An effective way to prevent skeletal-related events is to treat the cancer itself. However, the unique biology of bone metastasis warrants specific treatment approaches. Although radiopharmaceuticals are sometimes used to control bone pain, systemic treatment of patients with bone metastases is primarily with the use of bisphosphonates. The achieved mechanism of action for bisphosphonates is not well understood; however, they appear to exert their therapeutic effects through osteoclast activity.

Although bisphosphonates are valuable agents in reducing the risk of skeletal-related events in breast cancer patients, it is clear that improved treatments are needed. Despite the initiation of a bisphosphonate therapy, up to two-thirds of breast cancer patients will experience a skeletal-related event. The benefits of bisphosphonate therapy are also time-dependent; the reduction in skeletal-related morbidity is generally observed after 6 months of therapy. Moreover, the use of bisphosphonates has been associated with severe adverse events, including renal impairment, hypocalcaemia and osteonecrosis of the jaw. Generally, bisphosphonates have not been shown to increase survival in breast cancer patients with bone metastases.

There are currently several bisphosphonates that have been approved in the US for the treatment of bone metastases in patients with breast cancer; however, it is unknown whether one bisphosphonate is clearly better than the others, when both efficacy and safety are considered. Outstanding questions regarding the use of bisphosphonates also include, when to start therapy, the duration of therapy, and which patients are likely to benefit from bisphosphonates. Thus, there is a need to review the clinical data regarding the use of bisphosphonates in the treatment of breast cancer patients with metastases to the bone and to discuss both efficacy and safety issues pertaining to the use of these agents.

The bone of patients with breast cancer can also be compromised with the use of aromatase inhibitors and other treatments that target the estrogen pathway. These agents have been shown to decrease bone mineral density, increase bone turnover markers and induce bone loss. Currently, breast cancer patients who receive aromatase inhibitors are also treated with bisphosphonates. Thus, there is a need to discuss the management of bone integrity in breast cancer patients who receive hormonal therapy.

Increased understanding of bone biology and the process of bone metastasis have led to the identification of a new molecular target for the development of drug therapies: RANK ligand. The expression of RANK ligand is stimulated by cancer cells upon metastasis to the bone. When RANK ligand is secreted, it activates a variety of osteotropic factors and induces osteoclast formation. By blocking RANK ligand, bone remodeling is inhibited. A phase II clinical trial of breast cancer patients with bone metastases revealed a reduction in bone turnover markers and an increase of the estimated time to first (on-study) skeletal-related event in patients who received an investigational monoclonal antibody targeting RANK ligand compared to patients who received IV bisphosphonates. Because RANK ligand is a new target for the treatment of patients with bone metastases, a review of the biology of RANK ligand and the results of clinical trials targeting RANK ligand is warranted. Currently, a phase III clinical trial to evaluate inhibition of RANK ligand for the treatment of breast cancer patients with bone metastases is underway.

A New Targeted Strategy for Treating Bone Metastases in Breast Cancer Patients: Inhibiting RANK Ligand

The format of this symposium is designed to maximize the use of adult learning principles. It employs highly interactive learning techniques, including baseline pre-and post-testing of the audience, and questions and answers between the audience and the faculty panel utilizing an interactive audience response system.

At the conclusion of this symposium participants will be able to:

1. Evaluate the effects of breast cancer metastasis on the molecular biology of the bone
2. Evaluate the impact that bisphosphonates and drugs that target the estrogen pathway have on bone integrity
3. Consider the impact of skeletal-related events on quality of life and overall survival in patients with breast cancer
4. Evaluate preclinical and clinical data on the inhibition of RANK ligand as a strategy to maintain bone health and integrity in breast cancer patients
5. Describe how you will change your practice and devise strategies of inhibition of RANK ligand into current treatment regimens for your breast cancer patients in order to maintain bone health and integrity

Not an official event of the 2008 Breast Cancer Symposium. Not sponsored or endorsed by ASCO or The ASCO Foundation