Multiparameter Gene Expression Tests
for Breast Cancer

Why are they important?

Breast cancer is the most frequently diagnosed cancer in women, excluding skin cancer, and is the second leading cause of cancer death. The American Cancer Society estimates that 182,460 new cases of invasive breast cancer and 67,770 cases of in situ breast cancer will be diagnosed in 2008 and that 40,480 women and 450 men will die of breast cancer.

The keys to successful breast cancer treatment are to detect and treat it early and to tailor treatments to both the person and the cancer. Some cancers are more aggressive than others, some have estrogen or progesterone receptors on them that promote growth in the presence of these hormones, some over-express Her-2/neu, some are more sensitive to chemotherapy and others are less sensitive. Treatment of breast cancer typically includes combinations of surgery, radiation, chemotherapy, hormone therapy, targeted therapy, and sometimes biologic therapy.

The types of breast cancer treatment selected are based on several factors:

• patient's age and health
• tumor size
• presence or absence of progesterone and/or estrogen receptors
• presence of Her-2/neu over-expression
• cancer grade (how normal or abnormal the tumor’s cells are)
• stage of the cancer - whether it has remained localized (Stages I and II), spread to nearby tissues (Stage III), or spread to other organs (Stage IV)
• whether cancer cells are present in lymph nodes close to the tumor

Patients with small localized cancers that have not spread to their lymph nodes may or may not be treated with specific adjuvant therapies – additional systemic treatments such as chemotherapy and/or tamoxifen (for hormone sensitive cancers) - to lower the risk that some cancer cells have escaped detection and treatment and may cause a recurrence of the cancer later. Adjuvant therapies are not effective in all breast cancer patients. Multiparameter gene expression tests are intended primarily to help evaluate the patient’s prognosis and risk of breast cancer recurrence and secondarily to give the doctor potential information as to which patients may benefit from adjuvant chemotherapy.

Multiparameter gene expression tests for breast cancer are relatively new. They require a minimum quantity of tumor tissue and specific sample processing. 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 patients at highest and lowest risk of breast cancer recurrence, but their full clinical utility has yet to be established.

There are several multiparameter gene expression tests in development, but most are still considered primarily research tools. One of them, the MammaPrint test, has been cleared for marketing by the Food and Drug Administration. Oncotype DX was included in the American Society of Clinical Oncology (ASCO) 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer to be used to predict the risk of recurrence in patients treated with tamoxifen. ASCO felt that the MammaPrint test and several other multiparameter gene expression tests, including the Rotterdam Signature and the Breast Cancer Gene Expression Ratio, were promising but still needed additional supporting data defining their clinical utility before ASCO would recommend them. The National Comprehensive Cancer Network (NCCN) and the National Breast Cancer Coalition (NBCC) also acknowledge the potential for these tests but feel that further investigation is necessary to support their clinical use.

Research is continuing in several large clinical trials such as the TAILORx (Trial Assigning Individualized Options for Treatment) trial that will compare adjuvant hormonal therapy with adjuvant chemohormonal therapy in women with an Oncotype DX intermediate risk Recurrence Score, and the MINDACT (Microarray In Node-Negative Disease may Avoid Chemotherapy) trial that will compare the MammaPrint test with clinical and pathologic criteria in assigning patients to chemotherapy treatment. These trials will further delineate the clinical utility of the tests and will evaluate their ability to help guide breast cancer therapy, but it will be a number of years before results are available.