Therapeutic resistance to anti-oestrogen therapy in breast cancer

Although selective antagonism of oestrogen receptor signalling in breast cancer has been one of the most successful therapeutic approaches in oncology, resistance is a major clinical challenge. In this Review, Will et al. explore mechanisms of oestrogen-receptor-& alpha;-targeted therapeutic resistance and strategies to overcome it. The hormone receptor oestrogen receptor-& alpha; (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20-40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the 'evolvability' of ER+ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER+ breast cancers.