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  • Preference for injectable therapy over oral therapy contrary

    2019-04-17

    Preference for injectable therapy over oral therapy [17], contrary to our findings from a previous study [18], could reflect the fact that most patients have not received an oral bone-targeted agent for metastatic disease. However, the practical advantages of an injectable therapy and the lack of need for extra-care (taking the medication with water, not laying down shortly after PO administration) in an elderly patient population should not be ovelooked. There are limitations to our study. Our sample was recruited from two cancer centres in Ontario, Canada and therefore reflects prescriptions practices in that Province. In addition, as the REB requirement was to allow no patient identifiers on the questionnaires, we could not tell how common it was for patients to refuse participation (i.e. in place of a denominator for response rate, which we do not have). As a consequence, it is possible that our responding cohort consists of better informed, more motivated patients which may not be representative of all patients receiving treatment with bone targeted agents. This too could be reflected by the large number of breast cancer patients who are already receiving 3-monthly bone-targeted therapy [2].
    Conclusion
    Conflict of interest statement
    Introduction The occurrence of osteolytic lesions remains a feared long term complication in patients with breast cancer. Amino-bisphosphonates (BP) are a class of antiresorptive agents approved for the treatment of metastatic bone disease [1,2]. BP act via inhibition of the FPP-synthase, which is a key enzyme of the mevalonate pathway [3]. Aside from their potent antiresorptive properties, BP have been associated with a direct antitumor potential. In vitro, BP induce apoptosis and decrease proliferation and invasion of tumor cells [4]. While these results were confirmed in a number of preclinical in vivo models, results from two large clinical trials have yielded varying results regarding the adjuvant use of zoledronic nvp-aew541 in breast cancer patients [5,6]. One trial showed a significant reduction in the risk of disease progression in patients receiving zoledronic acid in addition to endocrine therapy compared to endocrine therapy alone in hormone-responsive breast cancer [5]. The other trial assessed the response of breast cancer patients with different hormone receptor expression and menopausal status to zoledronic acid in addition to their standard adjuvant treatment. This study failed to provide evidence to support the routine use of zoledronic acid in the adjuvant management of breast cancer [6]. One of the proposed antitumor effects of BP is their anti-angiogenic potential. A number of studies have shown that serum levels of VEGF decrease in tumor patients following treatment with bisphosphonates [7,8]. In one case, serum concentrations of VEGF were shown to be suppressed as early as 7 days after the first infusion of zoledronic acid and remained suppressed for the duration of the study, 84 days after the first infusion [7]. The finding of anti-angiogenic effects of these agents was further supported by the finding that bisphosphonates inhibited tumor vascularization in murine models of prostate carcinoma, melanoma and myeloma [9–11]. However, these results could not be confirmed in all studies and in some studies VEGF levels remained unaffected [12]. The molecular mechanisms responsible for these effects have not been looked at in detail. It remains unclear, if the observed regulation on VEGF is mediated via direct effects on cancer cells or by effects on other cells such as macrophages or endothelial cells.
    Materials and methods
    Results
    Discussion This study investigated VEGF expression in breast cancer cells following exposure to mevalonate inhibitors. An anti-angiogenic potential of bisphosphonates is generally assumed as several studies have reported decreased serum VEGF levels in patients following treatment with bisphosphonates [14]. This is line with the decrease in serum VEGF levels observed in our pilot study. Although the number of patients included in our study is too low to draw conclusions, it underlines VEGF as a target of the mevalonate pathway. Results from this study require validation in larger trial. Unlike serum assessment of VEGF, direct effects of BP on VEGF production by tumor cells has not been evaluated in detail. Unexpectedly, we did not observe a decrease in breast cancer-derived VEGF mRNA or protein levels following treatment with zoledronic acid or atorvastatin. Instead, both agents resulted in significant increases of VEGF levels in all cell lines tested. It is currently unclear which cell types are mainly responsible for the commonly observed changes in serum VEGF following the treatment of cancer patients with bisphosphonates. It is known that bisphosphonates have direct effects on endothelial cells by inhibiting proliferation sensitizing them to TNF-induced cell death [15]. VEGF levels have also been described to be supressed by zoledronic acid in myeloma-associated macrophages, an effect that was enhanced by co-treatment with the proteasome inhibitor bortezomib [16]. Little is known about the direct effects of zoledronic acid tumor cells. In this study, we show that different breast cancer cell lines increase VEGF levels following exposure to bisphosphonates. However, concentrations needed to achieve significant effects on VEGF were high and comparable to those previously shown to induce apoptosis and growth inhibition [17]. The in vitro concentrations used in our experiments exceeded those normally achievable in clinical routine. While this limits the direct translational relevance of our study, it is noteworthy that zoledronic acid, even when applied in low concentrations, did not suppress VEGF in breast cancer cells. To our knowledge there are no data from animal studies indicating that zoledronic acid increases angiogenesis following zoledronic treatment. However, even when high doses of zoledronic acid are used in animal models, these may still not reach the concentrations required to see effects in vitro. VEGF not only induces vascularization but also acts as a direct survival factor for tumor cells including breast cancer [18]. VEGF has been shown to prevent radiation-induced apoptosis [19] and to up-regulate Bcl-2 [20]. As the concentrations used in this study also increased apoptosis, one explanation may be that the VEGF increase is a result of increased cellular stress. This idea is supported by the finding that VEGF levels were normalized when protein prenylation is restored by supplementation of GGPP. As breast cancer VEGF levels stay unchanged at low levels and increase with high concentrations of zoledronic acid, our study provides some limited evidence that the decreases in VEGF serum levels following BP exposure results from a regulation of other cell types than the tumor cells.