Breast cancer is the most common cancer in women in the Western world. Because breast cancer is estrogen-dependent, reducing estrogen secretion by oophorectomy, hypophysectomy, or adrenalectomy can cause the cancer to regress. The need for these surgical procedures was reduced by the introduction of tamoxifen, which acts as an antiestrogen by inhibiting the binding of estrogen to estrogen receptors. Tamoxifen was approved by the Food and Drug Administration in 1977 for the treatment of women with advanced breast cancer and several years later for adjuvant treatment of primary breast cancer.

Pharmacology and Endocrinology

Pharmacologic and Pharmacokinetic Properties

The compound administered to patients is trans-tamoxifen (as the citrate salt), because this isomer has higher affinity for estrogen receptors than the cis isomer. These receptors are nuclear transcription factors present in normal breast and other tissues and in 60 to 70 percent of breast cancers. The trans-tamoxifen has not only antiestrogenic but also estrogenic properties, depending on the species, tissue, and gene.  Drugs such as tamoxifen are more properly referred to as selective estrogen-receptor modulators, because of their multiple activities.  The molecular basis for these properties is poorly understood, but the estrogen-agonist activity of tamoxifen may explain its favorable effects on bone and serum lipid concentrations and its ability to stimulate the endometrium. Its estrogen-antagonist activity in breast tissue accounts for its ability to inhibit tumor growth.

Tamoxifen is absorbed readily after oral administration. The serum half-lives of tamoxifen and its major metabolites range from 7 to 14 days, permitting once-daily administration. The usual dosage is 20 mg per day.  Tamoxifen can be detected in serum for several weeks and in tumor tissue for several months after treatment is discontinued.  As a result, for several months after tamoxifen treatment is stopped, ligand-binding assays of estrogen receptors in tumor tissue can give false negative results because of receptor occupancy by the drug.  Tamoxifen undergoes extensive metabolism in the liver and is excreted predominantly in the feces.

Tamoxifen increases the action of warfarin by competing with its metabolizing enzyme, cytochrome P450 3A4, a circumstance that can lead to potentially life-threatening bleeding. ( Therefore, patients receiving tamoxifen should be given less warfarin, and the international normalized ratio should be closely monitored. Erythromycin, cyclosporine, nifedipine, and diltiazem can inhibit tamoxifen metabolism by a similar mechanism.

Mechanism of Action

The antitumor effects of tamoxifen are thought to be due to its antiestrogenic activity, mediated by competitive inhibition of estrogen binding to estrogen receptors.   As a consequence, tamoxifen inhibits the expression of estrogen-regulated genes, including growth factors and angiogenic factors secreted by the tumor that may stimulate growth by autocrine or paracrine mechanisms. The net result is a block in the G1 phase of the cell cycle and a slowing of cell proliferation. Tumors may then regress because of this altered balance between cell proliferation and ongoing cell loss. Tamoxifen may also directly induce programmed cell death.

Estrogen-Receptor Status

Whether tamoxifen improves outcomes in women who have tumors with few or no estrogen receptors has been controversial. responses are uncommon (5 to 10 percent) in women with estrogen-receptor-negative metastatic breast cancer treated with the drug. The results of large trials of adjuvant therapy in women with estrogen-receptor-negative tumors were contradictory.  A 1992 meta-analysis of trials of adjuvant therapy suggested that tamoxifen has a small but statistically significant survival benefit in these women,   but the updated meta-analysis with longer follow-up and additional women did not.

For women with estrogen-receptor-positive tumors, tamoxifen therapy given for as little as one year results in a statistically significant recurrence and survival benefit. The benefits increase as the duration of treatment increases, so that among women treated for five years, tamoxifen results in a 50 percent annual reduction in the recurrence rate and a 28 percent annual reduction in the death rate. This means that about half of the recurrences and more than one fourth of the deaths each year are averted by tamoxifen treatment. The benefits are even greater in women whose tumors have very high concentrations of estrogen receptors. Relatively few studies have included measurements of progesterone receptors in tumor tissue. Among women with estrogen-receptor-positive tumors, the efficacy of tamoxifen was independent of the concentration of progesterone receptors in the tumor tissue. Among women with estrogen-receptor-negative tumors, those whose tumors contained progesterone receptors did benefit from tamoxifen.

Optimal Duration of Therapy

Preclinical studies suggest that tamoxifen is primarily a cytostatic agent and therefore that prolonged therapy would be more effective than short periods of treatment.   In the most recent meta-analysis, comparisons of the results of trials of about one, two, and at least five years' duration  suggest that in women with estrogen-receptor-positive tumors, prolonged therapy (about five years) is superior to shorter therapy in reducing the rates of recurrence and death. On the basis of these results, it now seems reasonable to recommend that tamoxifen be given for five years.

Benefits According to Age or Menopausal Status

Women less than 50 years old, most of whom would be expected to be premenopausal, benefit from tamoxifen as much as older women, and even women younger than 40 have reduced rates of recurrence and death. These data suggest that tamoxifen inhibits the proliferation of breast-cancer cells even in the presence of estrogen. An important question is whether the benefit of tamoxifen therapy is equivalent to or greater than that of chemotherapy in premenopausal women, as it appears to be in older women who have estrogen-receptor-positive tumors. Although the data i suggest that tamoxifen is at least as effective as adjuvant chemotherapy in women younger than 50 (chemotherapy was associated with a 36 percent reduction in the recurrence rate and a 24 percent reduction in the death rate),  few studies have directly addressed this question. In a single small study of premenopausal women with metastases to the lymph nodes and primary tumors containing estrogen receptors, chemotherapy was superior to tamoxifen, but the duration of tamoxifen treatment was only two years.  In a large, randomized trial comparing tamoxifen alone with chemotherapy plus tamoxifen, the combination was more effective.

Ancillary Benefits

Serum Lipoproteins and Mortality from Cardiovascular Causes

In women with breast cancer, tamoxifen does not reduce the incidence of non-cancer-related deaths.  However, accurate data on causes of death are difficult to obtain in some countries, and several individual trials of adjuvant therapy did suggest that the rate of non-breast-cancer-related deaths (deaths before relapse) may be reduced by tamoxifen treatment.  This reduction appears to be due largely to a decrease in deaths from cardiovascular causes. In addition, fewer hospitalizations for cardiac events have been reported among women taking tamoxifen.  The estrogenic properties of tamoxifen may account for these reductions. Serum concentrations of total cholesterol and low-density lipoprotein cholesterol are reduced by tamoxifen, which may also inhibit atherogenesis by directly affecting the metabolism of low-density lipoproteins in the arteries.

Changes in Bone Mineral Density

In postmenopausal women, long-term tamoxifen treatment slightly increases the bone density of the axial skeleton and stabilizes the bone density of the appendicular skeleton. In premenopausal women, however, tamoxifen may decrease bone mineral density, perhaps by antagonizing the more potent activity of endogenous estrogen.  Despite the apparently favorable effects of tamoxifen on bone density in postmenopausal women, in a one-year study the fracture rate was higher in women treated with tamoxifen than in those given placebo.  However, the fracture rate seems to be reduced with five years of treatment (see below).

Prevention of Contralateral Breast Cancer and of Breast Cancer in Women at High Risk

Tamoxifen reduces the incidence of cancer in the contralateral breast. Individual trials in women with invasive breast cancer as well as the updated meta-analysis from the Early Breast Cancer Trialists' Collaborative Group indicated that there is a nearly 50 percent reduction in the risk of contralateral cancer after about five years of treatment.

Toxicity

Tamoxifen is extremely well tolerated by most patients with breast cancer. In early trials of tamoxifen for adjuvant therapy, fewer than 5 percent of patients withdrew from therapy because of toxicity. In a more recent, large, randomized trial, 7 percent of tamoxifen-treated women withdrew for reasons apparently related to drug toxicity, but 5 percent of placebo-treated women also withdrew for those reasons.

Menopausal Symptoms

The most common adverse effects of tamoxifen are menopausal symptoms, and they are more common in women before menopause than afterward.  At least 50 percent of women treated with tamoxifen report hot flashes, but so do 20 to 40 percent of women given placebo. Many of these women have recently stopped estrogen-replacement therapy, at the time the diagnosis of breast cancer was made. Vaginal discharge and irregular menses are also slightly more common among women treated with tamoxifen than among those given placebo. However, in one study, the incidence of nausea, discomfort in the joints, difficulty sleeping, restlessness, depression, or fatigue was similar in the tamoxifen and placebo groups, and headache was less common in the tamoxifen group. Quality-of-life scores were similar in the two groups.

Ocular, Thromboembolic, and Hematologic Effects

Retinopathy has been reported in women given high doses of tamoxifen,  but reports of ocular toxicity with conventional doses in randomized trials are inconsistent.  In one large trial and in preliminary results from the tamoxifen prevention trial, no vision-threatening toxic effects were found, but among women with preexisting cataracts there was a slightly increased risk of posterior subcapsular opacities and a slightly increased need for cataract surgery in those receiving tamoxifen.

An increased incidence of thromboembolic phenomena has also been attributed to tamoxifen in some but not all studies, especially when tamoxifen is combined with chemotherapy.  This complication occurs in fewer than 1 percent of patients given tamoxifen, but deaths due to thromboembolism have been reported.  Many of the patients described had superficial phlebitis and did not require hospitalization. Moderate thrombocytopenia and leukopenia have been reported with tamoxifen, but they rarely require cessation of therapy.

Endometrial Cancer

The most serious adverse effect of tamoxifen is its potential tumor-promoting activity.   An increased incidence of liver tumors has been reported in rats, (but only a few cases of hepatoma have ever been reported in humans taking tamoxifen.  More serious is an increased incidence of endometrial cancer, similar to that in women receiving estrogen-replacement therapy; it has been reported in some but not all tamoxifen trials and may be related more to tamoxifen's estrogenic activity than to any direct carcinogenic effects. Nearly all reported endometrial cancers have been in postmenopausal women. In a large five-year trial of tamoxifen, the annual hazard rate was 1.7 per 1000 women, a relative risk of 2.2 as compared with population-based rates of endometrial cancer. Most of the cancers were of a low stage and grade, similar to those associated with estrogen therapy. In the most recent meta-analysis, the incidence of endometrial cancer was increased and the risk of mortality from endometrial cancer was slightly increased, especially with prolonged treatment.

Endometrial hyperplasia, the development of polyps, an increase in endometrial thickness, and ovarian cysts have also been attributed to tamoxifen. The value of routine screening for endometrial cancer in women receiving tamoxifen has not been established, but certainly any woman with unusual vaginal discharge or bleeding should be promptly evaluated. The large prospective trials of tamoxifen did not find a significantly increased incidence of other solid tumors,  and the reduction in the incidence of contralateral breast cancer (a more lethal disease) is about twice as large as the increase in the incidence of endometrial cancer.