Exploring the anti-tumour activity of bisphosphonates in early breast cancer

Bisphosphonates are potent inhibitors of osteoctast-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 potentiatly 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-ctinicat 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 antitumour activity outside of the bone microenvironment, coutd 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 severat 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. Finatty, the clinical relevance and strategies for the evaluation of anti-tumour activity in breast cancer witl. be discussed. We are currently exploring the potential synergistic anti-tumour effects of the sequential treatment of neoadjuvant chemotherapy followed by zotedronic acid in a randomised phase II study evaluating biological endpoints including apoptosis, proliferation and angiogenesis in patients with breast cancer. (c) 2008 Elsevier Ltd. AR rights reserved.