Estrogen has long been implicated in the promotion of human breast cancer, fostering the concept that prevention of the disease could be achieved by an antiestrogenic intervention. Experimental data showing that ovarian ablation or treatment with antiestrogens, such as tamoxifen (Nolvadex) or raloxifene (Evista), could prevent the development of endocrine-sensitive tumors in rats[2-4] supported the initiation of clinical trials in healthy high-risk women.
The choice of an intervention was difficult. Ovarian ablation was considered to be unacceptable, particularly in young women, because of the adverse effects of early menopause, particularly on bone and cardiovascular disease. However, the use of tamoxifen as adjuvant therapy for patients with primary breast cancer indicated early encouraging results, with evidence of a significant reduction in risk of relapse and death. Of particular interest at that time was the very low toxicity reported with long-term tamoxifen therapy, together with a reduction in the risk of contralateral new primary breast cancers.
By 1985, tamoxifen had been used extensively as adjuvant therapy in women with primary breast cancer, many of whom had a very good prognosis. It was likely that most of these women would survive for many years, and use of tamoxifen was considered safe in such women. However, use of tamoxifen in healthy women in a prevention trial, who had not had breast cancer, would require substantially more monitoring. In 1986, therefore, it was agreed that a feasibility trial should be started at the Royal Marsden Hospital to evaluate the safety and acceptability of tamoxifen in healthy women; this feasibility trial would then extend into a pilot program.
The Royal Marsden program started in October 1986 with a small feasibility trial of 200 healthy premenopausal and postmenopausal women aged 35 and 65 years old, who were randomized to receive either tamoxifen (20 mg/d) or placebo for 5 years. In 1988, the interim analysis of this feasibility trial indicated that healthy women could be accrued to a tamoxifen chemoprevention trial, acute toxicity was very low, and compliance was correspondingly high. Safety monitoring at this time indicated no evidence of bone loss or any adverse effects on clotting. Moreover, there were indications of a lowering of serum cholesterol. This trial, therefore, extended into the main pilot trial, which accrued 2,500 women over the following 8 years.
Accrual to this trial has now been completed. The clinical characteristics of participants randomized to tamoxifen or placebo are almost identical. The median age of all participants is 48 years (range, 30 to 70 years), 61% of participants are premenopausal, and 22.5% have had a previous benign biopsy. Most participants have a strong family history of breast cancer. The overall relative risk of developing breast cancer in all participants is approximately 3.7, compared to an age-matched population.
Acute toxicity was low for tamoxifen-treated participants, compared to placebo recipients. The only side effects occurring significantly more often in tamoxifen-treated patients than in placebo-treated patients were hot flushes (34% vs 20%) vaginal discharge (16% vs 4%), and menstrual irregularities (14% vs 9%). The compliance at 5 years was correspondingly high, at 77% for tamoxifen vs 82% for placebo.
Effects on Lipids and BoneSafety monitoring, including monitoring of clotting and lipid profiles, has shown no evidence of any adverse effects of tamoxifen in this trial. A reduction in serum cholesterol of about 15% has been maintained in premenopausal and postmenopausal women given tamoxifen; this is associated with a decline in low-density lipoprotein (LDL) but not high-density lipoprotein (HDL) cholesterol.
Monitoring of bone density has shown a transient increase of about 1% to 2% in bone mineral density in postmenopausal women treated with tamoxifen, compared to a small decline in bone density in women on placebo. However, in premenopausal women, tamoxifen caused a transient but significant reduction in bone mineral density, probably due to an antiestrogenic effect on bone.
Risk of Endometrial and Other CancersExperimentally, tamoxifen has been shown to be genotoxic, and clinically there have been reports of an increased incidence of some nonmammary cancers in patients who have received adjuvant tamoxifen. The main risk appears to relate to the incidence of endometrial cancer, which appears to be increased in women receiving tamoxifen.
The risk appears to be dose-dependent, particularly in relation to the total dose of tamoxifen. However, at the standard dose of 20 mg/d, retrospective studies indicate that the actual increase in risk is probably only about twofold in postmenopausal women receiving 2 to 5 years of tamoxifen. Any increased risk of endometrial cancer appears to be unrelated to the genotoxic properties of tamoxifen and more likely due to its estrogenic effects on an atrophic postmenopausal endometrium.
At the higher dose of 40 mg/d, an increased risk of gastrointestinal cancers has been reported in a retrospective study of adjuvant tamoxifen. This has not been confirmed in other trials or in the Oxford meta-analysis. Furthermore, there is no evidence that tamoxifen causes any increase in adducts in the liver of patients receiving the drug.
In the pilot tamoxifen program, only 15 non-endometrial, non-breast cancers have occurred, with no significant difference in incidence in the two arms.
Other gynecologic effects have been reported with tamoxifen, including an increased risk of endometrial cysts, polyps, and fibroids. In our pilot trial, over 40% of postmenopausal women receiving tamoxifen have an endometrium of > 8 mm, compared to only 5% of women taking placebo. This may be due, in part, to tamoxifen-induced hyperplasia. However, cysts, polyps, and fibroids have been detected by transvaginal ultrasound screening in about 30% of women treated with tamoxifen, indicating stromal changes in the uterus caused by tamoxifen. These gynecologic changes are, for the most part, asymptomatic but can lead to a small but significant increase in the requirements for a hysterectomy.
Summary of ResultsOverall, the pilot program indicated that it is possible to give tamoxifen/placebo in a double-blind trial to healthy women at risk of developing breast cancer. Furthermore, the acute toxicity profile of tamoxifen was low and compliance was high.
Overall, safety monitoring indicated that any possible long-term risks related to tamoxifen treatment were likely outweighed by the potential benefits on normal tissues, particularly the lowering of cholesterol and the increase in bone mineral density. The long-term risks of tamoxifen on bone in premenopausal women and the gynecologic effects of tamoxifen in postmenopausal women, in particular, will need continued surveillance.
Overall, however, the benefits of tamoxifen, particularly the potential for a substantial reduction in the risk of breast cancer, were considered likely to outweigh the risks. On this basis, various international multicenter trials were initiated.
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