Vironment affecting itsFigure 3 Overall survival analysis with regard to detection of
Vironment affecting itsFigure 3 Overall survival analysis with regard to detection of persistent disseminated tumor cells at 12 months after diagnosis.Banys et al. BMC Cancer 2013, 13:480 http://www.biomedcentral.com/1471-2407/13/Page 6 ofFigure 4 Proportion of patients with DTC-positive bone marrow at 12 and 24 months after diagnosis.recent data indicate that nitrogen-containing BP can inhibit the proliferation of human cancer cell lines and induce their apoptosis [26]. Data from animal studies confirm that BP exert potent effects on visceral metastases as well [27,29]. These reports suggest that BP affect the invasive behavior of metastatic cells in secondary sites through both direct and indirect effects and have the ability to interact with tumor cells at each step of the metastatic process.Clinical relevance of bisphosphonate treatment in adjuvant settingThe presence of DTC correlates significantly with increased risks of distant metastasis, locoregional recurrence, and death in breast cancer patients [1,30]. Therefore, treatment strategies that target DTC in BM may potentially improve disease-free and overall survival. We hypothesize that bisphosphonates affect the role of bone marrow as a suitable microenvironment for DTCs. Indeed, protective effects of bisphosphonates were reported in clinical trials exploring ZOL as adjuvant therapy in early breast cancer. Three large prospective studies evaluated the impact of addition of ZOL to systemic treatment on survival (Table 4) [6,8,31]. The randomized open-label Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial (NCT00295646) evaluated the influence of adding ZOL to adjuvant endocrine therapy [31]. In this fourarm trial, 1,803 premenopausal women with hormone receptor positive early stage (stage I-II) breast cancer were randomized to receive goserelin 3.6 mg every 28 Olumacostat glasaretil cost PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/26780312 days plus either tamoxifen 20 mg daily PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27766426 or anastrozole 1 mg daily, with or without ZOL 4 mg every 6 months for 3 years. At a median follow-up of 62 months, the addition of ZOL reduced risk of disease-free survival events compared with endocrine therapy alone (p = 0.009). The reduction in recurrence was observed locally and distantlyboth in and outside the bone. The risk of death was also reduced but did not reach statistical significance, although it approached significance in women older than 40 years (p = 0.057). In the Zometa-Femara Adjuvant Synergy Trials (Z-FAST/ ZO-FAST/E-ZO-FAST), designed to investigate the boneprotective effects of zoledronic acid, an exploratory analysis was conducted to assess the anticancer potential of zoledronic acid. A total of 2,194 postmenopausal women with hormoneresponsive early breast cancer received letrozole 2.5 mg daily [6]. Patients were randomized to receive zoledronic acid 4 mg administered every 6 months for 5 years starting either upon randomization (up-front) or upon a predetermined measure of bone loss (delayed start). After 36 months of follow-up, a 34 reduced incidence of disease-free survival (DFS) events with up-front zoledronic acid treatment compared with delayed treatment was observed in the ZO-FAST trial (P = 0.0375). These studies show a DFS benefit or overall survival (OS) benefit in postmenopausal women or women who have chemical ovarian suppression. In contrast to ABCSG-12 and ZO-FAST trials, the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE; BIG 01/04) trial (NCT00072020) did not show a benefit from adding bisphosphonates to adjuvant therap.