br Materials and methods br
Materials and methods
Discussion This retrospective analysis examined data from patients with early breast cancer treated over a 12-year period (1997–2009) in a real-world setting. The proportion of patients receiving adjuvant BP therapy dramatically increased during the study period, from <2% in 1997 to nearly 100% in 2009 (Fig. 1), presumably because of proactive management of bone health and accumulating evidence of the potential anticancer benefits of BPs [18,19,24–26]. For example, the earliest clinical evidence of such benefits, demonstrated with clodronate, contributed to a modest increase in BP use of approximately 10% in 1998 and 1999. In 2001 and 2002, BP use more than doubled with the introduction of zoledronic acid. Moreover, initial reports from the Austrian Breast and Colorectal Cancer Study Group-12 (ABCSG-12) and Zometa–Femara Adjuvant Synergy Trial (ZO-FAST) trials of the anticancer potential of zoledronic Ketorolac tromethamine salt cost increased BP use to 90% or more in 2008 and 2009. Our analysis revealed that BP therapy initiated within 1 year of breast cancer diagnosis and continued for at least 3 months was associated with significantly prolonged DFS compared with no BP therapy in women receiving adjuvant therapy for early breast cancer. The benefits of adjuvant BP therapy appear more pronounced in women with hormone receptor-positive vs. hormone receptor-negative tumors and increased with the extent of lymph node involvement; indeed, even OS benefits could be observed in this patient subgroup. These findings are consistent with those of previous clinical trials evaluating anticancer benefits with BPs in the adjuvant breast cancer setting [18,19,27,28]. To date, the most promising data on the potential anticancer benefits of BPs have been reported with zoledronic acid. Three clinical trials have directly assessed the effects of adjuvant zoledronic acid on disease recurrence and survival in women receiving various adjuvant therapies for breast cancer. In the ABCSG-12 trial, 1803 premenopausal women with hormone receptor-positive early breast cancer received ovarian suppression with the gonadotropin-releasing hormone analogue goserelin and were treated with tamoxifen or anastrozole with or without zoledronic acid for 3 years . At a median follow-up of 48 months, the combination of zoledronic acid plus endocrine therapy significantly reduced the relative risk of disease progression by 36% (HR=0.64; P=0.01) and the risk of recurrence by 35% (HR=0.65; P=0.01) compared with endocrine therapy alone. These zoledronic acid benefits were maintained at the 84-month follow-up, more than 5 years after treatment completion, for both DFS (HR=0.72; P=0.014) and OS (HR=0.63; P=0.049), and were greatest among women >40 years of age at study entry compared with women ≤40 years of age (DFS: HR=0.66, P=0.013; OS: HR=0.57, P=0.042) . The ZO-FAST trial evaluated the effects of immediate versus delayed zoledronic acid on bone mineral density, disease recurrence, and survival in 1065 postmenopausal women with hormone receptor-positive early breast cancer who received adjuvant therapy with letrozole . Compared with delayed zoledronic acid treatment, immediate zoledronic acid was associated with a significant 41% reduction in the risk of DFS events (HR=0.59; P=0.0314) at 36 months , and continued to reduce the risk at 60 months (HR=0.66; P=0.0375) . Treatment with immediate zoledronic acid reduced both skeletal and nonskeletal DFS events compared with delayed zoledronic acid . In contrast, in the AZURE trial (N=3360) in women with breast cancer who received standard adjuvant systemic therapy (including endocrine therapy), zoledronic acid therapy did not show a survival benefit at 59 months in the overall population . However, prespecified subgroup analyses in women who had been postmenopausal for more than 5 years at baseline (N=1041) showed that adding zoledronic acid significantly improved invasive DFS (HR=0.75; P=0.02) and OS (HR=0.74; P=0.04) [23,28]. In contrast to our retrospective analysis, the beneficial effects of zoledronic acid on disease recurrence and survival outcomes in the postmenopausal subset in AZURE were independent of hormone-receptor status and the extent of lymph node involvement (all study participants in AZURE were node positive at study entry) . Data from these trials suggest that estrogen effects on the bone microenvironment may play a role in determining the characteristics of patients most likely to benefit from adjuvant zoledronic acid therapy. Therefore, patients with hormone receptor-negative disease in our analysis likely did not benefit from BP therapy because they did not receive endocrine therapy and consequently would have had higher estrogen levels. Ongoing trials evaluating bone-targeted therapies in the adjuvant setting for anticancer benefits include denosumab in women with high-risk early breast cancer receiving neoadjuvant or adjuvant therapy (D-CARE)  and zoledronic acid, clodronate, and ibandronate in women with stage 1, 2, or 3 breast cancer receiving adjuvant therapy after surgery .