Role of denosumab in breast cancer

Recent advances in adjuvant treatment have improved progression-free and overall survival in patients with early stage breast cancer. However, up to one third of women will experience tumour recurrence, with bone being a common metastatic site. Current treatment options for metastases to bone comprise systemic antitumour therapy, irradiation, surgery and biphosphonates. As osteoclast activation is mediated by the receptor activator of NF-kappaB (RANK)/RANK ligand pathway and inhibited by osteoprotegerin (OPG), it was suggested that inhibition of this system may treat bone metastases. Recombinant Fc-OPG was evaluated in women with osteoporosis and malignant bone disease. The fully human antibody denosumab has demonstrated superior activity in reducing markers of bone turnover; therefore this drug was further developed in clinical settings. In advanced breast cancer, denosumab reduced urinary-N-telopeptide:creatinine ratio with potentially fewer side effects compared with bisphosphonates. Proof of direct antitumor activity is missing. Here we review the development and current status of denosumab in breast cancer. Data were obtained by searching the Medline database and abstracts from the American Society for Clinical Oncology (ASCO) annual meeting, European Cancer organization (ECCO), European Society for Medical Oncology (ESMO) and the San Antonio Breast Cancer Symposium, using search terms including bone metastases, bisphosphonates, breast cancer, denosumab, osteoprotegerin, RANK and skeletal-related events.