Sixty is the new forty--or is it the other way around?

The review article by Drs. Figueroa-Magalhäes and Miller provides a concise description of adjuvant bisphosphonate studies and contains well-constructed summary tables. [12] The authors review preclinical data suggesting that bisphosphonates can inhibit angiogenesis, prevent tumor cell invasion and adhesion in bone, and induce tumor cell apoptosis. They provide the current evidence for use of bone-modifying agents as part of adjuvant treatment in patients with early-stage breast cancer, [12] highlighting the potential benefit of adjuvant bisphosphonate in postmenopausal and/or older women as noted in subset analyses. Figueroa-Magalhäes and Miller emphasi2e the results of the Austrian Breast and Colorectal Cancer Study Group 12 (ABCSG- 12) [9] and the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trials, [11] as they discuss the potential benefit of off-label use of zoledronic acid in the adjuvant setting in postmenopausal women. It is perplexing that the prospectively collected data from the adjuvant bisphosphonate studies need to be scrutinized to find subsets of patients who may gain potential benefit and that bone metastases are not significantly affected. At present, the subset analyses are hypothesis-generating. Much is being made of the theory of the "low-estrogen state,"[13] but it is difficult to accept that women treated with 3 years of ovarian ablation are the "menopausal equivalent" of women who are more than 5 years postmenopausal. The cutoff for "older" in the adjuvant bisphosphonate studies may be 40, 50, or 60 years of age, depending on the study and the subset analysis. Although not discussed by Figueroa-Magalhäes and Miller, the randomized phase II study of zoledronic acid (neo)adjuvant therapy in women with clinical stage II/ III breast cancer suggests that at a median follow-up of 62 months, addition of zoledronic acid to standard therapy improved disease-free and overall survival only in women with estrogen receptor-negative tumors.[14] The suggestion that the estrogen status of tumor may impact the significance of bisphosphonate therapy is consistent with the findings of Park et al in metastatic breast cancer. [15] The variability within the studies and their analyses does not build a cohesive argument for a specific patient population likely to benefit from a specific adjuvant bisphosphonate therapy. At present, if bisphosphonates do alter the course of breast cancer in certain subsets, the most advantageous drug, dose, schedu