Guide treatment	Routine testing at time of diagnosis highly recommended, as overexpression of gene is associated with response to specific targeted therapy.
Gene expression analysis	Tumor tissue	Determine prognosis/guide treatment	Testing recommended for distinct population (women with early-stage ER/PR+ cancer with no evidence of disease in the lymph nodes); low risk score indicates that adjuvant chemotherapy will offer minimal benefit.
CA (cancer antigen) 15-3 or CA 27.29	Blood	Monitor response	May be used in conjunction with diagnostic imaging, history and physical examination.
CEA (carcinoem-bryonic antigen)	Blood	Monitor response	May be used in conjunction with diagnostic imaging, history and physical examination.
uPA (urokinase-type plasminogen activator), PAI-1	Tumor tissue	Determine prognosis/guide treatment	Testing recommended for newly diagnosed ER/PR+ cancer that has not spread to lymph nodes; low level (low risk) indicates that adjuvant chemotherapy will offer minimal benefit.
Chronic Myeloid Leukemia
BCR-ABL	Blood	Aid diagnosis Guide treatment	Testing done routinely, as presence of gene is distinguishing feature of the disease. Gene is associated with response to specific targeted therapy.
Colorectal Cancer
CEA	Blood	Determine prognosis Monitor response Detect recurrence/progression	Testing recommended during initial work-up; high level before treatment may indicate cancer is metastatic. Biomarker of choice for monitoring metastatic colorectal cancer during chemotherapy. Testing recommended during follow-up of nonmetastatic disease to detect recurrence or metastasis.
KRAS	Tumor tissue	Guide treatment	Testing recommended, as over-expression of gene is associated with lack of response to some targeted therapies.
MMR	Tumor tissue	Determine prognosis	Testing recommended; mutation is associated with good prognosis.
Gene expression analysis	Tumor tissue	Determine prognosis/guide treatment	Testing recommended for distinct population (people with stage II disease); low risk score indicates that adjuvant chemotherapy will offer minimal benefit.
Gastrointestinal Stromal Tumor
KIT	Tumor Tissue	Aid diagnosis Guide treatment	Testing done routinely, as presence of mutation is distinguishing feature of the tumor. Presence of mutation associated with response to specific targeted therapies.
Liver Cancer
AFP (alpha- fetoprotein)	Blood	Aid diagnosis Detect recurrence/progression	Testing recommended at initial work-up; very high levels can indicate liver cancer (but high levels can be increased in other noncancerous conditions). Testing done throughout follow-up if level was initially elevated.
Melanoma
LDH (lactate dehydrogenase)	Blood	Determine Prognosis	Testing recommended at initial work-up, as level is a factor in determining stage of disease. Testing done throughout follow-up of stage IV disease (metastatic melanoma); high level is predictor of poor prognosis.
BRAF	Tumor tissue	Guide treatment	Testing currently done only in clinical trials of targeted therapy for malignant melanoma.
S-100	Blood	Detect progression	Evidence is currently insufficient to recommend testing, but level is elevated in most individuals with metastatic melanoma.
Multiple Myeloma
Beta-2-microglobulin	Blood	Determine prognosis Monitor prognosis	Testing recommended at initial work-up, as level is factor in determining stage of disease. Measured throughout follow-up; high level indicates high tumor burden (and poor prognosis).
Nonsmall Cell Lung Cancer
EGFR	Tumor tissue	Guide treatment	Testing is becoming routine, as targeted therapy is more effective when gene is overexpressed.
KRAS	Tumor tissue	Guide treatment	Testing recommended, as over-expression is associated with lack of response to some targeted therapies.
EM4-ALK	Tumor tissue	Guide treatment	Testing has started in some cancer centers, as presence of gene is associated with poor response to some targeted therapies.
Ovarian Cancer
CA-125	Blood	Aid diagnosis Detect recurrence/progression	Testing recommended at initial work-up (if symptoms suggest ovarian cancer). Testing done throughout follow-up.
Pancreatic Cancer
CA 19-9	Blood	Determine prognosis Monitor response	Testing recommended at initial work-up; high level is associated with poor prognosis Testing done during active treatment for locally advanced metastatic disease; increase in level may indicate recurrence. (Decreased level after surgery or chemotherapy indicates better survival.)
Prostate Cancer
Prostate-specific antigen (PSA)	Blood	Screening Aid diagnosis Detect recurrence/progression	Usefulness as screening tool is debated, as the level is elevated in benign conditions of the prostate Testing recommended at initial work-up, as level is factor in determining stage of disease. Testing done throughout follow-up.
Testicular Cancer
AFP	Blood	Aid diagnosis	Testing recommended at initial work-up, as level is a factor in determining stage of disease.
hCG (human chorionic gonadotropin)	Blood/urine	Aid prognosis	Testing recommended at initial work-up, as level is a factor in determining stage of disease.
LDH	Blood	Guide treatment	More aggressive treatment is recommended if elevated levels persist.
Thyroid Cancer
Thyroglobulin	Blood	Detect recurrence/progression	Testing done throughout follow-up.