Oestrogens, oestrogen receptors and breast cancer

Tamoxifen has been the endocrine treatment of choice for all stages of oestrogen receptor positive breast cancer for 20 years and the first chemical therapeutic to be tested to reduce the incidence of breast cancer in high-risk women. It is now clear that the oestrogen receptor is proving to be an invaluable target for the treatment and chemoprevention of breast cancer. The success of tamoxifen clinically can be quantitated: 400 000 women are alive today because of the application of 5 years of adjuvant tamoxifen therapy in node-positive and node-negative breast cancer. This advance has resulted in vigorous efforts to reduce side-effects and to improve objective response rates by the rapid application of laboratory principles. Tamoxifen is known to have a mixture of oestrogen-like and anti-oestrogen actions so it is reasoned that completely anti-oestrogenic agents would enhance treatment response rates while lowering the incidence of oestrogen-like side-effects such as endometrial cancer and blood clots. A new pure anti-oestrogen, fulvestrant, that destroys the oestrogen receptor, is available after drug resistance to tamoxifen develops. The group of drugs known as aromatase inhibitors block the production of oestrogens from androstenedione and testosterone in the body fat of postmenopausal women. New agents such as anastrozole, exemestane, and letrozole have shown promise as new treatment modalities for advanced breast cancer. Most importantly, the successful testing of anastrozole as an adjuvant treatment for breast cancer has enhanced enthusiasm for the evaluation of aromatase inhibitors and selective oestrogen receptor modulators (SERMs) to be tested as chemopreventives. SERMs express anti-oestrogenic actions in the breast but oestrogen-like actions in bone and lower circulating cholesterol. This insight not only allowed the safe application of tamoxifen to well high-risk women to test the worth of an 'anti-oestrogen' to prevent breast cancer, but also caused a paradigm shift in the strategy of chemoprevention. The question was posed that if, tamoxifen prevents breast cancer but an added benefit is the maintenance of bone density, why not develop a drug to prevent osteoporosis or atherosclerosis that prevents breast cancer in the general population as a beneficial side-effect? Raloxifene is the result of this new strategy to seek multifunctional medicines for women's health. Raloxifene is currently available for the treatment and prevention of osteoporosis but is being tested in high-risk postmenopausal women for the prevention of breast cancer against tamoxifen in the study of tamoxifen and raloxifene (STAR trial) and for the prevention of coronary heart disease (CHD) in a placebo-controlled trial in women at high risk for CHD called raloxifene use for the heart (RUTH).