The Role of Targeted Therapy in Breast Cancer Treatment
by Tejal A. Patel, MD, and Edith A. Perez, MD
Targeted therapies form the mainstay of current treatment for women with breast cancer. Each form of targeted therapy functions by blocking a specific protein or pathway and interfering with the ability of the cancer cell to grow, divide, and metastasize. The four general types of targeted treatments currently used in breast cancer are directed against estrogen, HER2, angiogenesis, and apoptosis:
Anti-estrogen therapies target hormone-receptor (estrogen or progesterone) positive breast cancers, as they are partially dependent on signals from estrogen to grow. By reducing the amount of estrogen in the body or blocking the effects of estrogen, anti-estrogen therapy can slow the growth or shrink hormone receptor positive cancers.
Tamoxifen (Nolvadex®) is the oldest and arguably best-characterized targeted therapy. For pre-menopausal women with hormone positive breast cancers, five years of tamoxifen after surgery (called adjuvant therapy) significantly reduces the risk of recurrent breast cancer and improves survival. It is also an active therapy in advanced (metastatic) disease. This agent is well tolerated in most women, although some possible side effects can include hot flashes, depression, and slightly increased risk of blood clots and uterine cancer.
Aromatase inhibitors block the estrogen produced in the adrenal gland, the main source of estrogen in post-menopausal women. Three aromatase inhibitors commercially available are Arimidex® (anastrozole), Aromasin® (exemestane), and Femara® (letrozole). In post-menopausal women with hormone receptor positive breast cancers, adjuvant aromatase inhibitors are part of standard treatment in the majority of cases. They are also used as active therapy in advanced disease. Although generally well tolerated, notable side effects can include hot flashes, joint pain, and thinning of bones (called osteopenia or osteoporosis).
The HER receptor family consists of four closely related proteins: HER1, HER2, HER3, and HER4. The HER2 growth signal receptor is abnormally over-expressed in about 15 percent to 20 percent of breast cancer cases. HER2-positive breast cancers tend to grow and spread more aggressively than those that are HER2-normal.
Trastuzumab (Herceptin®) is an intravenous treatment that blocks the HER2 receptor protein, preventing the cells from multiplying. It may also stimulate the immune system to attack the cancer more effectively. Trastuzumab can reduce breast cancer recurrence by as much as 50 percent when given after breast cancer surgery along with chemotherapy. This agent is well tolerated and part of standard treatment after surgery or for women with advanced HER2-positive disease. Due to a possible side effect of heart failure in about 0.5 percent to 4 percent of women, periodic heart evaluation should be performed during treatment.
Lapatinib (Tykerb®) targets two members of the HER family – HER1 and HER2 – and is available in tablet form. In women with advanced breast cancer who have been previously treated with trastuzumab, the combination of lapatinib and capecitabine lengthens the amount of time before cancer growth, compared with capecitabine chemotherapy alone. Clinical trials are ongoing to evaluate its use earlier in the disease as part of adjuvant therapy. The possible side effects of lapatinib include diarrhea, skin rash, and elevated liver function tests.
Dr. Edith Perez
Anti-angiogenesis is defined as the growth of new blood vessels (“angio” means blood vessel, and “genesis” means beginning). This process is felt to be necessary for growth of tumor beyond certain size and is stimulated by a protein called vascular endothelial growth factor (VEGF).
Bevacizumab (Avastin®) is a monoclonal antibody used against VEGF. Targeting VEGF may also normalize the blood vessels within the tumor, improving delivery of chemotherapy. There is documented benefit of the addition of bevacizumab to Paclitaxel (Taxol®) or docetaxel (Taxotere®) in women with advanced breast cancer. Although most women tolerate the drug well, possible side effects include high blood pressure and blood clots, as well as, rarely, bowel perforation and protein in the urine. Clinical trials are ongoing to evaluate its use in earlier stages of breast cancer.
Apoptosis is a programmed sequence of events leading to the death of cells without the release of harmful substances. Most available chemotherapy agents work via this mechanism. Novel and pro-apoptotic agents are currently undergoing evaluation.
Targeted therapies are already an important component of breast cancer therapy, and newer agents matched with prognostic and predictive markers are paving the way toward individualized chemotherapy. Designing, conducting, and participating in clinical trials is instrumental in the timely and efficient evaluation of novel targeted approaches to improve the outcomes of women with breast cancer.
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Dr. Tejal Patel is a fellow in Hematology/Oncology, and Dr. Edith Perez is the named Serene M. and Frances C. Durling Professor of Medicine, director of the Breast Program, and chair of the Cancer Clinical Study Unit, both at the Mayo Clinic in Jacksonville, FL.
This article was originally published in Coping® with Cancer magazine, September/October 2009.
Coping® does not endorse or recommend any particular treatment protocol for readers, and this article does not necessarily include information on all available treatments. Articles are written to enlighten and motivate readers to discuss the issues with their physicians. Coping believes readers should determine the best treatment protocol based on physicians’ recommendations and their own needs, assessments and desires.