The metastatic microenvironment of breast cancer: clinical implications.

Metastasis to bone, and indeed potentially to other sites, results from the numerous interactions between cancer cells, haematopoietic stem cells and normal bone cells within the bone marrow microenvironment. These interactions are in turn influenced by multiple endocrine, paracrine and physical factors. Bone-targeted treatments may modify the course of the disease via both direct and indirect inhibitory effects on this "vicious cycle" of growth factor and cytokine signalling between tumour and bone cells. Improvements in both disease free (DFS) and overall survival in women with early breast cancer have been demonstrated in several large randomised adjuvant trials of oral clodronate and intravenous zoledronic acid. The evidence for a beneficial impact on disease outcome is particularly strong in patients with low levels of reproductive hormones, including pre-menopausal women receiving ovarian suppression therapy and those who have passed through menopause at the time of diagnosis. A recent meta-analysis of postmenopausal women treated with adjuvant bisphosphonates showed an 18% improvement in DFS (hazard ratio [HR] = 0.82; 95%CI 0.74-0.92, 2P = <0.001), with reductions in relapse rates not only in bone but also at extra-skeletal and loco-regional sites. These exciting findings are beginning to change clinical practice.