Breast Cancer

Tumor Markers in the Diagnosis and Treatment of Breast Cancer

Tumor markers, or biomarkers, are substances that are produced by the body’s cells. Most tumor markers are proteins found in the blood, body tissues, in or around a tumor or in urine, but the expression of certain genes and DNA changes are also considered tumor markers. Though created by both non-cancerous and cancerous cells, cancerous cells typically produce much higher levels.

Advances in the study of tumor markers have changed the way doctors prescribe cancer treatment. Tumor markers can provide information that can help doctors identify, diagnose and manage certain types of cancer. Knowing this type of information is also important because treatments and monitoring milestones, such as the length of time without progression and response to therapy, vary by subtype.

For example, breast cancer used to be considered one general disease, but with the identification of tumor markers, researchers have found that breast cancer tumors vary in several important ways. The presence of tumor markers and genetic profiling on breast tumor tissue has led to additional classifications of breast cancer according to subtypes based on molecular or genetic changes. Breast cancer can now be characterized as a spectrum of histologic patterns as well as molecular and genetic subtypes.

Tumor markers have been identified in ovarian, fallopian tube and peritoneal cancers that are used to help determine treatment, predict prognosis and monitor progression. Researchers are also conducting clinical trials to learn how those and others, such as BRAF, BRCA, KRAS, PI3KCA, PTEN and TP53, respond to different types of targeted therapy treatments.

No single test provides the complete picture of how your cancer is responding to treatment. As a result, the American Joint Committee on Cancer (AJCC) recommends tissue testing along with staging to better determine the treatments that are most likely to be effective. Your doctor will recommend the kind of testing that is best for you.

Types of Biomarkers

Following are some well-known genetic mutations and biomarkers that help guide treatment.

ER and PR (estrogen and progesterone receptors)

Estrogen and progesterone are hormones that circulate naturally in the body. They send signals to special receptor proteins inside normal breast cells. These normal breast cells depend on estrogen and/or progesterone to grow. Many hormonal functions in women are affected by estrogen and progesterone, including breast development.

Estrogen and progesterone hormones can also send signals to some breast cancer cells (those that carry the ER and/or PR tumor markers) to “turn on” the growth of breast cancer cells. Breast cancers are classified according to the presence (ER+/PR+) or absence (ER-/PR-) of these receptors in the cells, and the amount (or expression) of receptors.

ER and/or PR are expressed in approximately three-fourths of all breast cancers. ER+/PR+ breast cancers tend to grow more slowly and are typically less aggressive in comparison to other subtypes. This subtype can respond well to hormone therapy (anti-estrogen agents), also called endocrine therapy. Antiestrogen agents inhibit the production or block the effects of female hormones, helping to slow or stop the growth of breast cancer cells. ER-/PR- breast cancers do not respond to hormone therapy.


When multiple copies of the human epidermal growth factor receptor-2 (HER2) gene are present (known as gene amplification), an excess production (overexpression) of the HER2 protein occurs. The protein sends signals that increase the growth of breast cancer cells. High levels of HER2 are associated with fast-growing tumors that are more likely to recur. Breast cancers with overexpression of HER2 are likely to respond to treatment with an anti-HER2 agent that prevents HER2 from sending signals.


The presence of the BRCA1 and BRCA2 (breast cancer 1 and breast cancer 2) genetic mutations increase the risk for breast, ovarian, fallopian tube and peritoneal cancers. They also cause a condition known as hereditary breast and ovarian cancer syndrome. The presence of a BRCA mutation in a triple-negative breast or ovarian cancer patient may also help determine the types of drug therapy treatments that may be most effective.


CA-125 is a standard tumor marker for ovarian, fallopian tube and primary peritoneal cancer. High levels of CA-125 in the blood may also be found in lung, pancreatic, breast, liver, colon and uterine cancers, as well as in some noncancerous conditions. CA-125 may help doctors diagnose and manage ovarian cancer, as well as evaluate risk of recurrence.

Tumor Markers & Tools to Help Monitor Breast Cancers

Marker Type of Sample Potential Function
BRCA1/BRCA2 Blood High levels identify ovarian tumors most and least likely to respond to targeted therapy.
CA (cancer antigen) 15-3, CA 27.29 Blood Rising levels over time suggest progression of breast cancer.
CEA (carcinoembryonic antigen) Blood Should not be used alone to monitor response or to monitor patients with early-stage breast cancer.
Estrogen receptor/progesterone receptor (ER/PR) Tumor tissue High levels identify breast tumors most and least likely to respond to hormone therapy.
HER2 protein/HER2 gene Tumor tissue High levels identify breast tumors most and least likely to respond to treatment with an anti-HER2 agent and to some specific chemotherapy drugs.
PAI-1 (plasminogen activator inhibitor 1) and uPA (urokinase-type plasminogen activator) Tumor tissue

Tumor tissue
Low levels (low risk) indicate minimal benefit from chemotherapy.

Low levels indicate low risk of recurrence in receptor-positive breast cancer.
Other Tools
Circulating tumor cells (CTC) Blood For metastatic breast cancer, a low count before starting treatment indicates better prognosis; decreasing count during treatment might indicate response to treatment; high count indicates no response. An increasing count indicates progression; a steady count indicates no progression.
Gene expression profiling (MammaPrint) Tumor tissue May predict risk of recurrence for early-stage breast cancer; may guide treatment decisions for clinical high risk, hormone receptor-positive, HER2-negative breast cancer or for 1-3 lymph node-positive early-stage breast cancer patient.
Gene expression profiling (Oncotype DX) Tumor tissue May predict risk of recurrence for newly diagnosed early-stage breast cancer that is ER+/PR+, HER2-negative, and with no evidence of disease in the lymph nodes. Low recurrence score indicates that treatment with endocrine/hormone therapy alone (without chemotherapy) will be adequate as adjuvant systemic therapy; a high-risk recurrence score indicates that chemotherapy in addition to endocrine therapy will be necessary.

Genetic Testing

Genetic testing is an analysis of a person’s genes, proteins and chromosomes and is designed to look for inherited gene abnormalities (changes, alterations or mutations) that may increase the risk of cancer. Genetic testing can be done by analyzing a variety of different tissue samples but is most frequently based upon blood, saliva or swabs from inside of the mouth. After being examined in a laboratory, the results are sent back to your doctor and/or genetic counselor, or may be sent directly to you. Decisions to pursue genetic testing are complicated for emotional, financial and technical reasons. It is, therefore, useful to have a consultation with a trained genetic counselor before, as well as after, undergoing the testing so that the results are interpreted properly. Genetic tests are usually requested by a doctor or other health care provider, but the decision to have genetic testing is a personal one that should be discussed with not only your doctor and genetic counselor, but also your family. There are several strong “indicators” that may encourage you to investigate genetic counseling.

Mutations in the BRCA1 and BRCA2 (BRCA stands for breast cancer) genes increase the risk for breast cancer and cause a condition known as hereditary breast and ovarian cancer syndrome. Mutations in the BRCA 1 and 2 genes can increase the risk of cancers in the ovaries, fallopian tubes and peritoneum. They have also been associated with risk of melanoma, male breast cancer and prostate cancer.

Identification of hereditary breast cancer is now becoming important in treatment decisions. Studies have shown that tumors with BRCA1 and/or BRCA2 mutations have distinct characteristics that may make some types of targeted therapy more effective than traditional treatment strategies.

A CA-125 test can be used to measure the amount of the protein CA-125 (cancer antigen 125) in the blood. High levels are commonly found in women who have ovarian, fallopian tube or peritoneal cancer; however, increased levels are also found when certain non-cancerous conditions are present.

Consulting with a genetic counselor before testing will help you understand your risks for other cancers. After testing, your counselor can help you interpret the results and use them to plan future health care, such as a schedule for screenings. If a genetic mutation is identified, your genetic counselor may discuss options to reduce your risk, including earlier or more frequent screenings, lifestyle changes or preventive treatments.

Your doctor may strongly encourage you to share the results of genetic testing with your family. A positive result may confirm a hereditary cancer syndrome and/or indicate a higher chance of a mutation in a first-degree relative (sibling, child or parent). Understanding your results will allow family members to make more informed decisions about their own health care and lifestyle. It’s important to remember, however, that genetic test results provide clues regarding likelihood of cancer developing in an individual, but they do not provide 100% certainty. A person with a negative test result, therefore, may still develop cancer, and some individuals testing positive for a mutation might not develop cancer. Furthermore, the genes that have been linked to cancer risk can have a variety of different types of mutations or abnormalities, and some of these abnormalities are more strongly associated with cancer risk than others.

Genetic testing can be expensive, and the cost depends on several factors, such as the complexity of the test and how many family members are tested. The initial testing is usually the most expensive, but once a mutation is identified in a family, the cost may drop significantly for relatives who are tested subsequently because they can undergo targeted testing to look for the previously-identified specific mutation. Medicare and private health insurance cover testing in most cases, but always investigate your insurance coverage first. Some testing laboratories are also able to help verify insurance coverage before testing is done.

Though genetic testing can be helpful in some cases, it’s important to note that most cancers occur because of changes or mutations to a gene as a result of an outside cause rather than a hereditary genetic abnormality. For instance, exposure to sunlight or tobacco may cause gene changes, or gene changes can be the result of other random events with no definite cause.

Many people who have a family history of cancer worry about hereditary risk, but most cancers – even those within a single family – occur simply by chance. In fact, only 5-10 percent of cancers are strongly linked to inherited genetic mutations.

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