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  • The finding that baseline VEGF


    The finding that baseline VEGF in the Zamboney study was not associated with clinical outcomes are in Bleomycin Sulfate to other published studies. VEGF was previously shown to be associated with better treatment outcomes in metastatic breast cancer patients treated with bevacizumab [26,31]. This discrepancy may be due to the fact that 100% of patients enrolled in Zamboney had bone predominant metastases, while only ~60–70% of patients enrolled in the AVADO or AVEREL studies had metastases to bone. Alternatively, bevacizumab, which was used in the AVADO and AVERAL studies, is an antibody based therapeutic that binds VEGF ligands directly, while vandetanib is a receptor tyrosine kinase inhibitor that targets the VEGFR2 receptor along with other kinases. Also, as approximately 79% of Zamboney patients were either previously or concurrently treated with bisphosphonates at the time of study entry, this may further confound results, as bisphosphonate administration can result in decreased VEGF levels in patients [32]. The majority of Zamboney patients were also previously treated with either tamoxifen, which causes platelet release of VEGF, or aromatase inhibitors which have no effect on VEGF release [33]. This could also confound the results for VEGF levels obtained in serum at baseline study entry depending on whether patients were given tamoxifen versus aromatase inhibitors. The lack of association of the alternative measured bone biomarkers TGF-β or activinA with clinical outcome is supported by our recent findings in similar patient cohorts in other studies [34,35]. It is important to note that many of the putative predictive and pharmacodynamic markers used to assess response to anti-angiogenic therapies are differentially affected by concurrent treatments, and as such great care should be taken to consider these variables when performing such biomarker measures. The current sub-study is purely exploratory in nature and the current biomarker hypotheses were not pre-specified, nor was the study powered to detect significant differences in biomarkers or their associations. As such these results should be considered hypothesis generating. Our sample sizes are also relatively small, and due to study design, we were limited to measuring circulating biomarker levels at baseline. Further, over 20% of study patients declined participation in the correlative sub-study. Many studies have suggested that changes in biomarkers from baseline to on treatment are more predictive of treatment response [36–39]. In the current sub-study we were unable to interrogate this question, however given the possible association of sVEGFR2 with clinical outcome in bone metastatic breast cancer patients treated with an anti-angiogenic agent, changes in sVEGFR2 levels from baseline to on treatment should be evaluated in bone metastatic breast cancer patients in the future.
    Acknowledgments This work was funded by a grant to CLA from the Ontario Institute of Cancer Research High Impact Clinical Trials Program with support from the Government of Ontario.
    Introduction The Bone and Oncologist New Updates (BONUS) meeting is an annual conference, based in Canada that focuses on new advances in the multidisciplinary management of cancer related bone disease. An important goal of the meeting has been to drive research collaboration within the attending audience of basic scientists and clinicians, but also to produce guidelines and recommendations to the broader audience of health care workers involved in the care of cancer patients. The meeting has previous produced a number of documents covering basic science [1], translational research [2–4], clinical research [5–10] and practice guidelines [11,12]. Each year a debate is held on a controversial bone-related topic and so for the 2014 BONUS meeting, the debate focused on the recently presented meta-analysis by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) on the use of adjuvant bisphosphonates in early stage breast cancer [13].