Endocrine therapy and other targeted therapies for metastatic breast cancer.

The most important change in the treatment of advanced breast cancer that will emerge over the next 10 years is the shift from adjuvant tamoxifen to adjuvant aromatase inhibitors. This will mean an increasing proportion of tamoxifen-naive aromatase inhibitor-resistant breast cancer. Research of the most appropriate methods of optimizing remaining endocrine sensitivity in these patients is needed. The rapid expansion in the understanding of the molecular basis of breast cancer biology provides potential targets for novel therapies. Despite these pivotal developments, resistance to endocrine therapy remains a key limitation in the management of advanced breast cancer. Until recently, the only option following the development of resistance to an endocrine agent was to change endocrine therapy and, on exhaustion of endocrine sensitivity, to move to cytotoxic chemotherapy. Understanding of at least some of the mechanisms underlying the development of endocrine resistance is now emerging. We now have the tools that may allow us to both overcome resistance and restore sensitivity, or to pre-empt certain types of resistance from developing. These tools include the increasing array of signal transduction inhibitors in combination with standard endocrine agents. Correct clinical management strategy can be guided by preclinical modeling but can only be validated by carefully designed clinical trials. These will, at the very least, need to be conducted with correlative translational research elements that will track changes in tumors as resistance emerges and will allow us to select the most appropriate treatment strategy for individual patients. Amongst the myriad of promising drugs there will undoubtedly be some that fail to meet current hopes, but we can be optimistic that a handful will find a useful place in keeping advanced breast cancer at bay for longer than can be achieved at present. However, the holy grail of a cure is likely, in the medium term, to remain elusively at the end of the rainbow for most of these patients. Several other methods for the management of these patients are in development. These include strategies to overcome endocrine resistance and methods to target deregulated endocrine and growth factor signaling pathways using gene and immunotherapy approaches.