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

Summary

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.

Introduction

There were approximately 430,000 cases of breast cancer diagnosed in Europe in 2006, representing 13.5% of all malignancies and the most commonly diagnosed cancer in women.¹ Most patients present with localised disease, but unfortunately a significant percentage of women develop metastatic disease. Breast cancer cells have a propensity to metastasise to the skeleton, representing the first site of metastasis in almost 50% of patients with relapsed disease.² Furthermore, 65–75% of women with metastatic breast cancer have skeletal involvement.³

Osteoclast-mediated bone resorption occurs at an accelerated rate in the presence of tumour cells in bone. Bisphosphonates (BPs), as potent inhibitors of osteoclast-mediated bone resorption, have become firmly established in the management of patients with metastatic skeletal disease, and their use is increasing.⁴ Although the main target of BPs is the osteoclast, there is increasing evidence from pre-clinical studies conducted over the last decade, summarised in Fig. 1, to indicate that BPs demonstrate anti-tumour activity.⁵In vitro studies have shown that BPs inhibit tumour cell adhesion and invasion, induce tumour cell apoptosis, reduce tumour cell viability and proliferation and exhibit anti-angiogenic effects. Furthermore, in vivo animal studies of cancer induced bone disease treated with BPs have demonstrated anti-tumour activity characterised by reduced skeletal tumour burden in a variety of different cancers. Importantly, from recent animal models, it has emerged that BPs, particularly zoledronic acid, may have anti-tumour activity outside of the bone environment. It has also been reported that BPs have additive or synergistic anti-tumour effects when combined with cytotoxic drugs that are commonly used in the treatment of breast cancer. This could be of significant importance in the clinical management of the disease.

The evidence of anti-tumour activity of BPs in the clinical management of breast cancer is conflicting and as yet inconclusive. Recently published meta-analyses have shown that clodronate (1600 mg daily), given in the adjuvant and metastatic settings did not significant improve 5-year overall survival, bone-metastasis-free or extra-skeletal metastasis-free survival compared to those receiving no active treatment.⁶ Results from NSABP-34 and AZURE, two large international trials, are awaited to see if the addition of BPs in the adjuvant treatment setting improves recurrence and survival in patients with early breast cancer. If these trials demonstrate positive results, it still remains to be established whether this is attributable to a direct anti-tumour activity of BPs, or rather an indirect mechanism as a result of the inhibition of osteoclast-mediated bone resorption.

This paper reviews the current evidence of the anti-tumour activity of BPs in breast cancer, with particular focus on the anti-tumour activity of zoledronic acid. Three key areas related to breast cancer will be reviewed: the pre-clinical evidence for anti-tumour activity, the potential interaction and synergy with anti-cancer agents and the clinical relevance and strategies for evaluation of anti-tumour activity in the management of breast cancer. Literature searches using PubMed, with supplemental evidence from abstracts from major international conferences were used to identify relevant publications.