Understanding response and resistance to oestrogen deprivation in ER-positive breast cancer.

Oestrogens (E) and oestrogen receptor alpha (ERα) play fundamental roles in the development and progression of more than three-quarters of breast cancers (BC). The ability to influence the natural history of BC by hormonal manipulation is well established and endocrine therapies represent the cornerstone of systemic management for women with ERα-positive disease. Endocrine agents abrogate oestrogenic signalling through distinct and incompletely overlapping mechanisms, either impeding the transcriptional activity of ERα or diminishing E-synthesis. In post-menopausal women, E-production is chiefly attributable to the enzymatic conversion of androgens in extra-gonadal tissues by the cytochrome P-450 superfamily member aromatase. Greater understanding of steroid biosynthesis has underpinned rational drug design and pharmacological development of potent and specific aromatase inhibitors (AIs). Contemporary agents induce profound E-suppression in post-menopausal women and are first-line neo-adjuvant, adjuvant and metastatic therapies, with greater efficacy and tolerability than tamoxifen. The principal qualifier for endocrine treatment, including AIs, remains ERα expression. However, it is increasingly apparent that ERα expression is not synonymous with sensitivity to treatment and insufficient to account for the considerable heterogeneity of response. Better predictive biomarkers of de novo resistance are required to improve patient selection and identify those poor-responders who may benefit from alternative or additional systemic treatment from the outset. Among patients who do respond well initially, many relapse during their clinical course and there is also an unmet need for biomarkers of acquired resistance. The majority of women who relapse on AIs continue to express functional ERα which remains a legitimate target for second-line endocrine therapy. Understanding and overcoming acquired resistance to AIs requires a greater appreciation of ERα biology and the mechanisms though which E-dependence can be subverted. In this article, we review the impact of therapeutic E-deprivation on the natural history of ERα-positive breast cancer. Consideration is given to established and emerging biomarkers and/or determinants of response and resistance to E-deprivation. In vitro and in vivo evidence of the molecular mechanisms underpinning the transition from sensitivity to resistance are reviewed in the context of current models of ERα activity and their potential translational relevance.