提示: 手机请竖屏浏览!

依西美坦在预防绝经后女性乳腺癌的作用
Exemestane for Breast-Cancer Prevention in Postmenopausal Women


Paul E. Goss ... 肿瘤 • 2011.06.23
相关阅读
• 阿那曲唑是否对乳腺癌发挥长期预防作用 • 美国预防服务工作组关于乳腺癌化学预防的新建议 • 芳香酶抑制剂长期辅助治疗早期乳腺癌

摘要


背景

他莫西芬和雷洛昔芬在乳腺癌的一级预防中患者的接受度有限。对于早期乳腺癌患者,芳香化酶抑制剂比他莫西芬可以更好地预防对侧乳腺癌的发生,而且副作用更少。


方法

在一项随机、安慰剂对照、双盲的依西美坦临床试验中,设计的终点目标为使浸润性乳腺癌的发病率相对下降65%。入组标准包括≥35岁的绝经后女性,且至少满足以下一条危险因素:≥60岁;Gail系统评估5年发病风险评分>1.66%(5年内发展为浸润性乳腺癌的百分比);既往有乳腺导管或小叶非典型增生或者小叶原位癌病史,或因导管原位癌行乳房切除术的患者。该研究同时对入组患者的毒性反应、健康相关和绝经特异性生活质量进行了测定。


结果

共计入组的4,560名女性,中位年龄为62.5岁,中位Gail乳腺癌风险评分为2.3%,她们被随机分配到依西美坦组和安慰剂组。在组的的患者进行35个月的中位随访结果显示,依西美坦组检测出11例浸润性乳腺癌,安慰剂组为32例,提示依西美坦组浸润性乳腺癌的年发病率相对降低了65%(0.19%对0.55%;风险比0.35;95%可信区间[CI],0.18~0.70;P=0.002)。浸润性及非浸润性(导管原位癌)乳腺癌总年发病率,在依西美坦组为0.35%,在安慰剂组为0.77%(风险比,0.47;95% CI,0.27~0.79;P=0.004)。不良事件发生率在依西美坦组为88%,在安慰剂组85%(P=0.003)。两组间在骨折、心血管相关事件、其他肿瘤的发生和治疗相关死亡方面,无显著性差异。两组间患者的生活质量只存在极小差异。


结论

依西美坦显著降低了存在乳腺癌中度发病风险的绝经后女性浸润性乳腺癌的发生。在为期3年的中位随访期间,依西美坦没有引起严重的毒性反应,仅对患者健康相关生活质量引起微小变化(由辉瑞公司[Pfizer]等资助;NCIC CTG MAP.3在ClinicalTrials.gov注册号为NCT00083174)。





作者信息

Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D., José E. Alés-Martínez, M.D., Ph.D., Angela M. Cheung, M.D., Ph.D., Rowan T. Chlebowski, M.D., Ph.D., Jean Wactawski-Wende, Ph.D., Anne McTiernan, M.D., John Robbins, M.D., Karen C. Johnson, M.D., M.P.H., Lisa W. Martin, M.D., Eric Winquist, M.D., Gloria E. Sarto, M.D., Judy E. Garber, M.D., Carol J. Fabian, M.D., Pascal Pujol, M.D., Elizabeth Maunsell, Ph.D., Patricia Farmer, M.D., Karen A. Gelmon, M.D., Dongsheng Tu, Ph.D., and Harriet Richardson, Ph.D., for the NCIC CTG MAP.3 Study Investigators*
From Massachusetts General Hospital Cancer Center (P.E.G.) and Dana–Farber Cancer Institute (J.E.G.) — both in Boston; Mayo Clinic, Rochester, MN (J.N.I.); Hospital Nuestra Señora De Sonsoles, Ávila, Spain (J.E.A., on behalf of the Spanish Group for Breast Cancer Research); Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA (R.T.C.); University at Buffalo, Buffalo, NY (J.W.-W.); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle (A.M.); University of California, Davis, Sacramento (J.R.); University of Tennessee Health Science Center, Memphis (K.C.J.); George Washington University School of Medicine, Washington, DC (L.W.M.); University of Wisconsin School of Medicine and Public Health, Madison (G.E.S.); Kansas University Medical Center, Kansas City (C.J.F.); Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France (P.P., on behalf of the National Federation of French Cancer Centers); University Health Network, Toronto (A.M.C.), London Health Sciences Centre, London, ON (E.W.), Unité de recherche en santé des populations de l'Université Laval, Quebec (E.M.), Queen's University Pathology and Molecular Medicine, Kingston, ON (P.F.), British Columbia Cancer Agency, Vancouver, BC (K.A.G.), and NCIC Clinical Trials Group, Kingston, ON (D.T., H.R.) — all in Canada. Address reprint requests to Dr. Goss at Massachusetts General Hospital Cancer Center, Lawrence House, LRH-302, Boston, MA 02114, or at pgoss@partners.org. *The NCIC Clinical Trials Group MAP.3 (NCIC CTG MAP.3) investigators are listed in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001;344:276-285[Erratum, N Engl J Med 2001;344:1804.]

2. Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE. Circulating 2-hydroxy- and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev 2008;17:2029-2035

3. Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TIA. Growth patterns and the risk of breast cancer in women. N Engl J Med 2004;351:1619-1626

4. The Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94:606-616

5. Fisher B, Costantino JP, Wickerham DL, 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;90:1371-1388

6. Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361:296-300

7. Cuzick J. Long-term follow-up in cancer prevention trials (It ain't over till it's over). Cancer Prev Res (Phila) 2010;3:689-691

8. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125-137

9. Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004;96:1751-1761

10. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-2741

11. Armstrong K, Quistberg DA, Micco E, Domchek S, Guerra C. Prescription of tamoxifen for breast cancer prevention by primary care physicians. Arch Intern Med 2006;166:2260-2265

12. Lippman SM. The dilemma and promise of cancer chemoprevention. Nat Clin Pract Oncol 2006;3:523-523

13. Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer chemoprevention: a systematic review and meta-analysis. J Clin Oncol 2010;28:3090-3095

14. Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical Oncology 2008 clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 2009;27:3235-3258

15. Waters WA, Cronin KA, Graubard BI, Han PK, Freedman AN. Prevalence of tamoxifen use for breast cancer chemoprevention among U.S. women. Cancer Epidemiol Biomarkers Prev 2010;19:443-446

16. Chlebowski RT, Col N, Winer EP, et al. American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 2002;20:3328-3343

17. Gail MH. Personalized estimates of breast cancer risk in clinical practice and public health. Stat Med 2011;30:1090-1104

18. Goss PE. Breast cancer prevention -- clinical trials strategies involving aromatase inhibitors. J Steroid Biochem Mol Biol 2003;86:487-493

19. Lubet RA, Steele VE, Casebolt TL, Eto I, Kelloff GJ, Grubbs CJ. Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats. Carcinogenesis 1994;15:2775-2780

20. De Coster R, Van Ginckel RF, Callens MJ, Goeminne NK, Janssens BL. Antitumoral and endocrine effects of (+)-vorozole in rats bearing dimethylbenzanthracene-induced mammary tumors. Cancer Res 1992;52:1240-1244

21. Schieweck K, Bhatnagar AS, Batzl C, Lang M. Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol 1993;44:633-636

22. Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003;98:1802-1810

23. The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747-57. [Erratum, N Engl J Med 2006;354:2200.]

24. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092[Erratum, 2004;351:2461, 2006;355:1746.]

25. van de Velde CJ, Rea D, Seynaeve C, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomized phase 3 trial. Lancet 2011;377:321-331

26. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802

27. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28:509-518

28. Goss PE, Qi S, Josse RG, et al. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 2004;34:384-392

29. Joahannessen DC, Engan T, Di Salle E, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 1997;3:1101-1108

30. Goss PE, Hadji P, Subar M, Abreu P, Thomsen T, Banke-Bochita J. Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. Breast Cancer Res 2007;9:R52-R52

31. Tu D. Minimization Procedure. In: Chow SC, ed. Encyclopedia of biopharmaceutical statistics. 3rd ed. New York: Marcel Dekker, 2010:795-8.

32. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879-1886

33. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080

34. Ware JE Jr. SF-36 health survey update. Spine (Phila Pa 1976;25:3130-3139

35. Hilditch JR, Lewis J, Peter A, et al. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas 1996;24:161-175[Erratum, Maturitas 1996;25:231.]

36. Ware JE, Kosinksi M, Dewey JE. How to score version 2 of the SF-36 health survey. Lincoln, RI: QualityMetric, 2000.

37. Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, version 3.0. March 31, 2003. (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.)

38. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003;41:582-592

39. Wyrwich KW, Fihn SD, Tierney WM, Kroenke K, Babu AN, Wolinsky FD. Clinically important changes in health-related quality of life for patients with chronic obstructive pulmonary disease: an expert consensus panel report. J Gen Intern Med 2003;18:196-202

40. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23:6931-6940

41. Perez EA, Josse RG, Pritchard KI, et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 2006;24:3629-3635

42. Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol 2008;26:1051-1057

43. Coleman RE, Banks LM, Girgis SI, et al. Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study. Breast Cancer Res Treat 2010;124:153-161

44. Geisler J, Lonning PE, krag LE, et al. Changes in bone and lipid metabolism in postmenopausal women with early breast cancer after terminating 2-year treatment with exemestane: a randomised, placebo-controlled study. Eur J Cancer 2006;42:2968-2975

45. Eastell R, Adams J, Clack G, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol 2011;22:857-862

46. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:1135-1141

47. Mouridsen H, Keshaviah A, Coates AS, et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol 2007;25:5715-5722

48. Ingle JN, Tu D, Pater JL, et al. Duration of letrozole treatment and outcomes in the placebo-controlled NCIC CTG MA.17 extended adjuvant therapy trial. Breast Cancer Res Treat 2006;99:295-300

服务条款 | 隐私政策 | 联系我们