Hormonal therapy for postmenopausal breast cancer: the science of sequencing

Oestrogens play important roles in the natural history of breast cancer. Consequently, therapies have been developed to reduce oestrogen levels or to block signalling through oestrogen receptors (ER). These therapies include tamoxifen, selective oestrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective oestrogen receptor downregulators (SERDs). All have proven clinical efficacy in postmenopausal women with ER-positive breast cancer and can be effective in the neoadjuvant and adjuvant settings, and in the management of advanced disease. This range of endocrine therapies offers the opportunity for prolonging benefit from treatment and delaying tumour recurrence/progression by combining the different classes of drugs or by using them sequentially. Evaluation of the potential clinical benefits of concomitant or sequential endocrine therapies should be based on considerations of efficacy and safety profiles, mechanisms of action/resistance and effects on tumour biology. Evidence from preclinical models and from randomized clinical trials in patients with postmenopausal breast cancer suggests that concomitant endocrine therapies are no more effective than AIs alone. However, using AIs either as initial therapy or sequentially after tamoxifen appears to produce more benefits beyond the use of tamoxifen alone.Currently, there are no proven algorithms for the planned, sequential use of the full range of endocrine therapies, particularly for the majority of patients who present with early breast cancer. Prospective, randomized clinical trials are needed to determine the best use of therapies in particular settings, taking into account the spectrum of molecular phenotypes in different tumours.