New and translational perspectives of oestrogen deprivation in breast cancer.

Over the last 20 years, aromatase inhibitors have been developed to become a highly effective treatment strategy for treatment of hormone receptor positive breast cancer. Despite their success, poor response and resistance limit the effectiveness of these agents in up to 50% of patients. In recent years, studies using highly sensitive hormone assays have provided insight into the source of oestrogen production for the stimulation of oestrogen receptor positive breast cancer growth, suggesting that uptake from the circulation is likely to make a significant contribution to intratumoural oestradiol. To obtain insight into how tumours become resistant to oestrogen after aromatase inhibition, long term oestrogen deprivation of cultured cells has been used to mimic acquired resistance to aromatase inhibitors. This work has aided the selection of agents to rationally combine with aromatase inhibitors to combat resistance. Molecular profiling using genome-wide approaches has shed new light on the heterogeneity of responses to oestrogen deprivation and predictors of resistance in vivo. Testing new agents and combinations in short-term pre-surgical studies using biomarkers such as Ki67 is critical for increasing the rate at which new rational combinations can be assessed for efficacy.