Targeting new therapies in combination with hormonal therapies for ER-positive breast cancer

Hormonal therapies involving estrogen deprivation or SERMs such as tamoxifen reduce the risk of relapse and improve the survival of the >75% of breast cancer patients with ER-positive tumours. Nonetheless, many of these patients relapse with disease that was either intrinsically resistant to treatment or that has acquired resistance to the endocrine treatment. Laboratory studies have revealed that growth factor receptor pathways form an important route of growth signalling in both these circumstances, and there is now a series of agents available that target these pathways at different points. This provides the opportunity to utilise these agents in combination with endocrine treatment and the possibility that this may extend the effectiveness of the hormonal agents. The effective delivery of such combinations depends on a detailed knowledge of the degree to which the highly encouraging laboratory findings are translated into the clinical scenario. We have demonstrated that almost all breast ER-positive cancer shows some proliferative dependence on oestrogen, but that this is very variable. We have begun to identify in clinical samples the key genes whose expression both determines this variability and are themselves dependent on it. The development of novel models of drug development that allow the assessment of the expression of these genes, particularly within the presurgical setting, offers major opportunities to assess the potential of the various new targeted agents to be combined with endocrine therapy.