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Many questions remain about chemoprevention of breast cancer (64). First, we need to learn more about the effects of the drugs. We need better information about the optimal dose, the duration of effect, the presence and magnitude of any reduction in breast cancer mortality, and the magnitude of the known and any unknown adverse or beneficial effects (65,66). Studies in women with breast cancer indicate that treatment with tamoxifen for longer than 5 years confers no additional benefit. Not known is what happens to the incidence of breast cancer once women stop the chemopreventive drug. Studies of adjuvant tamoxifen use for the treatment of breast cancer have found that the benefit lasts at least another 5 years and probably longer after the 5-year treatment period (67,68). Whether the same holds true for chemoprevention is not known.
Second, we need to learn how best to use tamoxifen and raloxifene. This includes finding better ways to select those women most likely to benefit and least likely to be harmed, and better ways to counsel them about the effects of chemoprevention (69,70). How many eligible women will choose to take tamoxifen or raloxifene for 5 years is uncertain.
Further clinical trials are needed to answer these and other questions. Many women in the BCPT placebo group began taking tamoxifen after the study results were made public. Thus, the BCPT is unlikely to provide further information on the many unanswered questions of chemoprevention. The International Breast Cancer Intervention Study (IBIS), based in the United Kingdom, Europe, and Australia, is an ongoing placebo-controlled study of breast cancer chemoprevention with tamoxifen (71). The National Cancer Institute has launched a study that will directly compare tamoxifen and raloxifene, the Study of Tamoxifen and Raloxifene (STAR) trial (NSABP P-2) (72). Results are anticipated by 2006. Another RCT, the Raloxifene Use for the Heart study (RUTH), will assess the effectiveness of raloxifene compared with placebo on both coronary heart disease and breast cancer (73). An important question is whether RUTH will corroborate the MORE finding of a beneficial CV effect of raloxifene.
Although the trade-off between benefits and harms for the present drugs, given current evidence, may be acceptable for a relatively small number of women, the findings from the studies of tamoxifen and raloxifene signal a new and promising direction for research in the control of breast cancer. We should pursue this direction energetically.
We acknowledge the assistance of David Atkins, MD, MPH, Director; Dana Best, MD, MPH; and Eve Shapiro of the AHRQ Clinical Prevention Program. We are grateful to Carmen Lewis, MD, MPH and Margaret Wooddell, MA, for their assistance in reviewing the studies of tamoxifen and raloxifene cited in this paper. We are also grateful for the superb assistance of Audrina J. Bunton, BA and Lynn Whitener, MSLS, DrPH, of UNC and Sonya Sutton, BSPH and Loraine Monroe of the Research Triangle Institute. We would also like to acknowledge Bahjat Qaqish, MD, PhD for statistical assistance.
This study was developed by the RTI-UNC Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0011), Rockville, MD.
7. Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292-9.
8. Cauley JA, Lucas FL, Kuller LH, Stone K, Browner W, Cummings SR. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1999;130:270-7.
9. Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, Banerjee S, Koenig KL, Shore RE, Strax P, Pasternack BS. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 1995;87:190-7.
13. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:1-15.
15. Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, Smith R, Begovic M, Dimitrov NV, Margolese RG, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993-2000.
16. Veronesi U, De Palo G, Marubini E, Costa A, Formelli F, Mariani L, Decensi A, Camerini T, Del, Turco M, et al. Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J Natl Cancer Inst 1999;91:1847-56.
17. Kinsinger L, Harris R, Lewis C, et al. Chemoprophylaxis of Breast Cancer. Systematic Evidence Review. Rockville, MD: Agency for Healthcare Research and Quality; 2001. Online at http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat3.chapter.2527.
19. Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, Tidy A, Viggers J, Davey J. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998;352:98-101.
20. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-88.
21. Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998;352:93-7.
22. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, 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;281:2189-97.
24. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, Mulvihill JJ. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879-86.
25. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Ng KW, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 2001;65:125-34.
26. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445-51.
27. Love RR, Newcomb PA, Wiebe DA, Surawicz TS, Jordan VC, Carbone PP, DeMets DL. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer [see comments]. J Natl Cancer Inst 1990;82(16):1327-32.
28. Barrett-Conner E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD. Raloxifine and cardiovascular events in osteoporotic postmenopausal women: Four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847-57.
29. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637-45.
30. Day R, Ganz PA, Constantino JP, Cronin WM, Wickerham DL, Fisher B. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Adjuvant Surgical Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659-69.
32. Rutqvist LE, Cedermark B, Glas U, Mattsson A, Skoog L, Somell A, Theve T, Wilking N, Askergren J, Hjalmar ML, et al. Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. J Natl Cancer Inst 1991;83:1299-306.
33. Fisher B, Redmond C. Systemic therapy in node-negative patients: updated findings from NSABP clinical trials. National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst Monogr 1992;11:105-16.
36. Potter JD, Cerhan JR, Sellers TA, McGovern PG, Drinkard C, Kushi LR, Folsom AR. Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women's Health Study: how many kinds of breast cancer are there? Cancer Epidemiol Biomarkers Prev 1995;4:319-26.
38. King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, Tait J, Ford L, Dunn BK, Costantino J, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001;286:2251-6.
41. National Cancer Institute (NCI) and National Surgical Adjuvant Breast and Bowel Project (NSABP). Breast Cancer Risk Assessment Tool. 2000; Available at: http://bcra.nci.nih.gov/brc/. Accessed Feb 8, 2002.
44. Costantino JP, Gail MH, Pee D, Anderson S, Redmond CK, Benichou J, Wieand HS. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 1999;91:1541-8.
47. Rockhill B, Spiegelman D, Byrne C, Hunter DJ, Colditz GA. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 2001;93:358-66.
49. Gail MH, Costantino JH, Bryant J, Croyle R, Freedman L, Helzlsouer K, Vogel V. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer . J Natl Cancer Inst 1999;91:1829-46.
54. Rosamond WD, Folsom AR, Chambless LE, Wang CH, McGovern PG, Howard G, Copper LS, Shahar E. Stroke incidence and survival among middle-aged adults: 9-year followup of the Artherosclerosis Risk in Communities (ARIC) cohort. Stroke 1999;30:736-43.
56. Kuller L, Fisher L, McClelland R, Fried L, Cushman M, Jackson S, Manolio T. Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1998;18:283-93.
67. Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529-42.
71. Cuzick J. A brief review of the International Breast Cancer Intervention Study (IBIS), the other current breast cancer prevention trials, and proposals for future trials. Ann NY Acad Sci 2001;949:123-33.
72. National Cancer Institute (NCI) and National Surgical Adjuvant Breast and Bowel Project (NSABP). Prevention Study of Tamoxifen and Raloxifene (STAR) in Postmenopausal Women at Increased Risk for Invasive Breast Cancer. 1999 July; Available at: http://www.nsabp.pitt.edu/STAR/Index.html. Accessed 08 Feb 2002.
73. Barrett-Connor E, Wenger NK, Grady D, Mosca L, Collins P, Kornitzer M, Cox DA, Moscarelli E, Anderson PW. Coronary heart disease in women, randomized clinical trials, HERS and RUTH. Maturitas 1998;31:1-7.
Select for Appendix.
[a] Linda S. Kinsinger: Cecil G. Sheps Center for Health Services Research; Department of Medicine; University of North Carolina at Chapel Hill, Chapel Hill, NC.
[b] Russell Harris: Cecil G. Sheps Center for Health Services Research; Department of Medicine; University of North Carolina at Chapel Hill, Chapel Hill, NC.
[c] Steven H. Woolf: Department of Family Practice; Virginia Commonwealth University, Fairfax, VA.
[d] Harold C. Sox: American College of Physicians-American Society of Internal Medicine, Philadelphia, PA.
[e] Kathleen N. Lohr: Research Triangle Institute, Research Triangle Park, NC.
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Source: U.S. Preventive Services Task Force. Chemoprevention of breast cancer: summary of the evidence. Ann Intern Med 2002;137:59-67.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
U.S. Preventive Services Task Force. Chemoprevention of Breast Cancer: Summary of the Evidence. Article originally in Annals of Internal Medicine 2002;137:59-67. http://www.uspreventiveservicestaskforce.org/3rduspstf/breastchemo/brstchemosum1.htm