Rudi Hayden

Urologist

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Blood-tests Explained


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This website is intended to assist with patient education and should not be used as a diagnostic, treatment or prescription service, forum or platform. Always consult your own healthcare practitioner for a more personalised and detailed opinion

Breast Cancer, Gene Expression


What is gene expression?

Gene expression is the translation of genetic information from genes to proteins that results in the characteristics that cells and tissues exhibit. Genes are the basic units of DNA that code for the production of proteins. Genes are made up of nucleotides, which are composed of phosphates, a sugar, and one of four different nitrogen-containing bases: adenine, guanine, thymine, or cytosine. The arrangement of the bases in each gene is used to produce RNA, which in turn produces a protein. Gene expression tests evaluate the RNA in a person's sample of tissue to determine its characteristics.

What are multiparameter tests?

Unlike many standard laboratory tests that evaluate or measure one analyte at a time, multiparameter tests evaluate many analytes together 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. 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 predict prognosis, 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 codes for the proteins. As noted above, the genes that make up DNA control the production of RNA. RNA controls the production of proteins that in turn promote and regulate growth and the rate of reactions in the body, and this is referred to as gene expression. The reactions typically take place in a series of steps, with key enzymes required to move along the reaction pathway. Mutations in genes may result in changes in the steps, the enzymes, and/or the pathway in characteristic ways. Sometimes the changes result in the excess or malfunction of a protein that regulates growth, resulting in uninhibited growth of cells.

Genetic mutations and the expression of the mutations can lead to unchecked growth and division of cells, eventually causing them to become cancerous. They can invade other tissue and may not die as other cells do. Cancer cells and tumors are genetically different from the normal cells around them.

Different types of breast cancer have different genetic alterations that distinguish them from the normal tissue. The mutated genes in the tumor, and the expression of those genes, regulate how rapidly the tumor will grow, 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 tumor genes 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.

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 230,480 new cases of invasive breast cancer and 57,650 cases of in situ breast cancer (i.e., ductal carcinoma in situ or DCIS) are diagnosed in women each year and that 39,520 women and 450 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 overexpression of HER2/neu (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 combination of 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/neu overexpression 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

For example, based on these parameters, patients with small localized breast cancers that have not spread to their lymph nodes may or may not be treated with specific adjuvant therapies, such as chemotherapy and/or tamoxifen (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/neu-positive may be more likely to respond to Herceptin® and have an improved prognosis. A health care 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.

Tests

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. All of them are currently intended to be used only on cancers that have not yet spread to the lymph nodes, and 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.

  • MammaPrint® test
    • Evaluates the expression profile of 70 genes
    • Cleared for marketing by the U.S. Food and Drug Administration (FDA)
    • For newly diagnosed patients with Stage I or II breast cancer that is equal to or less than 5 centimeters (2 inches) and has not spread to the lymph nodes
    • Preserved, fresh or frozen breast tissue sample
    • Categorizes women into a high versus low risk for recurrence within 10 years but does NOT predict benefits from adjuvant chemotherapy
    • Available from locations in the U.S. and in the Netherlands
  • Oncotype DX®
    • 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
    • Preserved 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)
    • Included in the American Society of Clinical Oncology (ASCO) 2007 Update (Recommendations for the Use of Tumor Markers in Breast Cancer), 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, NCCN, and other professional organizations maintain that the MammaPrint® test and others, such as the Rotterdam Signature and the Breast Cancer Gene Expression Ratio, are promising but that none are currently sufficiently validated to warrant inclusion into standard guidelines for the management of patients with breast cancer.

Clinical trials are currently underway to address the use of these assays:

  • The TAILORx (Trial Assigning Individualized Options for Treatment) trial is comparing adjuvant hormonal therapy with adjuvant chemohormonal 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.

All of 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, health care 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 health care provider about whether one of these tests might be right for you.

For additional details on these and other similar tests, visit the following web sites:

  • National Comprehensive Cancer Network 
  • American Society of Clinical Oncology 
  • National Breast Cancer Coalition