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Breast Cancer: The New World of Gene Expression Profiling and Targeted Therapy

Breast cancer is an important health issue for women; it is the most common cancer and the second most common cause of cancer death in women.  In 2008, there were more than 180,000 new diagnoses of breast cancer and more than 41,000 deaths from breast cancer in the United States.  Over the past decade there has been a rise in the incidence of breast cancer.  However, the mortality from breast cancer is decreasing, and this is due to the increasingly effective treatments that are available to cure women who are diagnosed with early stage breast cancer. 

One of the challenges faced by a medical oncologist today is to decide which patients warrant aggressive adjuvant systemic therapy in addition to local therapy (surgery with or without breast irradiation).   The types of adjuvant systemic therapy available are chemotherapy, endocrine therapy, and targeted therapy.  In general, all women with estrogen and/or progesterone responsive breast cancer are treated with endocrine therapy.  Until recently, tamoxifen was the only adjuvant endocrine therapy with proven efficacy.  In December of 2001, initial results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial were released, with anastrozole associated with improved outcomes in postmenopausal women compared with tamoxifen.  Updated results have confirmed the efficacy and tolerability of anastrozole over tamoxifen, as have several other studies evaluating the other aromatase inhibitors, letrozole and exemestane.  Thus, aromatase inhibitors have become the standard adjuvant endocrine therapy for postmenopausal women with hormone-responsive breast cancer.  Tamoxifen remains the standard treatment for premenopausal women.

Adjuvant systemic chemotherapy is another treatment modality that is widely administered.  While there are several accepted regimens, those that contain an anthracycline, a taxane, and cyclophosphamide are considered the standard of care.  Historically, the decision to treat a patient with chemotherapy has been based on certain prognostic features of the patient and the tumor – the age and health of the patient, the size and grade of the tumor, the presence and number of involved axillary lymph nodes, the status of the estrogen and progesterone receptors, and the presence of HER2 over expression.  While these factors remain critically important, many oncologists now additionally utilize gene expression assays that are commercially available to provide genomic information about an individual’s tumor to assist in the decision regarding chemotherapy.  The two assays that are commercially available in the U.S. are Oncotype Dx® and Mammaprint®.  Oncotype Dx® evaluates a set of 21 genes known to be important in the molecular pathway of breast cancer, and from this analysis generates a Recurrence Score (RS), which assigns the patient into a low-, intermediate- or high-risk group.  Numerous studies have shown the RS to be both prognostic and predictive in that a patient with a low risk RS has a lower risk of distant recurrence at 10 years, and also a lower likelihood of receiving benefit from chemotherapy, while a patient with a high risk RS has a higher risk of recurrence, and a greater likelihood of benefit from chemotherapy.  Similarly, the Mammaprint® assay analyzes 70 genes important in breast cancer, and assigns patients to either a low- or high-risk group.  Patients in the low-risk group have a lower risk of recurrence compared to those in the high-risk group.  Trials evaluating the predictive benefit from chemotherapy are ongoing.

Treatment of cancer with targeted, or biologic therapies is a rapidly growing field of oncology research.  There are many antibodies and small molecule inhibitors available for the treatment of various tumor types in different settings.  Most of the benefits seen from targeted agents involve their use in conjunction with, rather than in place of, chemotherapy.  Trastuzumab (Herceptin®) is the most widely used targeted therapy in breast cancer outside of endocrine therapy.  Trastuzumab is a monoclonal antibody against the HER2 protein, which is over expressed in 25% of breast cancers.  When used in combination with adjuvant chemotherapy, trastuzumab confers a 50% relative-risk reduction in recurrence above the benefit seen with chemotherapy alone.  Emerging data shows that even very small tumors (less than 1 cm), which would not typically be treated with chemotherapy, experience that same magnitude of benefit when treated with trastuzumab in combination with chemotherapy.  To date, there is no data to support the use of trastuzumab without chemotherapy in the adjuvant setting.

Two other targeted agents have more recently become available for the treatment of metastatic breast cancer.  Trials are ongoing to evaluate their role in the adjuvant treatment of early stage breast cancer.  Lapatinib (Tykerb®) is a small molecule inhibitor against HER2 as well as EGFR (epidermal growth factor receptor).  In combination with chemotherapy, lapatinib has been shown to be effective in the treatment of HER2-positive metastatic breast cancer that has progressed through trastuzumab-based treatment.  Bevacizumab (Avastin®) is a monoclonal antibody against VEGFR (vascular endothelial growth factor receptor), and has also been shown, in combination with chemotherapy, to be effective in the treatment of metastatic breast cancer.  Bevacizumab is used to treat many other tumor types as well, and is currently being evaluated in the adjuvant treatment of “triple-negative” early stage breast cancer – breast cancer that does not express hormone receptors or HER2.

Recently, trials studying zoledronic acid, or ZometaÒ, a bisphosphonate used for the treatment of osteoporosis and bone metastases, have shown a significant improvement in breast cancer recurrence when given in the adjuvant setting to women with early stage breast cancer every six months for about three years.  This represents another major breakthrough in breast cancer treatment.

Breast cancer research and treatment is a dynamic field, with multiple ongoing clinical trials and many new diagnostic and treatment modalities available.  It is this progressive research that has led to decreased mortality from breast cancer and higher cure rates for our patients.

 

Tiffany H. Svahn, MD received her medical oncology training at Stanford University.  She now practices at Diablo Valley Oncology and Hematology Medical Group which is part of the California Cancer and Research Institute in Pleasant Hill. She is on the medical staff of John Muir Medical Center in both Walnut Creek and Concord, and the medical staff at San Ramon Regional Medical Center.  Dr. Svahn specializes in the treatment of breast cancer.

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