CHEMOPREVENTION OF BREAST CANCER

The end of this millennium has been marked by the demonstration, for the first time, that breast cancer can be delayed and probably prevented by drugs. This remarkable breakthrough is proof of principle that chemoprevention of cancer is possible and opens the door to the development of new pharmaceuticals or nutraceuticals that may reduce the incidence and mortality rate of cancer, with minimal adverse side effects. 25 Minimizing adverse side effects is of critical importance for agents being used over the long term to prevent disease in healthy, unaffected individuals. Until now, women at increased risk for breast cancer had only two options: (1) close surveillance 26,27 and (2) prophylactic mastectomy. 16,33 The relationship between estrogen and breast cancer has been documented for more than 150 years. 28 In 1836, Sir Astley Cooper, 5 a surgeon in London, observed fluctuations in tumor size over the menstrual cycle. One hundred years ago, Beatson, 1 a surgeon in Scotland, extrapolating from the practice of removing the ovaries in livestock to prevent lactation in animals, hypothesized that the "ovarian irritation" of the mammary glands and breast cancer might be influenced by removal of the ovaries. Beatson reported in 1896 the dramatic response of advanced breast cancer to ovariectomy; soon afterward Boyd, 3 at Charing Cross Hospital in London, reported similar responses in premenopausal women. The relationship between estrogen and its mechanism of action on target tumors was not understood until 1960, when Jensen and Jacobson, 17 at the University of Chicago, synthesized radioactive estradiol and observed that it was concentrated in the uterus. In 1961, the relationship between estrogen and breast-cancer response was studied by Folca et al, 12 who demonstrated that radiolabeled estrogen concentrated in breast tumors that responded to endocrine ablation. The measurement of estrogen receptor (ER) showed that 60% of patients with ER-positive tumors responded to endocrine ablation, and 10% of those with ER-negative tumors responded. 22 This led to the search for drugs that could block the action of estrogens on the tumor (i.e., antiestrogens) and avoid the need for surgical endocrine ablation. In 1958, the nonsteroidal antiestrogen ethamoxytriphetol was developed by Lerner et al 21 at the William S. Merrel Company in Cincinnati, Ohio. The drug was not only an antiestrogen but also had the property of preventing pregnancy in animals after mating and stimulated interest in its potential as a "morning-after" pill. Ethamoxytriphetol, however, had low potency and significant adverse side effects. Other related drugs were developed, such as clomiphene in 1964, which, instead of being a contraceptive natoxidine drug, induced ovulation and is in use today as a fertility drug. In 1978, the Upjohn Company in Kalamazoo, Michigan, developed an antiestrogen, mafoxidine, which was abandoned because of severe adverse side effects. In 1967, Harper and Walpole, 15 working at Imperial Chemical Industries Pharmaceuticals in the United Kingdom (now Zeneca), on analogues of the synthetic estrogen triphenylethylene, discovered a transisomer now known as tamoxifen (Nolvadex). 15 In 1971, Cole et al, 4 at the Christie Hospital in Manchester, England, conducted the first preliminary study of tamoxifen in patients with metastatic breast cancer and found a 22% response rate. The drug was found to have few toxic effects and subsequently became the most widely prescribed anticancer drug in history. In 1976, Jordan 19 first reported that a 1-month course of tamoxifen given 1 month after the administration of a powerful rat mammary carcinogen dimethylbenzanthracene (DMBA) delayed the development of tumors. A 6-month course of tamoxifen resulted in a 90% suppression of tumors, which then developed when tamoxifen administration was stopped; this was the first experimental demonstration of the chemoprevention of breast cancer. Subsequent studies showed that tamoxifen blocked breast cells at the G1 phase of the cell cycle 19,34 and that significant suppression of rat mammary cell division occurred after initiation with the carcinogen nitrosomethylurea (NMU) to below that of uninitiated cells. 29 Successful clinical studies of tamoxifen for the treatment of stage IV metastatic breast cancer led to its introduction as an adjuvant endocrine therapy for earlier-stage disease with ER-positive tumors. Many trials and the meta-analysis overview showed that not only were recurrences reduced and overall survival improved but also that contralateral breast cancer was reduced by nearly 50% (Fig. 1). During the course of these trials, tamoxifen was a selective antiestrogen and, contrary to initial expectations, had an estrogenic effect on bone reducing osteoporosis, did not increase coronary artery disease, and exerted an estrogenic effect on the uterus, resulting in endometrial hyperplasia and an increase in the low rate of endometrial cancer. Sufficient preclinical and clinical data were available by the late 1980s to justify large, randomized, clinical trials to determine the worth of tamoxifen in preventing breast cancer in women at increased risk. Three groups embarked on these prevention trials: in 1986, the United Kingdom's Royal Marsden Hospital group, led by Powles et al 30 ; in 1992, the European Institute of Oncology Group in Italy, led by Veronesi et al 37 ; and in 1992, the United States North American Surgical Adjuvant Breast and Bowel Project (NSABP), led by Fisher et al. 10 All three groups published their results in 1998 (Table 1).