Alternatives to tamoxifen

Several other pharmacologic agents that affect reproductive hormones or their actions are being examined to reduce the risk of breast cancer. While raloxifene’s only approved indication is for the treatment of osteoporosis, secondary data analysis from the Multiple Outcomes of Raloxifene Evaluation (MORE) clinical trial showed a 76% reduction in the frequency of breast cancer in the raloxifene group. The analysis was criticized because the study was never designed as a breast cancer prevention study. Participants were not randomized based on their breast cancer risk, so it is unknown if the placebo and raloxifene groups had the same average risk. Also, the study population was at high risk for osteoporosis, and some research shows that such women have a lower overall risk of breast cancer. Since the follow-up period is now only 4 years, the question of suppression of growth versus true prophylaxis awaits resolution. The data are powerful evidence, however, of an anti-breast cancer effect of raloxifene.

The Study of Tamoxifen and Raloxifene (STAR) trial, currently enrolling participants, is aimed at clarifying the benefits of raloxifene. This will be the first breast cancer prevention trial to incorporate an active agent (tamoxifen instead of placebo) as the standard of care. Two additional ongoing trials that will add more raloxifene data are Raloxifene Use for The Heart (RUTH) and Continuing Outcomes Relevant to Evista (CORE). Now 4 years into the trials, researchers have preliminarily reported a lack of cognitive decline.

Another agent being examined for risk reduction is a chlorinated derivative of tamoxifen, toremifene. This agent is approved for the treatment of breast cancer in postmenopausal women with ER-positive or receptor-unknown status tumors. Clinical experience with toremifene is limited. This agent has bone antiresorptive effects comparable to those of tamoxifen, but its effect on the uterus and endometrium has not been clearly defined in clinical trials. The risk of DVT is probably comparable to that for tamoxifen. Trials are under way in postmenopausal women comparing the efficacy of tamoxifen with toremifene for the adjuvant treatment of early-stage breast cancer.

Finally, some researchers see aromatase inhibitors as the wave of the future. Early but valid studies indicate that these agents, which block estrogen formation throughout the body, are approximately one third more effective at shrinking breast lesions than SERMs like tamoxifen. This evidence, plus the other data mentioned earlier in this article, indicate a role for endogenous estrogen in breast cancer development that is much more profound than that due to conventional doses of ERT/HRT.

Conclusions
Many unsettling questions remain to be answered. But evidence is still lacking that ERT or HRT contribute to breast cancer. Rather, there may be a marginal increase in diagnoses after a decade or more of ERT/HRT use that actually represents a very small number of cases per 1,000 women at risk. It remains to be seen whether the additional cases are a result of the increased longevity of women who receive ERT/HRT. On the other hand, there is considerable evidence that estrogen formed in the breast may play a key role in the development of breast cancer and that this local estrogen plays a dominant role in the disease’s cause.

Patients who are diagnosed with breast cancer and are on ERT/HRT have a better prognosis stage for stage, and large series appear to show no change in recurrence rates in women receiving ERT/HRT after apparently successful primary treatment for breast cancer. Mammography is the most successful tool in early diagnosis of breast cancer and the current controversy over mammography deals with the possibility that early diagnosis may lead to unnecessary treatment of early lesions whose propensity to metastasize is not yet defined. Tamoxifen, raloxifene, toremifene, and aromatase inhibitors are all very promising agents that obviate locally formed and circulating estrogens at the level of the breast. They have been shown effective in preventing and treating breast cancer.

REFERENCES

_{1. Vogel VG. Breast cancer prevention: a review of current evidence. CA Cancer J Clin. 2000;50:156-170.}

2. Smith RA, Mettlin CJ, Davis KJ, et al. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin. 2000;50:34-49.

3. Parker SL, Davis KJ, Wingo PA, et al. Cancer statistics by race and ethnicity. CA Cancer J Clin. 1998;48:31-48.

4. Flaws JA, Newschaffer CJ, Bush TL. Breast cancer mortality in black and in white women: a historical perspective by menopausal status. J Womens Health. 1998;7:1007-1015.

5. Olsen O, Gotzsche PC. Cochrane review on screening for breast cancer with mammography. Lancet. 2001;20;358:1340-1342.

6. Kolata G. Expert panel cites doubts on mammogram’s worth. The New York Times. January 24, 2002: sect 1:A16.

7. Beers MH, Berkow R, eds. The Merck Manual of Geriatrics. Whitehouse Station, NJ: Merck Research Laboratories; 2000:1217-1228.

8. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991;151:67-72.

9. Steinberg KK, Thacker SB, Smith SJ, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA. 1991;265:1985-1990.

10. Bush, TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508.

11. Colditz GA, Stampfer MJ, Willett WC, et al. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA. 1990;264:2648-2653.

12. Colditz GA. Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995;332:1589-1593.

13. Holli K, Isola J, Cuzick. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol. 1998;16:3115-3120.

14. Gambrell RD Jr., Maier RC, Sanders BI. Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet Gynecol. 1983;62:435-443.

15. Voelker R. Hormone confusion creates “credibility gap.” JAMA. 2000;284:424-428.

16. Ross RK, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328-332.

17. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;383:485-491.

18. The American College of Obstetricians and Gynecologists. Guidelines for women’s health care. Washington, DC: ACOG; 1996:104.

19. Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med. 2000;343:1086-1094.

20. Fisher B, Constantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989;320:479-484.

21. Fisher B, Constantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994;86:527-537.

22. Reis SE, Costantino JP, Wickerham DL, et al. Cardiovascular effects of tamoxifen in women with and without heart disease: Breast Cancer Prevention Trial. J Natl Cancer Inst. 2001;93:16-21.

23. The American College of Obstetricians and Gynecologists. ACOG News Release: ACOG says use of tamoxifen in preventing breast cancer must be individualized. Washington, DC: ACOG; September 30;1999.

24. Chlebowski RT, Collyar DE, Somerfield MR, et al. American Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene. J Clin Oncol. 1999;17:1939-1955.

25. Gail MH, Constantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91:1829-1846.

26. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-2197.

27. Vastag B. Breast cancer prevention study aims to overcome drug bias. JAMA. 2001;285:399-400.

28. Results of the ATAC Adjuvant Breast Cancer Study in Postmenopausal Women. Presented at the 24th annual San Antonio Breast Cancer Symposium. Dec 10-13, 2001, San Antonio, Tex.

By Frederick Naftolin, MD, DPhil, Dahlia Mishell Sataloff, MD, and Trudy L. Bush, PhD, MHS