Osteoclast inhibition in postmenopausal breast cancer: Is the evidence too strong to ignore?

With the recognized heterogeneity and plasticity of tumor cells, efforts to target the genetically stable cells that compose the tumor microenvironment are emerging as an effective anticancer therapeutic approach. The recent enthusiasm for immunotherapies, antiangiogenics, and bone-targeted agents is a direct outcome of the realization that targeting the normal cells that support tumor growth and progression may yield more effective and durable responses for treating cancer and preventing metastasis than standard cytotoxic or tumor-directed targeted therapies. In particular, bone-targeted agents have been proven to be well tolerated by postmenopausal breast cancer patients with estrogen receptor–positive tumors with associated benefits of improved bone mineral density and reduced fractures. The evidence in favor of the benefit of bone-targeted agents is furthered by the recent findings of Lipton et al. In their post hoc analysis of the MA.27 adjuvant trial, the authors examine the effects of oral osteoporosis therapy (OPT) on the primary endpoint of event-free survival (EFS) and the secondary endpoint of distant disease–free survival (DDFS) in 7576 postmenopausal women with hormone receptor–positive early-stage breast cancer randomized to aromatase inhibitor (AI) therapy with either anastrozole or exemestane in the adjuvant setting. The diagnosis of osteoporosis and the use of OPT were self-reported, with bone mineral density reports available for the majority of patients. The use, duration, and choice of OPT were determined by the treating physician, and the OPT was predominantly oral bisphosphonates, with a few patients receiving the selective estrogen receptor modulator raloxifene. In MA.27, postmenopausal women with early disease on AI therapy who were receiving OPT had significantly improved EFS and DDFS with hazard ratios of 0.67 and 0.57, respectively, in comparison with patients not receiving OPT. The effect of OPT on DDFS was observed only in patients who had bone metastases as their first metastatic event with no significant difference for patients who developed visceral metastases as their first recurrence. Because the MA.27 trial was restricted to postmenopausal patients, a lack of effect on visceral metastasis affirms the safety of these agents for exclusive use in postmenopausal women. This contrasts with their use in premenopausal women: some trials testing bisphosphonates in the adjuvant setting have reported an increase in visceral metastases in younger or premenopausal women receiving adjuvant bisphosphonate therapy. Because of the limitations of the MA.27 study, including the variable duration and choice of OPT, the relatively low numbers of EFS events (693 total events, of which 493 were breast cancer–related) and DDFS events (313 total events), and the short median follow-up of 4.1 years, it is best to view these results in the setting of the larger literature on bone-targeted agents for patients with early-stage breast cancer. There have now been at least 10 major adjuvant trials as well as several meta-analyses examining the role of bisphosphonates in the prevention of breast cancer metastases. They include the report from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which encompassed individual patient data from more than 18,500 randomized women. Consistently, the positive effect of bisphosphonates in preventing bone metastases has been confined to women in a definitively postmenopausal or low-estrogen state. The definition of postmenopausal status has been variable in clinical trials, with cutoffs for menopausal status varying from an age older than 50 years [National Surgical Adjuvant Breast and Bowel Project (NSABP)-34 trial] to an age 5 years after menopause or an age older than 60 years (AZURE/BIG 1-04) to an age> 55 years (the EBCTCG meta-analysis) to an age older than 40 years among premenopausal women receiving a