Bisphosphonates and denosumab (Xgeva) are approved by the US Food and Drug Administration to reduce the risk of skeletal-related events in breast cancer patients with bone metastases, and for the treatment of osteoporosis.[1] Preclinical studies and emerging clinical observations have suggested that, in addition to improving bone health, bisphosphonates may possess inherent antitumor activity and be synergistic with chemotherapy.[2] Data have been reported from adjuvant breast cancer clinical trials evaluating the oral bisphosphonates clodronate and ibandronate (Boniva)[3-6] as well as the intravenous bisphosphonates zoledronic acid(Drug information on zoledronic acid) and pamidronate(Drug information on pamidronate),[7-11] with mixed results.
The review article by Drs. Figueroa-Magalhães 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-Magalhães and Miller emphasize 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-Magalhães 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, scheduling, time of initiation, and duration of therapy are not known.[16]
Additional noteworthy reports include the recent clinical outcomes data from the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.37 clinical trial.[17] This prospective clinical trial randomized 7576 postmenopausal women to anastrozole(Drug information on anastrozole) (Arimidex) or exemestane(Drug information on exemestane) (Aromasin) for 5 years. An exploratory subset analysis evaluating 1294 patients on (unspecified) osteoporosis therapy found a significant improvement in event-free survival (hazard ratio [HR] = 0.7; P < .00001). Similarly, epidemiologic studies have suggested that the use of bisphosphonates for osteoporosis may decrease the risk of developing breast cancer.[18] As mentioned by Figueroa-Magalhães and Miller, the Southwest Oncology Group trial S0307, which randomized patients with stage I to III breast cancer to 3 years of zoledronic acid, clodronate, or ibandronate, in addition to standard adjuvant therapy, closed to accrual in February 2010.[19] In addition, a phase III clinical trial investigating the impact of denosumab on breast cancer recurrence is ongoing.[20] The primary data and correlative analyses from these, and other, clinical trials are eagerly awaited.
It is conceivable that bone-modifying agents impact the viability of tumor cells, through osteoclast inhibition or an unformulated mechanism. We believe that addressing such fundamental questions is an opportunity to learn about bone biology, cancer metastasis, and bone-modifying agents. Until more data are available, we reserve bisphosphonates for women with evidence of decreased bone mineral density who are at increased risk of fracture and for those on clinical trials.
Financial Disclosure: Dr. Van Poznak has received research funding from Amgen and Novartis. Dr. Barginear has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
