title: Exploring the anti-tumour activity of bisphosphonates in early breast cancer.
abstract: Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are firmly established in the management of breast cancer patients with metastatic skeletal disease. There are extensive data that bisphosphonates, particularly nitrogen-containing bisphosphonates such as zoledronic acid, exhibit anti-tumour activity potentially via both indirect and direct mechanisms in vitro. In vivo studies using animal models of breast cancer induced bone disease have shown that bisphosphonates exert anti-tumour effects via inhibiting osteolysis and reducing skeletal tumour burden. Furthermore, pre-clinical studies have demonstrated synergistic anti-tumour effects between chemotherapy agents commonly used in breast cancer treatment and nitrogen-containing bisphosphonates. This, coupled with emerging evidence from pre-clinical in vivo studies suggesting that bisphosphonates may have additional anti-tumour activity outside of the bone microenvironment, could be of significant importance in the clinical management of breast cancer. The evidence in favour of an anti-tumour effect of bisphosphonates in the clinical setting is inconclusive however, with conflicting evidence from several trials. This review focuses on the anti-tumour activity of bisphosphonates in breast cancer, with particular focus on zoledronic acid. The pre-clinical evidence for anti-tumour activity will be reviewed, followed by the synergistic effects with anti-cancer agents. Finally, the clinical relevance and strategies for the evaluation of anti-tumour activity in breast cancer will be discussed. We are currently exploring the potential synergistic anti-tumour effects of the sequential treatment of neoadjuvant chemotherapy followed by zoledronic acid in a randomised phase II study evaluating biological endpoints including apoptosis, proliferation and angiogenesis in patients with breast cancer.
authors.affiliation: Academic Unit of Clinical Oncology, Section for Cancer, Cancer Research Centre, University of Sheffield, Weston Park Hospital, Sheffield S10 2SJ, UK. m.c.winter@sheffield.ac.uk
authors.forename: M C
authors.initials: MC
authors.lastname: Winter
authors.forename: I
authors.initials: I
authors.lastname: Holen
authors.forename: R E
authors.initials: RE
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004164:Diphosphonates