Tamoxifen, Raloxifene, and the Prevention of Breast Cancer*

Abstract

IN 1896, George Beatson demonstrated that the removal of the ovaries from premenopausal women with metastatic breast cancer could, in some cases, cause regression of the disease and improve the prognosis of the patient (1). However, by 1900 Stanley Boyd had established that only one in three patients would obtain improvement for about 1 yr (2). Despite this disappointment, a link was established between an ovarian factor and the growth of some breast cancers. This observation was to become the foundation of modern clinical practice and the rationale for the use of antiestrogens to treat breast cancer (3, 4). At the turn of the century, studies were being conducted in the laboratory to complement the clinical effort. Inbred strains of mice were being established for medical research, and it was found that certain strains of mice developed a high incidence of mammary tumors. Lathrop and Loeb (5) reported that an early ovariectomy could prevent the spontaneous development of tumors but it was not until Allen and Doisey (6) identified “estrus stimulating principle” that ovarian hormones could be linked to the development of breast cancer. By 1936, Professor Antoine Lacassagne, again working with high-incidence strains of mice, suggested that if breast cancer was caused by a special hereditary sensitivity to estrogen, then the disease could be prevented by developing a therapeutic antagonist to estrogen action in the breast (7). However, there were no therapeutic antagonists of estrogen at that time, nor was there a target to design drug molecules. Nevertheless, exciting developments in the discovery of nonsteroidal estrogens would establish the structural basis of carrier molecules, which resulted in the design of the two drugs, tamoxifen and raloxifene (Fig. 1), both originally described as antiestrogens and used today in a clinical trial to prevent breast cancer in high-risk women (see Section IX).