Clinical benefits of bone targeted agents in early breast cancer

Through their profound effects on the bone microenvironment, bone targeted treatments can potentially modify the process of metastasis and have important effects on disease outcomes as well as on bone health. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) evaluated the effect of adjuvant bisphosphonates in early breast cancer by performing a meta-analysis of individual patient data (n = 18,766) from all available randomized trials initiated between the early 1990s until 2006. In postmenopausal women, bisphosphonates reduced bone recurrence (RR = 0.72; 95%CI 0.60-0.86, 2p = 0.0002) and breast cancer mortality (0.82; 95%CI 0.73-0.93, 2p = 0.002); no effects on disease outcomes could be identified in premenopausal women. Somewhat surprisingly, these effects could not be reproduced in the large adjuvant trial of denosumab (DCARE). In this study, neither bone metastasis free survival (the primary endpoint) or disease-free survival were improved by the addition of this targeted antibody inhibitor of osteoclast activity. Efforts are ongoing to try to understand the biologic implications of these results. For now, the use of denosumab in early cancers is limited to its use for fracture prevention using the 60mg every 6 months dosing schedule.