Approval of tamoxifen for use in women at increased risk of breast cancer was based on the results of a study reported in September 1998; the study followed 13,175 women for a mean of four years. Medical Letter consultants reviewed the current data on tamoxifen as a prophylactic agent for breast cancer.

Tamoxifen competes with estrogen to bind to estrogen receptors in the cell nucleus, thus altering gene transcription and protein synthesis, and inhibiting the growth of estrogen-dependent tumor cells. In some tissues, however, tamoxifen acts as an estrogen agonist, which relates to its effects on bone mineral density, lipid levels, the endometrium and clotting mechanisms.

The large-scale study of breast cancer prevention with tamoxifen (dosage of 20 mg per day) included women 35 years of age or older with at least one of the following risk factors for breast cancer: (1) an age of 60 years or greater; (2) a history of lobular breast cancer in situ; or (3) an estimated risk of breast cancer within five years that is greater than 1.66 percent. Of the 13,175 women in the study, 244 in the placebo group and 124 in the tamoxifen group developed breast cancer. In the subgroup of women over 60 years of age but otherwise at low risk, breast cancer developed in one of 297 women receiving placebo and in three of 284 women receiving tamoxifen.

Although smaller than the American study and utilizing different eligibility criteria, two European studies failed to demonstrate any effect of tamoxifen on the incidence of breast cancer. The findings from these two studies were also reported in 1998.

The incidence of endometrial cancer was higher in the women receiving tamoxifen. It developed in 18 women in the placebo group and 37 women in the tamoxifen group. All cancers occurring in the tamoxifen group were low grade and diagnosed at an early stage.

The incidence of myocardial infarction and fractures of the hip, spine or radius was similar in the two groups. Tamoxifen was associated with an increased incidence of deep venous thrombosis (35 versus 22 in placebo-treated patients), pulmonary embolism (18 versus six) and stroke (38 versus 24). The incidence of these disorders was increased in women over 50 years of age. Women receiving tamoxifen also had cataract formation more frequently (574 patients compared with 507 patients).

Currently, it is assumed that tamoxifen would need to be taken indefinitely to provide prophylaxis against breast cancer. The authors note that the long-term effects of tamoxifen on mortality are unknown. They estimate that the cost of 20 mg of tamoxifen per day for five years would be $6,000.

editor's note: Tamoxifen belongs to a new class of drugs called selective estrogen reup-take modulators (SERMs). Clinical trials of a number of SERMs are currently under way. Although raloxifene is marketed for prevention of postmenopausal osteoporosis, it also has been reported to decrease the incidence of breast cancer. Unlike tamoxifen, however, raloxifene has not been associated with an increased risk of endometrial cancer. Nevertheless, clinical use of this agent for prevention of osteoporosis seems to be lagging behind marketing efforts. Symptoms of estrogen deficiency, specifically vasomotor instability, may be slowing clinical acceptance of this agent. Whether or not the physician endorses the use of traditional hormone replacement therapy, the long-term safety issues of hormone replacement therapy are clearer than those connected with the use of SERMs.—b.a.