Tamoxifen (Nolvadex), a nonsteroidal antiestrogen initially developed as an antifertility agent, was approved for the treatment of metastatic breast cancer in postmenopausal women in the 1970s. Since that time, tamoxifen(Drug information on tamoxifen)'s therapeutic role has continued to expand to include the management of early breast cancer in postmenopausal women, early and advanced breast cancer in premenopausal women, and breast cancer in men. In addition, it is currently studied for chemoprotection in healthy women at increased risk for breast cancer (Table 1).[1-27]
In this review, the impact of menopausal, estrogen-receptor (ER), and nodal status on the role of tamoxifen in the medical management of breast cancer is discussed. In addition, current opinion regarding the optimum duration of tamoxifen therapy, the efficacy of tamoxifen-chemotherapy combinations, and tamoxifen's potential for toxicity are presented.
The results of a number of clinical studies support the efficacy and safety of tamoxifen when used as first-line endocrine therapy in the management of advanced breast cancer in both premenopausal and postmenopausal women[1,2,17-27] and stress the importance of the presence of estrogen receptors in response.
Postmenopausal Women: Complete or partial responses to tamoxifen therapy have been observed in 30% to 40% of postmenopausal women with metastatic disease.[1,2,17-20] Response rates increase to 50% in women with ER-positive tumors and to 60% to 70% in women with ER-positive and progesterone(Drug information on progesterone) receptor (PR)-positive tumors.[1,2,17-20] In women with ER-negative and PR-negative tumors, response rates on the order of 10% have been reported with response durations ranging from two months to more than 24 months.[1,2,17,19] However, more recent data from studies with better statistical reliability indicate that the percentage of receptor-negative pa-tients responding to tamoxifen is lower, and that tamoxifen may not have a significant role in receptor-negative patients.
The effects of tamoxifen in unselected postmenopausal women are similar to those observed with other agents such as diethylstilbestrol(Drug information on diethylstilbestrol) (DES), ethinyl estradiol(Drug information on estradiol), medroxyprogesterone(Drug information on medroxyprogesterone) acetate (MPA), and megestrol(Drug information on megestrol) acetate (MA); however, tamoxifen has been demonstrated to have a more favorable toxicity profile than other hormonal therapies.[1,2,21-25]
In postmenopausal women with advanced disease, tamoxifen administered in combination or sequentially with chemotherapy has been demonstrated to produce a higher overall response rate than tamoxifen alone, but survival rates associated with this combination have been either not significantly different from or lower than those observed in response to monotherapy with either agent. For postmenopausal women with advanced breast cancer, it may be appropriate to limit chemotherapy to patients who have failed to respond to tamoxifen or those with fulminating disease.
Premenopausal Women: Tamoxifen has consistently been demonstrated to be as efficacious as bilateral oophorectomy in premenopausal women with advanced disease with respect to response rates, response duration, and survival time, but with lower associated toxicity.[1,25] Response rates following daily administration of 20 to 120 mg of tamoxifen have ranged from 20% to 45%, with median response durations of 2.5 months to 36 months.  Results of the Mayo Clinic trial indicated that tamoxifen may be more effective than oophorectomy in patients with soft-tissue or osseous disease and less effective in patients with visceral-dominant disease.[1,26,27] Menstrual irregularities in premenopausal women with advanced breast cancer treated with tamoxifen are common and between 16% and 39% of women experience amenorrhea.
Males: Although male breast cancer is rare, studies have indicated that tamoxifen does have a role in its treatment. Male breast cancer patients are more likely to have tumors positive for estrogen receptors than are female patients, indicating a role for adjuvant tamoxifen treatment.
Several small studies have confirmed its efficacy[28-30]; studies have demonstrated an overall response rate of 50% in unselected patients and 71% in patients with tumors positive for estrogen receptors. In the absence of data from large, randomized trials in males, the treatment selection guidelines established for the use of adjuvant therapy in women have been recommended.
At the 1985 National Institutes of Health Consensus Conference on Breast Cancer Chemotherapy, the goals of adjuvant therapy in the management of breast cancer were defined as the prolongation of survival and the maintenance of an acceptable quality of life. To that end, the Consensus Committee recommended tamoxifen as the treatment of choice for postmenopausal women with positive nodes and ER-positive tumors. This recommendation was the first step in establishing the role of tamoxifen in the adjuvant setting.
Within eight years following this recommendation, the results of 14 randomized trials involving 2,559 pre-menopausal and 10,989 postmenopausal women with early breast cancer demonstrated that adjuvant tamoxifen therapy was consistently associated with improved disease-free survival.[1,10-14] However, a statistically significant increase in overall survival was reported for only four of these clinical trials (Table 2).[1,10-14]
In the Nolvadex Adjuvant Trial Organization (NATO) and Scottish studies, improvement in overall survival was independent of menopausal, ER, or nodal status.[1,10-14] In the trial conducted at Christie Hospital, a statistically significant improvement in overall survival with tamoxifen therapy was reported only when the entire population of patients was considered and not for either premenopausal or postmenopausal subpopulations. However, the duration of therapy in this study was only one year, compared with two years in the NATO and at least five years in the Scottish trials.[1,10,13,14] Women with receptor-positive, node-negative disease were found to have an improved survival with five years of tamoxifen therapy in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial.[1,11,12]
In an attempt to more clearly define the comparative therapeutic benefits of various therapies, as well as to illustrate the impact of menopausal, nodal, and ER status on these benefits, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) pooled the results from 133 randomized trials involving 75,000 women with early breast cancer receiving tamoxifen, chemotherapy, ovarian ablation, or immunotherapy.[15,16] Table 3 and Table 4 summarize the results from this overview with respect to the approximately 32,000 women enrolled in 45 clinical trials evaluating either adjuvant tamoxifen therapy versus no adjuvant therapy, tamoxifen plus chemotherapy versus chemotherapy alone, or varying durations of tamoxifen therapy.
The EBCTCG meta-analyses clearly demonstrated that tamoxifen therapy reduced annual rates of recurrence and death for all patients.[1-3,15,16] However, women aged 50 or older appear to derive a greater benefit from tamoxifen therapy than younger women, although the age-related differences in recurrence and mortality rates were small. A confounding variable may be related to the potential need to administer tamoxifen for a longer duration (more than two years) in premenopausal women than in postmenopausal women to achieve similar results. Both node-positive and node-negative women benefited from tamoxifen therapy with a similar proportional reduction in mortality risk.[1,15,16] The absolute improvement in 10-year survival and overall reduction in risk for recurrence were lower for patients with node-negative compared with node-positive disease, due to an initially lower risk for recurrence. [1,3,15,16] As expected, treatment of women with ER-rich tumors resulted in a greater reduction in mortality and recurrence than treatment of women with ER-poor tumors.
A previous diagnosis of breast cancer can result in a threefold increase in risk for contralateral breast cancer. The EBCTCG analysis demonstrated that adjuvant tamoxifen therapy reduced the risk for development of contralateral breast cancer by 39% compared with no adjuvant therapy, despite the fact that the longer recurrence-free survival associated with tamoxifen presented a greater opportunity for the disease to develop. Therapy durations longer than two years resulted in a 53% reduction in risk for contralateral disease compared with a 26% reduction with less than two years of treatment.
Tamoxifen in Combination with Chemotherapy: A significant improvement in disease-free survival for postmenopausal women has been observed with tamoxifen in combination with chemotherapy (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil)) and prednisone(Drug information on prednisone), compared with tamoxifen in combination with prednisone alone.[1,33] Similarly, the EBCTCG analysis demonstrated that, for women aged 50 to 69, chemotherapy plus tamoxifen resulted in a greater reduction in mortality rate than chemotherapy alone and a greater reduction in recurrence rate than either chemotherapy alone or tamoxifen alone.[15,16] However, due to the limited amount of available clinical data, the EBCTCG overview could not establish whether women under age 50 derived benefit from a combination of tamoxifen and chemotherapy compared with the use of either agent alone.
The consensus opinion of the 1995 International Conference on Adjuvant Therapy of Primary Breast Cancer was that the combination of chemotherapy and tamoxifen was an acceptable treatment option for premenopausal and postmenopausal women with node-positive disease as well as premenopausal and postmenopausal women with high-risk, node-negative disease. The optimum sequence and chemotherapy regimen for administration of a combination tamoxifen-chemotherapy regimen had not yet been determined. Certain clinical data suggest a possible negative interaction between tamoxifen and certain cytotoxic agents (eg, L-PAM, fluorouracil).
Optimum Dose and Duration of Adjuvant Tamoxifen Therapy: The EBCTCG analysis demonstrated that tamoxifen doses higher than the standard 20 mg/d did not appear to provide greater therapeutic benefits.[1,15,16] In the EBCTCG analysis, in which the most widely-tested regimen was 20 mg/d for two years, the overall reduction in recurrence rate associated with tamoxifen therapy maximized during the first four years, and remained essentially unaltered between five and 10 years after initiation of therapy.[15,16]
Survival benefits, however, continue to increase, with a 5% reduction in mortality at five years and an 8% reduction at 10 years.[3,15,16] Fifty-nine percent of women administered tamoxifen were alive 10 years after initiation of therapy, compared with 53% of women administered placebo.[1,15,16] This steady divergence in survival between tamoxifen-treated and control patients during years five through 10 following initiation of therapy had not been anticipated by the EBCTCG collaborators and should be considered in the interpretation of data pertaining to therapy duration.
The EBCTCG analysis demonstrated that, compared with less than two years of tamoxifen therapy, longer durations of administration were associated with larger reductions in annual risk for mortality (24% vs 11%) and risk for recurrence (38% vs 16%). [3,15,16] The typical percentage reduction in the annual odds of recurrence was greater for patients aged at least 50 years than for those aged less than 50 years for durations of tamoxifen treatment of no more than one year (19% vs 5%) and two years (33% vs 10%).
However, tamoxifen administered for more than two years produced similar reductions in both age groups (38% vs 43%). Similarly, for patients aged 50 years or more the typical percentage reduction in the annual odds of mortality from any cause was greater than for those aged less than 50 years for durations of tamoxifen treatment of less than or equal to one year (13% vs 4%) and two years (23% vs 4%), but similar for therapy of more than two years (23% vs 27%).
The EBCTCG analysis was unable to determine whether two years, five years, 10 years, or indefinite tamoxifen administration was the optimum duration of therapy. The recent Swedish study has established that five years of tamoxifen is more beneficial than two years in postmenopausal women with receptor-positive, early-stage invasive breast cancer.
The NSABP B-14 study results suggest that in node-negative patients, no significant additional therapeutic benefit was observed after five years of tamoxifen therapy. However, some members of the medical community felt that the available data were insufficient for the formulation of definitive duration guidelines, given that the relationship between age/menopausal status and/or nodal status and optimum therapy duration has not been extensively explored. In addition, the question of therapy duration must also address the effect of tamoxifen on other estrogen target tissues as well as individual patient risk factors for side effects.
Beneficial Bone and Cardiovascular Effects: Bone fractures due to loss of mineral density cause substantial morbidity and mortality in postmenopausal women. Tamoxifen therapy for more than one year appears to be associated with increased bone mineral density and in some studies decreased fracture rates. Tamoxifen may be as efficacious as estrogen replacement therapy for bone loss prevention in postmenopausal women.[2,36-38]
In addition, long-term adjuvant tamoxifen treatment (two or five years) is associated with a reduced risk for hospital admission due to cardiac disease and fatal myocardial infarction.[2,39,40]
Tamoxifen Safety Profile: Tamoxifen is a well-tolerated agent, and less than 5% of women with early breast cancer discontinue therapy due to side effects.[1,2] Side effects are usually limited to those associated with tamoxifen's antiestrogenic properties; for example, hot flashes are the most frequently experienced side effect, particularly in premenopausal women, and vaginal bleeding, fluid retention, irregular menses, irritability, headache, and dizziness have also been observed.[1,2]
In 1% to 3% of patients, long-term tamoxifen therapy has been associated with thromboembolic events.[1,2] Although rare at currently used doses, very high doses of tamoxifen, particularly with previous or concurrent cytotoxic therapy, have been associated with retinal changes, keratopathy, and optic neuritis.
The results of laboratory studies in rats have indicated that high daily doses of tamoxifen administered over a significant portion of the lifespan are hepatocarcinogenic. However, clinical observations and epidemiologic evidence do not support an increased risk for liver tumors in patients treated with tamoxifen.[1-3,41]
Tamoxifen administration appears to produce a modest increase in risk for endometrial cancer, with a rate of detection of 0.2% to 0.3% per year, compared with 0.1% in breast cancer patients not receiving tamoxifen.[1-3,41] However, the risk for high-grade endometrial cancers of poor prognosis is not increased with tamoxifen therapy. Tamoxifen may have a causative or stimulatory role. The general consensus of the medical community is that the benefits of tamoxifen in patients with breast cancer clearly outweigh the risk of endometrial carcinoma.[1-3,41] Whether the risk/benefit ratio is sufficient for administration of tamoxifen as a chemoprotective agent in healthy women at high risk for breast cancer remains to be determined.
Over the last 20 years, tamoxifen has become the most widely used endocrine agent for the management of advanced breast cancer in both pre- menopausal and postmenopausal women. In addition, tamoxifen is considered to be the adjuvant agent of choice for postmenopausal women with node-positive disease or good risk node-negative disease at high risk for recurrence. In addition, tamoxifen-chemotherapy combinations are another viable option for premenopausal or postmenopausal women with node-positive disease or high-risk, node-negative disease. However, the chemotherapy agents must be chosen with care since not all combinations provide beneficial results.
Controversy still exists in the medical community as to tamoxifen's role in premenopausal women with node-positive disease or high-risk, node-negative disease. However, the results of the EBCTCG analysis indicate that estrogen receptor status may be a better indicator than either menopausal or nodal status when determining the clinical role of tamoxifen.
While tamoxifen remains the agent of choice in the medical management of breast cancer, many issues still need to be resolved regarding the optimum duration of tamoxifen therapy and its potential use as a chemoprotective agent in healthy women at high risk for breast cancer.