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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e31828c5974
Original Research

Breast Effects of Bazedoxifene-Conjugated Estrogens: A Randomized Controlled Trial

Pinkerton, JoAnn V. MD; Harvey, Jennifer A. MD; Pan, Kaijie MS; Thompson, John R. PhD; Ryan, Kelly A. BSN, MS; Chines, Arkadi A. MD; Mirkin, Sebastian MD

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Author Information

Department of Obstetrics & Gynecology, Division of Midlife Health Center, and the Department of Radiology, University of Virginia Health System, Charlottesville, Virginia; and Women's Health, Pfizer, Collegeville, Pennsylvania.

Corresponding author: JoAnn V. Pinkerton, MD, Division of Midlife Health Center, University of Virginia, Box 801104, Charlottesville, VA 22903; e-mail: jvp9u@virginia.edu.

Sponsored by Wyeth Research, Collegeville, PA, which was acquired by Pfizer, in October 2009. Medical writing support was provided by Lisa Shannon, PhD, at MedErgy, and was funded by Pfizer.

Financial Disclosure Dr. Pinkerton has served as a consultant for Pfizer, Noven Pharmaceuticals, Shionogi, DepoMed (fees to the University of Virginia), and Novogyne Pharmaceuticals (fees to self), has received grants and research support (fees to the University of Virginia) from DepoMed, Bionova, and Endoceutics, and has received travel funds from Pfizer, Noven Pharmaceuticals, Shionogi, DepoMed, and Novogyne Pharmaceuticals. Dr. Harvey has received research support from Pfizer. Ms. Pan, Dr. Thompson, Ms. Ryan, and Dr. Mirkin are employees of Pfizer. Dr. Thompson holds stock and stock options in Pfizer. Dr. Chines was an employee of Pfizer at the time of the study and currently owns stock in Pfizer.

Presented in part at the 22nd Annual Meeting of the North American Menopause Society, September 21–24 2011, Washington, DC, and at the 9th European Congress on Menopause and Andropause, March 28–31 2012, Athens, Greece.

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Abstract

OBJECTIVE: To evaluate the effects of bazedoxifene-conjugated estrogens on mammographic breast density and other breast parameters in nonhysterectomized postmenopausal women enrolled in a randomized, double-blind, placebo-controlled, and active-controlled phase 3 study.

METHODS: The 1-year Selective estrogens, Menopause, And Response to Therapy-5 trial estimated the efficacy and safety of bazedoxifene-conjugated estrogens in 1,843 postmenopausal women seeking vasomotor symptom treatment. A substudy enrolled 940 women with technically acceptable digital mammograms at screening and at 1 year. Treatments included bazedoxifene 20 mg and conjugated estrogens 0.45 or 0.625 mg, placebo, bazedoxifene 20 mg, and conjugated estrogens (0.45 mg) and medroxyprogesterone acetate (1.5 mg). Mammograms were centrally read by a single radiologist blinded to treatment and time sequence; percent breast density was determined using validated software. Noninferiority was based on a predefined margin of 1.5% for comparison of adjusted mean differences in breast density at 12 months.

RESULTS: Bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg demonstrated noninferiority to placebo in breast density. Mammographic breast density decreased from baseline with bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg and placebo (mean −0.38% and standard error [SE] 0.22%, mean −0.44% and SE 0.22%, mean −0.32% and SE 0.23%, respectively). Conjugated estrogens–medroxyprogesterone acetate significantly increased breast density from baseline (mean 1.60%, SE 0.35%; P<.001) compared with placebo. Both bazedoxifene-conjugated estrogens doses showed rates of breast tenderness similar to placebo and significantly (P<.001) lower than conjugated estrogens–medroxyprogesterone acetate. No differences in incidence of breast-related adverse events were identified.

CONCLUSION: Bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg did not increase mammographic breast density or breast tenderness over the course of 1 year with a favorable breast-related safety profile.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00808132.

LEVEL OF EVIDENCE: I

Mammographic breast density, defined as the proportion of fibroglandular tissue compared with fat relative to total breast area, reflects variations in breast tissue composition among women.1,2 High mammographic breast density has been shown to be an independent moderate risk factor for, and may share a common genetic basis with, breast cancer;1,3–6 it also can reduce mammographic sensitivity and specificity.7,8

Hormone therapy (HT) has been shown to increase mammographic breast density in postmenopausal women9–11 and is associated with an increased risk of invasive breast cancer.12–14 Additionally, new-onset breast tenderness after starting estrogen–progestin therapy, but not estrogen therapy, is a common reason for treatment discontinuation15 and has been associated with increased breast density and breast cancer risk.16,17

The tissue-selective estrogen complex combines a selective estrogen receptor modulator with one or more estrogens.18 The pairing of bazedoxifene 20 mg with conjugated estrogens 0.45 and 0.625 mg is the first tissue-selective estrogen complex in clinical development and has been studied in the phase 3 Selective estrogens, Menopause, And Response to Therapy (SMART) trials19–22 with demonstrated efficacy in reducing moderate-to-severe hot flushes and vulvovaginal atrophy symptoms and in preventing osteoporosis in more than 7,500 nonhysterectomized postmenopausal women while maintaining endometrial and breast safety and a favorable overall safety and tolerability profile over 2 years.19–21,23–27

The breast density substudy of the SMART-5 trial examined the effects of bazedoxifene-conjugated estrogens on mammographic breast density. Effects on other breast parameters including breast pain were estimated for the overall SMART-5 population.

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MATERIALS AND METHODS

The SMART-5 trial was a 1-year, 171-center, randomized, double-blind, placebo-controlled, and active-controlled phase 3 study that enrolled healthy postmenopausal women seeking treatment for menopausal symptoms from 26 January 2009 to 8 February 2011. Women were randomized to receive once-daily oral doses of bazedoxifene 20 mg and conjugated estrogens 0.45 mg, bazedoxifene 20 mg and conjugated estrogens 0.625 mg, bazedoxifene 20 mg, conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg (a conventional estrogen–progestin therapy), or placebo (ratio of 2:2:1:1:2 with block size of 8). Women were allocated to treatment groups using the Computerized Operations Randomization Environment II (CORE II) system; randomization was stratified by site. Blinding was achieved by overencapsulation of study medication. The study protocol was approved by an Institutional Review Board or an independent ethics committee at each study site; the central Institutional Review Board used for all United States sites was the Independent Investigational Review Board, Inc (Plantation, FL).

Women eligible for enrollment in the SMART-5 main study were aged 40–65 years and had an intact uterus, body mass index of ≤34.0 (calculated as weight (kg)/[height (m)]2) or less, an acceptable endometrial biopsy report, and a mammography result of Breast Imaging and Reporting Data System category 1 (“negative”) or 2 (“benign finding”) at screening.28 Women from the SMART-5 trial who had a technically acceptable digital mammogram at screening were eligible for enrollment in the breast density substudy (mammograms conducted within 3 months of randomization were acceptable); those requiring additional mammographic views were not excluded from the analysis. Women who used prolactin-releasing medications within 6 months of screening or who had breast prosthesis or surgical breast interventions that may affect mammographic density were excluded from the substudy.

Women who met the inclusion and exclusion criteria were enrolled into the breast density substudy on a voluntary basis until maximum enrollment was met. Randomization was not stratified based on participation in the breast density substudy. Women were recruited at all sites with access to a radiology facility that performed digital mammograms, except for nine sites in Latin America that randomized women after enrollment for the substudy was closed.

For the breast density substudy, the primary endpoint was the change from baseline in percent dense breast tissue at 1 year. Breast density was evaluated using digital mammograms performed at baseline and at 1 year. Mammograms were centrally read by a single radiologist specializing in breast imaging (19 years of experience, 50 mammograms read per day). The radiologist was blinded to time sequence and study group. Percent breast density was determined using specifically developed software.29 For the main study, breast tenderness was assessed using daily diaries over 4-week cycles and breast-related adverse events were recorded and classified based on the Medical Dictionary for Regulatory Activities. Compliance was monitored by capsule counts and by comparing returned test article with dose administration information reported by the participant and with the prescribed dose at each visit.

The sample size for the breast density substudy was based on the number of women needed to demonstrate substantial evidence that bazedoxifene-conjugated estrogens is no worse than placebo in mean breast density increase using a margin of 1.5 percentage points. Approximately 800 women were planned for enrollment in the substudy to include 600 women in the analysis (150 each for bazedoxifene 20 mg–conjugated estrogens 0.45 and 0.625 mg and placebo, and 75 each for bazedoxifene 20 mg and conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg). This number of women for bazedoxifene-conjugated estrogens and placebo was expected to provide 90% statistical power to demonstrate noninferiority using a margin of 1.5 percentage points and alpha of 0.025.

The primary analysis population for testing the noninferiority of bazedoxifene-conjugated estrogens compared with placebo was the per-protocol population, composed of all women enrolled in the breast density substudy who had a baseline and one or more on-therapy assessments and had no major protocol violations. The secondary analysis population used for superiority testing was the modified intent-to-treat population composed of all randomized women who received one or more doses of study drug and had a baseline and one or more on-therapy assessments. Women were included in the analyses if they had a month 12 or end-of-study (early termination) mammogram that occurred at least 26 weeks after the previous mammogram.

The change from baseline in breast density was assessed using an analysis of covariance model with treatment and region as factors and baseline value as the covariate. Comparison of the adjusted mean difference in breast density between bazedoxifene-conjugated estrogens and placebo at 12 months was based on a prespecified noninferiority test with a predefined margin of 1.5% for the upper limit of the two-sided 95% confidence interval (CI). Within-group comparisons were evaluated using analysis of covariance.

The incidence of breast tenderness was assessed in randomized and dosed women who had 20 or more days of data at screening and within one or more on-therapy 4-week reporting interval. The percentage of women with 1 or more days of breast tenderness in each interval was determined; between-group comparisons were made using the Cochran-Mantel-Haenszel test stratified by baseline value. Comparisons of the incidence of breast-related adverse events between groups were performed using the Fisher exact test.

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RESULTS

Of the 1,843 women who were randomized and received one or more doses of the study drug in the main study (safety population), 940 participated in the breast density substudy (bazedoxifene 20 mg–conjugated estrogens 0.45 mg, n=231; bazedoxifene 20 mg–conjugated estrogens 0.625 mg, n=247; bazedoxifene 20 mg, n=122; conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg, n=100; placebo, n=240; Fig. 1). Of these, 770 (81.9%) completed the substudy and 747 (79.5%) and 742 (78.9%) were included in the modified intent-to-treat and per-protocol analysis populations, respectively. The demographic and baseline characteristics of women in the breast density substudy were balanced among groups, but there was a statistical difference noted for age (P=.04; Table 1); however, differences in age were small.

Participant disposit...
Participant disposit...
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Table 1
Table 1
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Of the 940 women enrolled in the breast density substudy, 193 (21%) and 198 (21%) women were excluded from the modified intent-to-treat and per-protocol analysis populations, respectively. The most common reasons for exclusion were not having a digital mammogram at baseline (bazedoxifene 20 mg–conjugated estrogens 0.45 mg, 41 [18%]; bazedoxifene 20 mg–conjugated estrogens 0.625 mg, 42 [17%]; bazedoxifene 20 mg, 21 [17%]; conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg, 26 [26%]; placebo, 41 [17%]; total, 171 [18%]) and not having postbaseline breast density data (bazedoxifene 20 mg–conjugated estrogens 0.45 mg, 42 [18%]; bazedoxifene 20 mg–conjugated estrogens 0.625 mg, 49 [20%]; bazedoxifene 20 mg, 23 [19%]; conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg, 29 [29%]; placebo, 49 [20%]; total, 192 [20%]). An additional five women (one each for bazedoxifene 20 mg–conjugated estrogens 0.625 mg and bazedoxifene 20 mg, and three for placebo) were excluded from the per-protocol analysis population for having less than 80% study medication compliance. In the main study, there was a significant difference (P=.006) in the rate of discontinuations because of breast tenderness, with none discontinuing with bazedoxifene 20 mg–conjugated estrogens 0.45 mg, one (0.2%) discontinuing with bazedoxifene 20 mg–conjugated estrogens 0.625 mg, one (0.4%) discontinuing with bazedoxifene 20 mg, four (1.8%) discontinuing with conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg, and one (0.2%) discontinuing with placebo.

At 12 months, there were no significant differences between the bazedoxifene-conjugated estrogens or bazedoxifene and placebo groups in change from baseline in percent dense breast tissue as determined by mammography (Fig. 2). The conjugated estrogens–medroxyprogesterone acetate group demonstrated a significant (P<.001) increase in percent dense breast tissue compared with placebo in the modified intent-to-treat population. Bazedoxifene 20 mg–conjugated estrogens 0.45 and 0.625 mg demonstrated noninferiority compared with placebo in the change from baseline in percent dense breast tissue at 12 months (Fig. 3).

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In the main SMART-5 study, abnormal mammograms (Breast Imaging and Reporting Data System category 4 or 5) were reported for 11 women during the on-therapy or follow-up period (N=1,843; abnormal mammograms were found for n=4 [0.9%; 95% CI 0.2%–2.3%] with bazedoxifene 20 mg–conjugated estrogens 0.45 mg; n=2 [0.4%; 95% CI 0.1%–1.5%] with bazedoxifene 20 mg–conjugated estrogens 0.625 mg; n=1 [0.4%; 95% CI 0.0–2.4%] with bazedoxifene 20 mg; n=3 [1.4%; 95% CI 0.3%–3.9%] with conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg; and n=1 [0.2%; 95% CI 0.0%–1.2%] with placebo). Of these, seven required biopsy and were determined to be benign (Table 2). Breast cancer was diagnosed in four women from the SMART-5 main study (two of these also were enrolled in the breast substudy). The rates of breast cancer were low (0.5% or less) and similar among groups (n=2 [0.4%] for bazedoxifene 20 mg–conjugated estrogens 0.45 mg; n=0 for bazedoxifene 20 mg–conjugated estrogens 0.625 mg and bazedoxifene 20 mg; n=1 [0.5%] for conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg; and n=1 [0.2%] for placebo; P=.523). Details of the four breast cancer cases are provided in Table 3.

Table 2
Table 2
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Table 3
Table 3
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Based on diary data, the percentages of women who reported 1 day or more of breast tenderness with bazedoxifene 20 mg–conjugated estrogens 0.45 and 0.625 mg were similar to those of women using placebo during 4-week intervals over 12 weeks, whereas those using conjugated estrogens 0.45–medroxyprogesterone acetate 1.5 mg showed a significantly higher breast tenderness rate compared with those in the placebo group (P<.001; Table 4). The percentages of women who reported 1 day or more of breast tenderness in the bazedoxifene 20 mg–conjugated estrogens 0.45 and 0.625 mg groups were significantly lower than that for the conjugated estrogens 0.45 mg–medroxyprogesterone acetate 1.5 mg group (P<.01 for all). Proportions of study participants reporting breast tenderness for bazedoxifene 20 mg–conjugated estrogens 0.45 and 0.625 mg were similar to those of participants using bazedoxifene 20 mg.

Table 4-a Percentage...
Table 4-a Percentage...
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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).

Table 4-b Percentage...
Table 4-b Percentage...
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Table 5
Table 5
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DISCUSSION

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.

However, estrogen therapy did not increase the risk of invasive breast cancer31 in the Women's Health Initiative trial and, at longer follow-up, showed significantly lower cumulative breast cancer incidence compared with placebo.32 Also, in phase 3 trials, the incidence of breast cancer with bazedoxifene was similar to that with placebo.33,34 Thus, bazedoxifene-conjugated estrogens combines two agents, conjugated estrogens 0.45 and 0.625 mg31,32 and bazedoxifene 20 mg,33,34 that, when administered individually, have not shown evidence of breast stimulation.

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.

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