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.
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