Bisphosphonates in the adjuvant treatment of early breast cancer

Bisphosphonates are the standard of care for preventing skeletal morbidity and treating hypercalcemia of malignancy in patients with bone metastases. Zoledronic acid (intravenous; 4 mg monthly) is approved to prevent skeletal-related events in patients with bone metastases from several tumor types, and can improve survival in some subsets of patients with skeletal metastases and high baseline bone turnover. In the adjuvant setting, bisphosphonates have shown clinical efficacy for preventing cancer treatment-induced bone loss and promise for reducing disease recurrence. For example, early studies of clodronate showed the potential for bisphosphonates to prevent bone metastases and prolong survival, but results with clodronate have been inconsistent. Recently, the more active bisphosphonate zoledronic acid (4 mg every 6 months) prevented bone loss and significantly reduced the risk of disease-free survival events by 36% (P = 0.01) compared with adjuvant endocrine therapy alone in a large phase III trial (n = 1,803) in premenopausal women with early breast cancer [1]. Notably, these benefits were not limited to bone because the addition of zoledronic acid reduced disease recurrence at all sites. This fuels the See-and-Soil hypothesis about dormant tumor (stem) cells in early disease, and hints towards a potential impact of bisphosphonate treatment on the bone marrow microenvironment. These results of twice-yearly zoledronic acid have been confirmed indirectly in bone-protection trials in postmenopausal patients [2]. In addition, several ongoing trials (involving more than 20,000 patients altogether) are evaluating the efficacy of bisphosphonates for the prevention of metastases in breast, prostate, and lung cancers, and multiple myeloma. Results from these studies are likely to expand the role of bisphosphonates, particularly zoledronic acid, in the adjuvant therapy setting, and help us in elucidating the underlying biology as well as resolving open clinical questions.