Advanced, metastatic breast cancer may be found at the time of initial diagnosis or may follow a recurrence of the disease. The cancer spreads most often to bone, lung, and liver tissue. Metastatic cancer can respond to treatment, and remission of the cancer can last for years. The goals for treatment of advanced breast cancer are to stabilize the disease, to extend life as long as possible, and to reduce complications such that an acceptable quality of life can be maintained.

When cancer spreads to bone, the resulting bone destruction is associated with a variety of skeletal complications. In addition, many of the treatments necessary to control the cancer may themselves cause an increased rate of bone loss, leading to osteoporosis and an increased risk of fracture. Osteoporosis in patients with breast cancer is likely to be of growing importance because of the increasing incidence of the disease and significant improvements in survival as a result of aggressive and intensive treatments.

Treatments that may be used in women with metastatic breast cancer include:

• Chemotherapy to shrink the tumor and stop its growth
• Hormonal therapy to interfere with growth of the tumor
• Radiation therapy to shrink the tumor and provide pain relief
• Medication to control pain
• Nutrition and supplement regimens

Patients' considerations, such as convenience, compliance, and personal decisions regarding treatment, are important. Also important are a review of potential toxicities associated with treatment that may affect normal function and other side effects such as the potential for alopecia and the possible need for an intravenous port.

Selecting a chemotherapeutic agent for use in metastatic breast cancer may include a review of the activity of the drug, the patients' prior therapy and performance status, and comorbidities, the results of which may suggest the benefit of one therapy over that of another.

Treatment options may be single-agent choices or a combination of agents. Some agents in use and the classes to which they belong include¹:

• Doxorubicin and epirubicin (anthracyclines)
• Paclitaxel and docetaxel (taxanes)
• Capecitabine (5-fluoropyrimidine analogue)
• Gemcitabine (nucleoside analogue)
• Vinorelbine (vinca alkaloid)
• Cyclophosphamide and cisplatin (alkykating agents)
• Methotrexate (antifolate)¹

See Table 1.

Estrogen is the master growth hormone upon which normal breast cells and most of the breast cancer cells depend for growth and proliferation. Therapeutic agents focused on endocrine or hormone regulation are based on either blocking estrogen production or blocking estrogen action once.² Estrogen production may be blocked by ovarian ablation or other major endocrine ablations and/or use of aromatase inhibitors. Aromatase converts androgens into estrogens in postmenopausal women. Anastrozole, letrozole, and exemestane are the aromatase inhibitors that are currently available.

Blocking estrogen action once the hormone is available is accomplished using selective estrogen receptor modulators (SERMs) and selective estrogen receptor down regulators (SERDs). For example, tamoxifen blocks estrogen from binding to tumor cells and retards tumor growth except in estrogen-negative tumors.²

In premenopausal women, a SERM is indicated. In postmenopausal women, a SERM or an aromatase inhibitor can be used. For women with metastatic breast cancer who are premenopausal, ovarian ablation will stop primary estrogen production; but in postmenopausal women, an aromatase inhibitor or antiestrogen may be used, depending on previous treatment,^2,3 to block conversion from androgens to estrogen.

Third-line therapy for postmenopausal women includes either a SERD or a progestin; for premenopausal women it is an aromatase inhibitor, after ovarian ablation. In the presence of intact ovarian function, there is no role for aromatase inhibitors.²

Considerable research is being done to develop targeted therapies to treat breast cancer and other cancers. The targets are crucial to the tumor's malignant phenotype but not to that of the host's normal tissues. One such target is the HER2 receptor, and the approved therapy is the anti-HER2 antibody trastuzumab for use in patients with HER2-overexpressing metastatic breast cancer. Other targeted therapies are still under investigation.⁴

The use of bisphosphonate therapy in breast cancer is finding increased interest and an expansion of research efforts. The rationale is based on the growing numbers of and needs in women with breast cancer. Increasing long-term survival puts a greater the emphasis on patient quality of life.⁵

Metastatic bone disease is associated with pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy, all of which affect the management of advanced cancer. Adjuvant chemotherapies and hormonal therapies make their own contribution to bone loss.⁵

Bisphosphonates have demonstrated important benefits in the management of women with metastatic breast cancer in the following ways^5,6:

• Treatment of malignancy-related hypercalcaemia
• Analgesic effect on metastatic bone pain
• Reduction and delay in the development of skeletal-related morbidity in patients with osteolytic metastases
• Possible role in adjuvant therapy with the aim to prevent the development of skeletal metastases
• One of several options for the preservation of bone mineral density in women who undergo early menopause induced by adjuvant cytotoxic therapy

Summary results of randomized clinical trials that tested bisphosphonates for bone metastases in breast cancer patients and showed the value of bisphosphonate therapy are presented in the table below.⁷

SMR = skeletal morbidity rate; SRE = skeletal-related event, ie, radiotherapy for bone pain or impending fracture, pathologic fracture, hypercalcaemia of malignancy, spinal cord compression, need for orthopedic surgery. *Not a placebo-controlled study. ^†Evaluation blinded. PO = by mouth; IV = intravenous.

Adapted from Coleman RE. Oncologist. 2000;5:463-470.

1.	Breast cancer chemotherapy: new chemotherapeutic and targeted biologic regimens. Available at http://www.medceu.com/tests/breastchemo.htm. Accessed December 2004.
2.	Life Extension Foundation. LifeExtension: Breast Cancer. Available at www.lef.org/protocols/prtcls-txt/t-prtcl-022.html. Accessed December 2004.
3.	National Cancer Institute. Aromatase Inhibitors. Available at http://www.nci.nih.gov/clinicaltrials/developments/ aromatase-inhibitors-digest/allpages/print. Accessed December 2004.
4.	Houck W, Miller KD, Schneider BP. Targeting HER2, EGFR, and VEGF in breast cancer: therapeutic potential and current results. http://www.medscape.com/viewprogram/2208. Accessed December 2004.
5.	Van Poznak, CH. The use of bisphosphonates in patients with breast cancer. Cancer Control. 2002;9:480-489.
6.	Brown JE, Neville-Webbe H, Coleman RE. The role of bisphosphonates in breast cancer and prostate cancer. Endocr Relat Cancer. 2004;11:207-224.
7.	Coleman RE. Management of bone metastases. Oncologist. 2000;5:463-470.