Abstract PD07-08: Zoledronic acid specifically inhibits development of bone metastases in the post-menopausal setting – evidence from an in vivo breast cancer model

Background: A number of recent clinical trials have suggested that the benefits of adjuvant bone targeted treatments on risks of recurrence or death in early breast cancer are restricted to women with established menopause. We have used a model system that mimics pre- and post-menopausal status to investigate the effects of zoledronic acid on breast tumour growth in bone, demonstrating a differential anti-tumour effect in these two settings. Methodology: Tumour growth was assessed by in vivo imaging following intra-cardiac inoculation of luciferase expressing MDA-MB-231 breast cancer cells in 12-week old female Balb-c nude mice. Animals underwent ovariectomy (OVX, mimicking the post-menopausal setting) or a sham operation (mimicking the pre-menopausal setting) 7 days after tumour cell implantation (n = 10/group). In treatment experiments, OVX and sham operated animals received either saline or 100ug/kg zoledronic acid (ZOL) weekly s.c. from day 4. Effects on bone were assessed by uCT analysis, bone histomorphometry and measurement of serum bone markers. Presence of tumour cells in bone was detected by multiphoton microscopy. Results: OVX induced significant bone loss compared to sham within 2 weeks, which was completely inhibited by ZOL. Tumour growth was detected in the long bones of 29% of animals in the sham group on day 35 following tumour cell inoculation, and this was not affected by ZOL treatment. In contrast, 83% of the OVX animals had detectable tumours in the long bones, demonstrating that OVX mediated changes to the bone microenvironment that stimulated tumour growth. Crucially, this OVX-induced increase in tumour growth was completely prevented by weekly ZOL treatment, with only 17% of animals in the OVX+ZOL group having detectable bone tumours compared to 83% in the OVX+saline group. Multiphoton microscopy revealed that numerous individual tumour cells were present in long bones of animals in the OVX+ZOL group, supporting that ZOL acts by inhibiting an OVX-mediated trigger of tumour cell proliferation. Conclusions: Our data are in agreement with those reported from clinical trials of adjuvant zoledronic acid, showing an anti-cancer effect exclusively in the post-menopausal setting. This is the first demonstration that zoledronic acid prevents tumour progression in bone specifically through inhibition of OVX-induced proliferation of tumour cells resident in the bone marrow. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-08.