Oestradiol and breast cancer prevention: a 40 year history and contemporary perspective.

Nearly 40 years ago one of us published a conceptual article arguing the case for studies of breast cancer prevention with tamoxifen. Recent observations on the interaction of plasma oestrogen levels with the preventive effect of the aromatase inhibitor anastrozole make it timely to consider the development of oestrogen-targeted prevention of breast cancer and the evidence upon which that development was made. In this article we review the understanding of the aetiology of breast cancer in the mid-1980s; its subsequent development, including the findings from the adjuvant treatment of early breast cancer with tamoxifen and from the trials that assessed tamoxifen as a preventive agent in women at increased risk. We then focus on results from the comparative trials of aromatase inhibitors (AIs) versus tamoxifen and the extension of the use of AIs in trials for prevention. We describe the relationship between plasma levels of oestradiol and its major protein binder, sex hormone binding globulin, on the development of oestrogen receptor positive breast cancer and how these impact on the preventive effect of the AI, anastrozole, in postmenopausal women. Lastly, we speculate on the potential role of routine measurement of oestradiol in managing risk and achieving prevention of breast cancer.