Breast Cancer Gene Expression Tests
- Also Known As:
- Breast Cancer Multiparameter Gene Expression Tests
- Breast Cancer Gene Expression Profiling
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What is gene expression?
Gene expression is the process of making specific proteins from the information contained in the genes. Different tissues express different sets of genes based on their role in the body. The information from the gene is put together to make a template for building ribonucleic acid (RNA). RNA then undergoes specific modifications to create the protein required by the cell. Gene expression tests evaluate the RNA in a person’s tissue sample to determine which genes are actively making proteins.
What are multiparameter tests?
Unlike many standard laboratory tests that evaluate or measure one analyte at a time, multiparameter tests evaluate many analytes at the same time. Results are typically interpreted together, not individually, and in relation to one another. This type of test is also called multiplex testing. The development of new technologies, such as microarrays, has advanced the use of these types of tests.
What are breast cancer multiparameter gene expression tests?
These are tests that evaluate the products (RNA) of specific groups of genes in malignant tumor tissue from the breast in order to determine which genes are making proteins in the tumor tissue. This information is used to predict prognosis by estimating risk of recurrence, and spread (metastasis) of the cancer, as well as to guide treatment. These tests are relatively new, but their use is increasing. They are ultimately aimed at developing a personalized approach to patient care and breast cancer therapy.
Cancers represent uncontrolled growth of abnormal cells that arise due to multiple factors, including malfunctioning proteins that normally keep cell growth in check. The proteins usually malfunction as a result of an acquired mutation in the DNA that contains the instructions for making the proteins. As noted above, genes control the production of RNA. RNA controls the production of proteins, and proteins in turn promote and regulate growth and the rate of reactions in the body. This entire process is referred to as gene expression. Many cellular processes are comprised of a series of steps, with key enzymes (specialized proteins) required to move through each step. Mutations in key genes may result in changes to how a step proceeds (or doesn’t) and may cause a change to the end product or any intermediate product along the pathway.
Genetic mutations can result in abnormal or absent protein, which in turn may lead to unregulated cell growth and division, eventually causing them to invade healthy tissues and become cancerous. Normally, there is a delicate balance between cells, but cancer cells can often “invade” and take over other tissues and may not undergo programmed cell death as they should when growing out of control. Cancer cells and tumors are genetically different from the healthy cells around them.
Each individual breast cancer has different genetic mutations that distinguishes it from the normal tissue. The mutation(s) in cancer cells and the change to the expression of those genes regulate how rapidly the tumor grows, its likelihood of metastasizing and moving throughout the body, whether or not its growth is supported by the hormones estrogen or progesterone, whether it over-expresses certain proteins such as HER2, and how responsive it will be to different treatments.
Through gene expression, breast tumor genes regulate the timing and quantity of production of gene-specific RNA and proteins. Patterns in gene expression include both the increase and/or decrease in the expression of genes (upregulation and downregulation) that are responsible for the production of RNA and proteins. Rather than evaluating a single gene, multiparameter gene expression tests analyze the RNA of multiple genes in a tumor at the same time. The result is a pattern of gene expression that is consolidated into a score and/or profile. This information is then used to help predict the likely behavior of the tumor and its response to treatment.
About Breast Cancer Gene Expression Tests
Why are these tests important?
Breast cancer is the most frequently diagnosed cancer in women in the U.S., excluding skin cancer, and is the second leading cause of cancer death. The American Cancer Society estimates that over 250,000 new cases of invasive breast cancer and over 63,000 cases of in situ breast cancer (i.e., ductal carcinoma in situ or DCIS) are diagnosed in women each year and that about 40,600 women and 460 men will die of breast cancer.
The keys to successful breast cancer treatment are early detection and appropriate treatment. The ultimate goal is to tailor treatments for the affected individual and the specific cancer type. For example, some breast cancers are more aggressive, some are estrogen or progesterone receptor responsive, promoting growth in the presence of these hormones; some show over-expression of HER2 (ERBB2); and some show enhanced sensitivity to chemotherapy while others are resistant to standard chemotherapy regimens. Depending on the characteristics of a tumor, treatment typically includes a combination of surgery, radiation, chemotherapy, hormone therapy, and/or targeted therapy.
The treatments selected for an individual are based on several factors. Guidelines established by the National Comprehensive Cancer Network outline resources and parameters for estimating the risk of relapse and/or death as well as the benefits of certain treatments in people with breast cancer. The traditional parameters used for these purposes include:
- Patient’s age and health
- Tumor size
- Presence or absence of progesterone and/or estrogen receptors (hormone status)
- Presence of HER2 over-expression and/or amplification
- Cancer grade (how normal or abnormal the tumor’s cells are)
- Stage of the cancer (whether it has remained localized, spread to nearby tissues, or spread to other organs)
- Whether cancer cells are present in lymph nodes close to the tumor
Gene expression tests will not be helpful for woman with advanced disease. However, they are useful for women with early stage breast cancer. Based on the above traditional parameters, patients with small localized breast cancers may or may not be treated with specific adjuvant therapies, such as chemotherapy and/or estrogen-deprivation therapy (for hormone-sensitive cancers), to lower the risk that some cancer cells have escaped detection and treatment, causing recurrence of the cancer later. Some patients with low risk of relapse and good prognosis may not require adjuvant therapies. These patients might forgo this therapy and avoid associated side effects. Additionally, some breast cancer patients benefit from adjuvant therapies while others do not.
Gene expression tests are used primarily to help evaluate the patient’s likely course of disease and risk of recurrence, and secondarily to provide information as to which patients may benefit from adjuvant chemotherapy. The use of gene expression profiling has led to the development of new breast cancer classifications. For example, breast cancer can be classified according to response to hormones like estrogen, and HER2 amplification. These categories can be used to predict overall survival. Breast cancer that is estrogen receptor positive may be more likely to respond to hormone therapy and have improved survival. Similarly, breast cancer that is HER2–positive may be more likely to respond to targeted therapy and have an improved prognosis. A healthcare provider may decide on a case-by-case basis whether to offer gene expression profiling and, based on the results (as well as other factors), whether to offer additional treatment.
As a category, multiparameter gene expression tests for breast cancer are relatively new, although their use is increasing. They require a minimum quantity of tumor tissue and specific sample processing. Many of these assays are effective in tissue that has been preserved in some way and stored for a period of time (archival tissue), which allows for the evaluation of patients well after surgery. Each has been developed to be used in specific populations of patients. They have the potential of helping to identify those with the highest and lowest risk of breast cancer recurrence.
Most frequently ordered tests include:
- MammaPrint® test
- Evaluates the expression profile of 70 genes
- For newly diagnosed patients with Stage I or II breast cancer that is equal to or less than 5 centimeters (2 inches) that fall into one of the two criteria:
- Women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, HER2-negative, node-negative breast cancer who are at a high clinical risk of recurrence based on standard prognostic factors, such as age, tumor size and tumor grade
- Women with estrogen receptor-positive or progesterone receptor-positive, HER2-negative breast cancer with 1-3 positive lymph nodes who are at a high clinical risk of recurrence
- This test should not be used in women who have a low clinical risk for recurrence.
- Requires availability of preserved, fresh or frozen breast tumor sample
- Categorizes women into a high versus low risk for recurrence within 10 years. It can help inform decisions on whether a woman would benefit from chemotherapy after surgery. Women meeting either of the above criteria who have a low MammaPrint® score may be treated with hormone therapy alone because they are unlikely to benefit from chemotherapy.
- Included in American Society of Clinical Oncology (ASCO) guidelines
- Available from locations in the U.S. and in the Netherlands
- Oncotype DX® Breast
- Evaluates the expression profile of 21 genes
- For newly diagnosed patients who have Stage I or II breast cancer that is estrogen receptor positive and has not spread to the lymph nodes
- Requires rreserved tumor tissue
- Used to predict the risk of recurrence in patients treated with tamoxifen and assesses the benefit of other chemotherapy regimens (i.e., CMF, methotrexate/5-fluorouraci/leucovorin); some women with low or intermediate risk scores may be able to forego chemotherapy.
- Included in ASCO guidelines, in guidelines from the National Comprehensive Cancer Network (NCCN), and is addressed by the National Breast Cancer Coalition (NBCC)
- Commercially available from one laboratory
Many other multi-gene or multi-gene expression assay systems have been developed. ASCO guidelines also recommend:
- EndoPredict—a 12-gene risk score that may be used to guide decisions for chemotherapy in patients with ER/PR–positive, HER2-negative (node-negative) breast cancers
- PAM50 ROR— this test evaluates 50 genes and uses the information to predict if a cancer will metastasize. The score may be used in conjunction with other variables to guide decisions on adjuvant therapy if a patient has ER/PR–positive, HER2-negative (node-negative) breast cancer
- Breast Cancer Index—may be used to guide decisions on adjuvant therapy if a patient has ER/PR–positive, HER2-negative, node-negative breast cancer
Clinical trials are continuing to address the use of gene expression tests:
- The TAILORx (Trial Assigning Individualized Options for Treatment) trial is comparing adjuvant hormonal therapy with adjuvant combination of chemo and hormonal therapy in women with an Oncotype DX intermediate risk Recurrence Score.
- The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) is designed to confirm that breast cancer that is ER-positive and has spread to a lymph node (node-positive) can be successfully treated with hormonal therapy with or without chemotherapy based on the Oncotype DX risk scores.
- The MINDACT (Microarray In Node-Negative Disease may Avoid Chemotherapy) trial is comparing the MammaPrint test with certain traditional (clinical and pathologic) criteria in assigning patients to chemotherapy treatment.
These trials, and future trials, will further delineate the clinical usefulness of the tests and will evaluate their ability to help guide breast cancer therapy. While it will be a number of years before results from trials are conclusive, healthcare providers may decide to use these molecular tests in monitoring and treating patients with breast cancer on an individual basis. If you would like to know more, talk to your healthcare provider about whether one of these tests might be right for you. You may also wish to check whether your health insurance will cover the cost of testing.
For additional details on these and other similar tests, visit the following web sites:
What if my breast cancer does not meet a gene expression test's criteria?
If it does not, then that particular test would not be able to be used. Future research findings may support a test’s use in additional patient populations, but currently the criteria are matched with the test’s supporting data. There are guidelines fully established for each of the multiparameter assays.
Should I have more than one multiparameter gene expression test done?
This would not generally be necessary. Even though the currently available tests evaluate different combinations of genes, their findings are all intended to stratify breast cancer recurrence risk or response to treatment.
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