Integration of endocrine therapy with targeted agents

Current clinical trials have investigated three approaches to overcoming endocrine resistance, including maximal blockade of ER signalling, combinations of endocrine therapy with novel therapies that target the HER family of growth factor receptors, and combinations with drugs that target relevant downstream signalling pathways. Not all approaches have been successful to date, despite often very encouraging preclinical data. As discussed below, various issues in appropriate clinical trial design and patient selection must be addressed in order to maximize the potential of this new integrated approach.Given the published evidence for retention of a functional ER pathway after acquired resistance to tamoxifen/oestrogen deprivation therapy, one strategy has been to develop endocrine therapies that deliver maximal ER signalling blockade. Fulvestrant is a novel type of ER antagonist that prevents ER dimerization and leads to rapid degradation of the fulvestrant-ER complex, producing loss of cellular ER [4]. It has been shown that, because of its unique mechanism of action, fulvestrant delays the emergence of acquired resistance compared with tamoxifen in an MCF-7 hormone-sensitive xenograft model [5]. Clinical data from phase II studies in post-menopausal women with advanced breast cancer suggested some modest efficacy for fulvestrant in a second/third-line setting [6-8]. This was confirmed in the large randomized phase III EFECT (Evaluation of Faslodex versus Exemestane Clinical Trial) study [9], which demonstrated similar efficacy for fulvestrant versus exemestane in patients who have progressed on treatment with nonsteroidal aromatase inhibitors (AIs) [9].Laboratory evidence has suggested that the efficacy of fulvestrant – especially in the setting of endocrine resistance, where activated ER signalling may still be dominant – could critically depend on the background oestrogen environment in which the cells exist. This has led to the concept that ER-positive endocrine