There were no differences among treatment groups in the overall incidence of breast-related adverse events in the SMART-5 main study. The incidences of selected breast-related adverse events also were low (less than 1.5% for each adverse event) and similar among groups (Table 5).
High mammographic breast density has been shown to be a moderate independent risk factor for breast cancer1,3–5 and shares a genetic basis with breast cancer through common genetic variants.6 High mammographic density also reduces mammographic sensitivity for detecting breast abnormalities.7,8 Therefore, it is important to examine the effects of various treatments, especially hormone-based therapies, on mammographic breast density.
Breast tenderness or pain is a common side effect of HT. New-onset breast tenderness after initiating estrogen–progestin therapy has been linked to greater increases in mammographic breast density17 and increased risk of subsequent breast cancer.16 Although the relationship between breast density and breast cancer and the role of estrogen–progestin therapy in this process are not completely understood, new treatment options for nonhysterectomized postmenopausal women that provide symptom relief without breast stimulation are needed.
Traditional HT (estrogen therapy for hysterectomized women; combined estrogen–progestin therapy for nonhysterectomized women) is an established treatment option for menopausal symptoms and osteoporosis prevention. Safety concerns associated with combination estrogen–progestin therapy include increased mammographic breast density9–11 and breast cancer risk.12–14 In the Women's Health Initiative trial, 5 years of continuous use of conjugated estrogens 0.625 mg–medroxyprogesterone acetate 2.5 mg was associated with increased incidence of invasive breast cancer12 and breast cancer mortality30 compared with placebo.
In this randomized double-blind substudy, minimal and nonsignificant changes in mean breast density comparable with bazedoxifene alone and placebo were found for both bazedoxifene-conjugated estrogens groups, whereas conjugated estrogens–medroxyprogesterone acetate showed a significant increase compared with placebo. Similarly, in the overall SMART-5 main study of 1,843 nonhysterectomized postmenopausal women, breast tenderness was reported by less than 10% of women in all study groups but conjugated estrogens–medroxyprogesterone acetate (more than 20%), incidences of breast cancer, abnormal mammogram results, and other breast-related adverse events were similar among groups. These results complement those from a retrospective substudy of the SMART-1 trial showing that 2-year treatment with bazedoxifene 20 mg–conjugated estrogens 0.45 or 0.625 mg did not affect mammographic breast density (mean percent change of –0.39% and –0.05%, respectively).27 The SMART-1, SMART-2, and SMART-3 trials also showed no increase in breast tenderness for both bazedoxifene-conjugated estrogens doses compared with placebo.19–21
The favorable breast safety profile observed with bazedoxifene-conjugated estrogens in clinical studies is consistent with data from preclinical studies showing that bazedoxifene combined with conjugated estrogens has antiproliferative effects on breast cancer cells.35,36 In studies evaluating the effects of selective estrogen receptor modulators on the mouse mammary gland in sexually immature ovariectomized mice, bazedoxifene was a more effective antagonist of conjugated estrogens activity than raloxifene or lasofoxifene.37 In a separate study,38 bazedoxifene, raloxifene, and lasofoxifene demonstrated significant antagonist effects against conjugated estrogens--stimulated MCF-7 breast tumor cell proliferation, with the greatest antagonism observed with bazedoxifene.
Strengths of the present study are the large number of mammogram pairs obtained and the ability to compare bazedoxifene-conjugated estrogens at different doses with both placebo and an active HT comparator. The analysis by a single mammographer blinded to time sequence and treatment eliminates investigator bias and interindividual variability. A limitation was that this was a substudy analysis. Initially, 51% of total study women were enrolled because power calculation estimated a need for 800 women. Women who completed the study comprised 41% (770 completed substudy of 1,843 enrolled in the main study). The subgroup was primarily white (90%), mean body mass index was 26 kg/m2, and mean years since menopause was 4.4, thus limiting the generalizability to women who are more obese, of different ethnic origins, or more than 5 years from menopause. There was potential selection bias because the substudy enrolled only women willing to have their mammograms analyzed. However, treatment groups were balanced and findings were consistent with earlier studies. No women from Latin America were randomized to the substudy, leading to possible demographic bias.
In summary, bazedoxifene 20 mg–conjugated estrogens 0.45 and 0.625 mg did not increase breast density or breast tenderness with an adverse event profile similar to bazedoxifene alone and placebo. These findings, taken together with previous reports demonstrating efficacy in relieving menopausal symptoms and preventing osteoporosis while ensuring endometrial safety,19–27,39 suggest that bazedoxifene-conjugated estrogens may provide a useful alternative menopausal therapy for nonhysterectomized women.
1. Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, et al.. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005;6:798–808.
2. Boyd NF, Martin LJ, Bronskill M, Yaffe MJ, Duric N, Minkin S. Breast tissue composition and susceptibility to breast cancer. J Natl Cancer Inst 2010;102:1224–37.
3. Heusinger K, Loehberg CR, Haeberle L, Jud SM, Klingsiek P, Hein A, et al.. Mammographic density as a risk factor for breast cancer in a German case-control study. Eur J Cancer Prev 2011;20:1–8.
4. McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006;15:1159–69.
5. Ursin G, Ma H, Wu AH, Bernstein L, Salane M, Parisky YR, et al.. Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomarkers Prev 2003;12:332–8.
6. Varghese JS, Thompson DJ, Michailidou K, Lindstrom S, Turnbull C, Brown J, et al.. Mammographic breast density and breast cancer: evidence of a shared genetic basis. Cancer Res 2012;72:1478–84.
7. Mandelson MT, Oestreicher N, Porter PL, White D, Finder CA, Taplin SH, et al.. Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 2000;92:1081–7.
8. Pinsky RW, Helvie MA. Mammographic breast density: effect on imaging and breast cancer risk. J Natl Compr Canc Netw 2010;8:1157–64.
9. Topal NB, Ayhan S, Topal U, Bilgin T. Effects of hormone replacement therapy regimens on mammographic breast density: the role of progestins. J Obstet Gynaecol Res 2006;32:305–8.
10. Kaewrudee S, Anuwutnavin S, Kanpittaya J, Soontrapa S, Sakondhavat C. Effect of estrogen-progestin and estrogen on mammographic density. J Reprod Med 2007;52:513–20.
11. McTiernan A, Martin CF, Peck JD, Aragaki AK, Chlebowski RT, Pisano ED, et al.. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women's Health Initiative randomized trial. J Natl Cancer Inst 2005;97:1366–76.
12. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al.. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.
13. Anderson GL, Chlebowski RT, Rossouw JE, Rodabough RJ, McTiernan A, Margolis KL, et al.. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103–15.
14. Boyd NF, Melnichouk O, Martin LJ, Hislop G, Chiarelli AM, Yaffe MJ, et al.. Mammographic density, response to hormones, and breast cancer risk. J Clin Oncol 2011;29:2985–92.
15. Regan MM, Emond SK, Attardo MJ, Parker RA, Greenspan SL. Why do older women discontinue hormone replacement therapy? J Womens Health Gend Based Med 2001;10:343–50.
16. Crandall CJ, Aragaki AK, Cauley JA, McTiernan A, Manson JE, Anderson G, et al.. Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone women's health initiative clinical trials. Breast Cancer Res Treat 2012;132:275–85.
17. Crandall CJ, Aragaki AK, Cauley JA, McTiernan A, Manson JE, Anderson GL, et al.. Breast tenderness after initiation of conjugated equine estrogens and mammographic density change. Breast Cancer Res Treat 2012;131:969–79.
18. Komm BS. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci 2008;15:984–92.
19. Lobo RA, Pinkerton JV, Gass ML, Dorin MH, Ronkin S, Pickar JH, et al.. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril 2009;92:1025–38.
20. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause 2009;16:1116–24.
21. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause 2010;17:281–9.
22. Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril 2009;92:1045–52.
23. Archer DF, Lewis V, Carr BR, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril 2009;92:1039–44.
24. Pickar JH, Yeh I-T, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril 2009;92:1018–24.
25. Pinkerton JV, Taylor H, Pan K, Chines A, Mirkin S. Breast parameters with bazedoxifene/conjugated estrogens in randomized, controlled trials of postmenopausal women. Menopause 2010;17:1221–2.
26. Pinkerton JA, Constantine GD, Komm BS, Yu H, Pickar JH. Breast effects of bazedoxifene/conjugated estrogens in a randomized, controlled trial of postmenopausal women. Menopause 2008;15:1221.
27. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Mirkin S, Chines AA. Evaluation of changes in mammographic breast density associated with bazedoxifene/conjugated estrogens in postmenopausal women. Endocr Rev 2011;32.
28. American College of Radiology. Breast Imaging Reporting and Data System (BI-RADS). 4th ed. Reston (VA): American College of Radiology; 2003.
29. Byng JW, Yaffe MJ, Jong RA, Shumak RS, Lockwood GA, Tritchler DL, et al.. Analysis of mammographic density and breast cancer risk from digitized mammograms. Radiographics 1998;18:1587–98.
30. Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al.. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684–92.
31. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, et al.. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647–57.
32. LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al.. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305–14.
33. Christiansen C, Chesnut CH III, Adachi JD, Brown JP, Fernandes CE, Kung AW, et al.. Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis. BMC Musculoskelet Disord 2010;11:130.
34. de Villiers TJ, Chines AA, Palacios S, Lips P, Sawicki AZ, Levine AB, et al.. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int 2011;22:567–76.
35. Komm BS, Lyttle CR. Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation. Ann N Y Acad Sci 2001;949:317–26.
36. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology 2005;146:3999–4008.
37. Peano BJ, Crabtree JS, Komm BS, Winneker RC, Harris HA. Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland. Endocrinology 2009;150:1897–903.
38. Chang KCN, Wang Y, Bodine PV, Nagpal S, Komm BS. Gene expression profiling studies of three SERMs and their conjugated estrogen combinations in human breast cancer cells: insights into the unique antagonistic effects of bazedoxifene on conjugated estrogens. J Steroid Biochem Mol Biol 2010;118:117–24.
39. Archer DF, Lobo RA, Pan K, Chines AA, Mirkin S. Safety and tolerability of bazedoxifene/conjugated estrogens in postmenopausal women: findings from a 1-year, randomized, placebo- and active-controlled, phase 3 trial. Menopause 2011;18:1355–6.