The role of tamoxifen in the treatment and prevention of breast cancer

Abstract

Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. Tamoxifen was originally introduced for the treatment of advanced disease in postmenopausal women; however, the drug is now also available for the palliative treatment of premenopausal women with estrogen receptor (ER) positive disease. The proven efficacy of tamoxifen and the low incidence of side effects made the drug an ideal agent to test as an adjuvant therapy for women with node-positive breast cancer. Laboratory studies indicate that long-term treatment schedules may provide maximal benefit in preventing recurrence, and recent analysis of clinical trials demonstrates that between 2 and 5 years of adjuvant tamoxifen therapy provides a survival advantage for postmenopausal women with node-positive disease. Similarly, adjuvant studies in node-negative breast cancer have demonstrated an increase in the disease-free survival of both pre- and postmenopausal patients with ER-positive tumors. However, the extended use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy. Of special concern is the impact of tamoxifen on ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs. Fortunately, there are no reports about the teratogenicity of tamoxifen in the human, but it is important that physicians counsel women about the risk of pregnancy. Tamoxifen should not be used if a patient is pregnant. Initial concerns that the long-term administration of an antiestrogen would increase bone loss and increase the risks of coronary heart disease appear to be unwarranted. Tamoxifen has some estogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and decrease in circulating cholesterol. Indeed, a reduction in fatal myocardial infarction (MI) has been noted during 5 years of tamoxifen therapy, possibly the direct result of a prolonged reduction in circulating cholesterol. However, the estrogen-like qualities of tamoxifen that could be valuable as a hormone replacement therapy for all postmenopausal women following a diagnosis of breast cancer may also increase the risk for developing endometrial carcinoma. To date, there are only a few reports of endometrial carcinoma being diagnosed during adjuvant therapy with tamoxifen; however, any instances of uterine bleeding or spotting should be followed up with an endometrial biopsy. There are some concerns about large doses of tamoxifen promoting liver cancer in rats. These results are of particular concern if tamoxifen is to be used as a preventive in normal women. However, tamoxifen is acting as a weak estrogen in the rat model, and other estrogens (eg, conjugated estrogens and estrogens used in oral contraceptives) are much more potent promoters of liver cancer. There are no reports of an increased incidence of hepatocellular carcinoma during long-term tamoxifen therapy; in fact, there is a report of the use of tamoxifen to treat the disease successfully. The estrogen-like properties of tamoxifen may encourage clones of breast cancer cells to grow in response to the drug. This form of drug resistance has been described in the laboratory, and a new pure antiestrogen is being evaluated for use as a second-line agent following the failure of long-term adjuvant tamoxifen therapy. The extensive clinical experience with tamoxifen has encouraged its evaluation as a preventive in women at risk of developing breast cancer. Several clinical studies are being positioned in different countries to address this question. All the laboratory studies demonstrate that tamoxifen will prevent or suppress mammary cancer, and clinical experience has shown a 40% reduction in the incidence of second primary breast cancers. The completion of randomized prevention trials with tamoxifen will place a valuable medical option in the hands of the physician who treats women at risk for breast cancer.