Status of Antiestrogen Breast Cancer Prevention Trials

March 2, 1998

Various ongoing double-blind clinical trials are evaluating the use of tamoxifen (Nolvadex) as chemoprevention for breast cancer. A total of over 24,000 healthy women have been randomized to these trials, and it should be possible, by the year 2000, to detect any preventive effect of tamoxifen in healthy women. Furthermore, with the large numbers of women involved, it should be possible to evaluate prevention in subgroups of participants according to risk of the disease, particularly those women carrying high-risk genes, such as BRCA1 and BRCA2.

ABSTRACT: Various ongoing double-blind clinical trials are evaluating the use of tamoxifen (Nolvadex) as chemoprevention for breast cancer. A total of over 24,000 healthy women have been randomized to these trials, and it should be possible, by the year 2000, to detect any preventive effect of tamoxifen in healthy women. Furthermore, with the large numbers of women involved, it should be possible to evaluate prevention in subgroups of participants according to risk of the disease, particularly those women carrying high-risk genes, such as BRCA1 and BRCA2. Adverse effects of tamoxifen have been identified, including a transient bone loss in premenopausal women and uterine effects, including polyps, cysts, and endometrial cancer, in postmenopausal women. Although the potential benefit of tamoxifen in preventing breast cancer in healthy women is likely to outweigh any potential long-term risks, the use of other tamoxifen-like drugs, such as raloxifene (Evista) and toremifene (Fareston) is now being investigated.[ONCOLOGY(Suppl 5):28-31, 1998]

Estrogen has long been implicated in the promotion of human breast cancer,[1] 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,[5] 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.[6]

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.

Royal Marsden Feasibility and Pilot Trial

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.[7] 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.

Toxicity

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 Bone—Safety 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.[8]

Risk of Endometrial and Other Cancers—Experimentally, tamoxifen has been shown to be genotoxic,[9] and clinically there have been reports of an increased incidence of some nonmammary cancers in patients who have received adjuvant tamoxifen.[10] 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.[11] 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.[12] Any increased risk of endometrial cancer appears to be unrelated to the genotoxic properties of tamoxifen[13] 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.[10] 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.[14]

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.[15]

Summary of Results—Overall, 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.

Other Tamoxifen Chemoprevention Trials

NSABP Trial

In 1991, the FDA granted approval for the National Surgical Adjuvant Breast and Bowel Project (NSABP) to begin a National Cancer Institute-supported multicenter trial evaluating tamoxifen (20 mg/d) or placebo in healthy women at risk of developing breast cancer. To be eligible for participation, women over 59 years old did not have to be at special risk of breast cancer, whereas those between 35 and 59 years old had to have an increased risk of breast cancer because of a family history, which raised their risk to the level of a 60-year old woman.

By 1996, over 12,000 women had been randomized to receive either tamoxifen or placebo. This trial is now closed to accrual, having enrolled over 13,000 women.

Italian Trial

In 1991, the National Cancer Institute in Milan commenced a randomized clinical trial, recruiting healthy women over 45 years old who were not at special risk of developing breast cancer but who had undergone a hysterectomy. By 1996, over 5,000 women had been randomized to tamoxifen or placebo, and follow-up evaluation of these women continues.

International Breast Cancer Intervention Study

In 1992, the multicenter International Breast Cancer Intervention Study (IBIS) began recruiting healthy women in the United Kingdom who were 40 to 65 years old and who had at least a twofold increased risk of breast cancer because of family history. Over 4,000 women have now been accrued to this trial, and enrollment is continuing. Patients are randomized to tamoxifen 20 mg/d or placebo.

Summary of Ongoing Trials

At present, approximately 24,000 women are enrolled in tamoxifen chemoprevention trials throughout the world. The various safety monitoring requirements for each individual trial should provide much more information about the effects of tamoxifen in normal healthy women. By the year 2000, several of these trials hopefully should be able to provide incidence data on the risk of developing breast cancer.

Furthermore, it is anticipated that an overview meta-analysis of all of these trials may be possible in the year 2000; this meta-analysis could establish accurate incidence data on tamoxifen in a chemoprevention setting. The large numbers of participants in such a meta-analysis could allow subgroup analysis of the relative effects of tamoxifen on the incidence of breast cancer in participants with a low risk of breast cancer, as well as those at increased risk because of a family history, including those who may have inherited a high-risk gene, such as BRCA1 or BRCA2. It is possible that the importance of endocrine promotion in these subgroups may vary, and that these differences could be identified only in a meta-analysis of all participants.

Other Agents

Raloxifene

Raloxifene has properties very similar to those of tamoxifen. It causes a small but significant increase in bone mineral density in postmenopausal women and a similar decrease in cholesterol. However, raloxifene has several added advantages over tamoxifen: It has no agonistic (estrogenic) effect on the endometrium, does not appear to cause stromal cystic and polypoid changes, and is not genotoxic.[16]

Several trials have evaluated the use of raloxifene to prevent osteoporosis or reduce the fracture rate in women at risk of osteoporosis, and the FDA recently approved the drug for this indication. These trials now involve over 14,000 otherwise healthy postmenopausal women at no special risk of developing breast cancer. Raloxifene has been shown to reduce the risk of hormone-dependent experimental tumors in rats, and therefore within these osteoporosis trials, an evaluation of the risk of breast cancer is being undertaken. Participants are having annual mammography, which will allow an evaluation of the incidence of breast cancer in women receiving raloxifene compared to placebo. Thus, these trials should identify any chemopreventive effect of raloxifene in a healthy population of postmenopausal women.

Toremifene

Toremifene (Fareston) is another antiestrogenic agent with properties similar to those of tamoxifen. However, toremifene appears to increase bone mineral density in postmenopausal women,[17] and also has a possible added advantage in terms of its effects on the lipid profile: Toremifene reduces cholesterol to a similar extent as tamoxifen, but evidence suggests that it also increases HDL cholesterol, which provides a better LDL/HDL cholesterol ratio with respect to protection against coronary heart disease. Furthermore, toremifene is not genotoxic and probably has less of a proliferative effect on the endometrium.

We have now started a small feasibility study comparing toremifene (60 mg/d) with tamoxifen and placebo. This three-arm trial will evaluate the effect of toremifene on normal tissues in healthy women who have an increased risk of breast cancer because of a strong family history.

Conclusions

Use of an antiestrogen, such as tamoxifen, as chemoprevention clearly has a real potential to substantially reduce the incidence of breast cancer. However, the risks of such an intervention in a large population of healthy women are significant. Although we now have a very substantial amount of data on the use of tamoxifen in more than 5 million women, many of whom have lived for more than 20 years since exposure, evaluation of the long-term risks are still inadequate. Even a very small toxic risk could be unacceptable in a healthy population of women.

It is therefore important that a careful evaluation be made of the long-term safety monitoring, together with an evaluation of the effect of tamoxifen on cancer incidence. Such evaluations are particularly important in subgroups of women at special risk among the large number of women in chemoprevention trials. It now seems likely that the potential benefits of tamoxifen use as chemoprevention in healthy, high-risk women are likely to outweigh its established and potential risks.

The possibility of developing the next generation of tamoxifen-like drugs, which have selective beneficial effects on bone, lipids, the uterus, and ovaries but do not have the detrimental effects and are not genotoxic, offers the potential for selectively preventing breast cancer and other major diseases in healthy women. The analyses of the tamoxifen chemoprevention trials, together with evaluations of these new agents for use in healthy women, may provide us with the real possibility of being able to safely prevent breast cancer.

References:

1. Dao T: The role of ovarian hormones in initiating the induction of mammary cancer in rats by polynuclear hydrocarbons. Cancer Res 22:973-981, 1962.

2. Jordan VC, Lababidi M, Mirecki D: The prolonged antiestrogenic and antitumor properties of prolonged tamoxifen therapy in C3H/OUJ mice. Eur J Cancer 26:718-721, 1990.

3. Jordan VC: Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12:419-425, 1976.

4. Jordan VC: Antitumor activity of the antiestrogen ICI 46,474 (tamoxifen) in the dimethylbenzantracene (DMBA)-induced rat mammary carcinoma model. J Steroid Biochem 5:354, 1974.

5. NATO: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer; Interim analysis at four years. Lancet 1:257-261, 1983.

6. Cuzick J, Baum M: Tamoxifen and contralateral breast cancer (letter). Lancet ii:282, 1985.

7. Powles T, Hardy J, Ashley S, et al: A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 60:126-131, 1989.

8. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996.

9. Han X, Liehr JG: Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 52:1360-1363, 1992.

10. Rutqvist L, Johansson H, Signomklao T, et al: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies: Stockholm Breast Cancer Study Group. J Natl Cancer Inst 87:645-651, 1995.

11. Fornander T, Rutqvist LE, Cedermark B, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1:117-120, 1989.

12. van Leeuwen FE, Benraadt J, Coebergh JWW, et al: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343:448-452, 1994.

13. Carmichael P, Ugwumadu A, Neven P, et al: Lack of genotoxicity of tamoxifen in human endometrium. Cancer Res 56(7):1475-1479, 1996.

14. Martin EA, Rich KJ, White IN, et al: 32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis 16:1651-1654, 1995.

15. Powles TJ, Jones AL, Ashley SE, et al: The Royal Marsden Hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res Treat 31:73-82, 1994.

16. Delmas P, Bjarnason N, Mitlak B, et al: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337(23):1641-1647, 1997.

17. Saarto T, Blomqvist C, Valimaki M, et al: Clodronate improves bone mineral density in postmenopausal breast cancer patients treated with adjuvant antioestrogens. Br J Cancer 75(4):602-605, 1997.