Changes in Breast Density Associated With Initiation, Discontinuation, and Continuing Use of Hormone Replacement Therapy FREE

Several studies have shown that initiation of hormone replacement therapy (HRT) increases parenchymal breast density,^1- 5 and there is growing evidence that opposed estrogen has a stronger effect on breast density than unopposed estrogen.^4- 5 Increases in density induced by HRT can have important consequences. Increased density reduces the accuracy of screening mammography.⁶ Hormone replacement therapy has been directly associated with decreases in both sensitivity and specificity of mammography,^7- 10 which is likely a result of corresponding increases in density. Studies have also associated increased density with increased risk of breast cancer.^11- 14

Although the effect of initiating HRT on breast density has been well studied, the effects of discontinuing HRT and continuing HRT have not been systematically examined. In this study, we investigated the relationship between HRT use and density in a population-based cohort of women undergoing at least 2 mammogram screenings.

Subjects were selected from women enrolled in Group Health Cooperative (GHC) of Puget Sound, a health maintenance organization with more than 400 000 members in western Washington State. Most mammographic screening at GHC is delivered through a breast cancer screening program (BCSP), which was established in 1985.¹⁵ The BCSP collects demographic data, health and screening history, and risk factor information through a self-administered survey mailed to women aged 40 years or older, and generates letters that invite women to begin breast cancer screening and periodically remind them to return for regular screening. During the study period, women were sent screening reminders every 1 to 2 years, with the reminder interval based on their breast cancer risk factors. The GHC physicians may also order mammography screening as part of well care.

Women were eligible for our study if they were postmenopausal and had at least 2 screening examinations occurring between January 1996 and December 1998, with the second screening examination occurring at least 11 months, but no more than 25 months, after the first. When women had more than 2 screening examinations during the study period, we chose the pair whose timing was closest to 2 years apart. Screening consisted of a 2-view mammogram and clinical breast examination at dedicated centers within the GHC delivery system.

Women were excluded from our study if they were younger than 40 years, had a hysterectomy, had a self-reported history of breast cancer, had a diagnosis of cancer prior to either screening mammogram, or had undergone breast augmentation. Because we relied on pharmacy data to estimate HRT, we restricted our sample to women who were continuously enrolled in GHC during the year prior to each mammogram.

Use of HRT was based on automated pharmacy records that capture all prescriptions filled at GHC pharmacies. We defined HRT to include estrogens alone and estrogens in combination with a progestin, delivered orally or by patch. We excluded women who used vaginal rings from our study because their use is not associated with higher blood levels of estrogen.¹⁶ Because estrogen creams were almost exclusively prescribed for use on an as-needed basis, we did not consider women using creams to be HRT users. We combined pharmacy dose and text instructions to estimate the duration of each prescription and the average dose per day of estrogen and progestin. We estimated the timing of HRT use by assuming that a woman began taking HRT the day after she filled her prescription, with refills extending the duration of HRT use. When a woman filled a prescription for a different HRT drug, or the same drug at a different dosage within 10 days of an earlier fill, we assumed that her physician had changed either the dose or formulation, effective the day after the new prescription was filled.

We classified HRT use (yes/no) prior to each mammogram using the date of prescription fills and the estimated duration of the prescription. Women classified as HRT users at the time of screening filled a prescription for estrogen that lasted for at least 30 days and was estimated to run out no more than 6 weeks before the screening mammogram. Women classified as nonusers at the time of screening had not filled a prescription for estrogen in the prior year, or had filled a prescription that was estimated to run out more than 24 weeks before the screening mammogram.

We compared the following 4 patterns of HRT use: nonusers were those who did not use HRT before either mammogram; discontinuers, those who used HRT before the first mammogram, but not before their second mammogram; initiators, those who did not use HRT before their first mammogram, but began using HRT before their second mammogram; and continuing users, those who used HRT prior to both mammograms. We confirmed analyses using a subset of women whose self-reported current HRT use agreed with pharmacy records. However, we did not use self-reported HRT use for primary analyses because as-needed creams were not distinguishable from daily preparations; there was no information about duration or recency of use; and self-reported data are subject to reporting errors and missing data.

Breast density was coded on a 4-point scale at the time of each mammogram using American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) coding.¹⁷ A score of 1 indicated almost entirely fat; 2, scattered fibroglandular tissue; 3, heterogeneously dense; and 4, extremely dense. Density was coded by clinical radiologists and was captured using an automated reporting system. Radiologists rated density separately for each breast, and the breast with the highest density was used for analysis. To focus on clinically important changes in density, we dichotomized density ratings into low (almost entirely fat and scattered fibroglandular tissue) and high (heterogeneously and extremely dense). Change in breast density was coded into 4 groups: low density (1,2) at both evaluations, decrease in density (3,4 to 1,2), increase in density (1,2 to 3,4), and high density (3,4) at both evaluations.

We examined the association between HRT and density adjusting for 2 covariates associated with changes in breast density: age at first study mammogram and change in body mass index (BMI), which is calculated as weight in kilograms divided by the square of height in meters. Change in BMI was based on a 5-category measure that captured clinically important changes in BMI: (1) lean at both examinations (BMI <20); (2) initial BMI between 20 and 25 and a change of less than 1 BMI unit; (3) initial BMI between 20 and 25 and a decrease of at least 1 BMI unit; (4) initial BMI between 20 and 25 and an increase of at least 1 BMI unit; and (5) heavy at both examinations (BMI ≥25). For a woman who is 167.6 cm (5'6"), a 1-unit change in BMI roughly corresponds to a 2.7-kg (6-lb) weight change. We examined the relationships between HRT and density while controlling for age and change in BMI using 3 separate logistic regression models to describe the probability of (1) increased density relative to all other changes, (2) decreased density relative to all other changes, or (3) high density at both examinations relative to all other changes. We added interaction effects to logistic regression models to test for differential effects of HRT change by age and BMI. Age was categorized into 3 groups of approximately equal size (40-49, 50-69, ≥70 years). Body mass index was grouped into low (<25 kg/m²) vs high (≥25 kg/m²). Adjusted relative risks (RRs) were approximated using a transformation of adjusted odds ratios (ORs): RR = OR divided by 1 + I_R (OR−1), where I_R is the rate of the outcome in the reference group.¹⁸ The RRs and 95% confidence intervals (CIs) were estimated by transforming confidence limits for corresponding ORs.

Among the 6313 women who met initial criteria for inclusion in our sample, 497 (7.9%) had HRT use patterns that did not correspond to 1 of our 4 groups. Among the remaining women, 604 (10.4%) were excluded from analyses because of missing data on breast density (1.1%) or BMI (9.4%). Our final sample included 5212 women with complete density and covariate information.

At the time of the initial mammogram, the mean age of women in our sample was 64.5 (SD, 9.5; range, 40-96) years. There were similar age ranges across the women with the 4 HRT use patterns: nonusers ranged from 43 to 96 years; discontinuers, 42 to 80 years; initiators, 42 to 91 years; and continuing users: 40 to 92 years. As shown in Table 1, women who were using HRT at the time of the first mammogram (discontinuers and continuing users) tended to be younger than women in other groups. Nonusers tended to be older than other groups. Across all groups, approximately one third of women were aged 60 to 69 years. However, 44.4% of nonusers were 70 years or older, while 25.7% of initiators, 18.0% of discontinuers, and 16.3% of continuing users were 70 years or older.

There were few differences in other risk factors across patterns of HRT use. Our sample was predominately white (92.0%), reflecting the overall racial composition of women enrolled in GHC and the surrounding population; 96.1% had a prior mammogram available to the radiologist at the time of their initial screening mammogram; 15.9% were nulliparous; and 13.8% had their first child after age 30 years. First-degree family history of breast cancer (mother, sister, or daughter) differed across groups with 24.7% of nonusers, 20.2% of initiators, 17.1% of discontinuers, and 16.6% of continuing users reporting a family history.

Differences in average BMI across patterns of HRT use were small, though discontinuers and continuing users tended to be somewhat leaner than other groups (Table 1). About half of the women (51.7%) in this sample had a BMI that was higher than 25 kg/m² at both examinations. Approximately equal numbers gained or lost 1 or more units on the BMI scale (7.6% and 7.2%, respectively). The BMI for about one third (29.6%) changed less than 1 BMI unit, and only a few (3.8%) had a BMI that was less than 20 kg/m²at both examinations.

The HRT dose and drug type were similar across the 3 groups of women who used HRT (initiators, discontinuers, and continuing users). Most women who received HRT (92.4%) received a combination of an estrogen and a progestin. The most common average daily dose of conjugated estrogen was 0.625 mg/d (examination 1, 62.1%; examination 2, 50.0%). Few women received estrogen doses that were greater than 0.625 mg/d (examination 1, 5.1%; examination 2, 5.3%). Most women were prescribed Estratab (Solvay, Brussels, Belgium; examination 1, 86.5%; examination 2, 86.8%). Among women receiving combination therapy, 99.4% were prescribed medroxyprogesterone acetate, with the remainder prescribed norethindrone acetate.

Most women (80.6%) had index screening examinations during 1996, and most (64.7%) had their second mammogram between 21 and 25 months after their first. There were no differences in timing of the index mammogram or time between mammograms across patterns of HRT use. Almost all of the women in our sample (99.0%) had equal density ratings in both breasts. As shown in Table 1, women using HRT at the time of the first mammogram (discontinuers and continuing users) tended to have higher density at the initial screening than women who were not using HRT at the time of their first mammogram (initiators and nonusers).

Table 2 shows the overall relationship between HRT use and breast density. Relative to the nonuser group, initiators were more likely to have an increase in density, discontinuers were more likely to have a decrease in density, and continuing users were more likely to have high density at both examinations.

Table 3 shows estimated associations between HRT use and breast density that were adjusted for age at initial examination and change in BMI via logistic regression. Because few women had BMI below 20 kg/m² at both examinations, these women were grouped with women who had a less than 1-unit change in BMI between evaluations. Relative to nonusers, initiators were more likely to have increased density and less likely to have a decrease in density; discontinuers were more likely to have a decrease in density; and continuing users were more likely to have an increase in density and more likely to have high density at both examinations.

There was a significant interaction between age and the effect of HRT initiation with greater risk of increased density associated with initiation among older initiators (RR not significantly different for <60 years vs 60-69 years [P = .05] and RR significantly greater for ≥70 years vs <60 years [P = .001]). These differences in RR across age groups reflect observed age differences in the proportion of initiators with increases in density (<60 years, 17.9%; 60-69 years, 29.6%; ≥70 years, 43.0%). There was also a significant interaction between baseline BMI and the risk of sustained high density among continuing users relative to nonusers (P = .002). However, this reflects observed differences in proportion of nonusers with sustained high density (39.0% with BMI <25 kg/m²; 14.2% with a BMI of ≥25 kg/m², respectively) since relatively more continuing users with low BMI had sustained high density than continuing users with high BMI (56.9% with BMI <25 kg/m²; 30.5% with a BMI of ≥25 kg/m², respectively). We found similar differentially increased risk for sustained high density among initiators relative to nonusers, with greater RR among women with high BMI (P = .04). These differential risks were also driven by differences between the 2 nonuser groups.

This study has several strengths that distinguish it from earlier research. Automated pharmacy data allowed us to measure HRT use across a large group of mammographically screened women whose breast density was routinely recorded. We believe that this is the largest study to date of HRT use and breast density changes. This is the only study to simultaneously examine HRT initiation, discontinuation, and continuing use relative to women not using HRT. We focused on clinically significant changes in breast density, and distinguished women with fatty breasts at both examinations from women with dense breasts at both examinations. This is also the first published study to explore changes in density adjusting for co-occurring changes in BMI.

Our analyses provide important new information about women who discontinue HRT use and women who are continuing HRT users. Discontinuation of HRT was associated with subsequent decreases in density, and increases in breast density were sustained by continued HRT use. We also found that initiation of HRT was associated with increases in parenchymal breast density. These results provide strong evidence that breast density changes associated with HRT are dynamic, increasing with initiation, and decreasing with discontinuation.

Our analyses confirmed findings from previous studies demonstrating an association between initiation of HRT use and increases in parenchymal breast density.^1- 5 Like these earlier studies, we examined changes in breast density among women who began using HRT. Studies that have failed to find an association compared the parenchymal patterns in women using HRT with patterns in women not using HRT, rather than examining within-woman changes as we have.^19- 20

We measured density using American College of Radiology BI-RADS coding, with assessments made by a variety of clinical radiologists. Studies finding increases in density associated with initiation of HRT have used a variety of measures, though all relied on expert readers. Greendale et al⁴ used BI-RADS coding. Several earlier studies were based on the Wolfe classification scheme^2- 3,5 and 1 study¹ used a simple measure of dense, heterogeneous, and fatty. These studies consistently demonstrated an association between initiation of HRT and increased breast density across a variety of density measures. Our study is consistent with previous research, showing clear associations between initiation of HRT and increased breast density as measured in clinical practice.

Our findings suggest that the probability of experiencing an increase in density following HRT initiation, or sustained high density following continued HRT use, may be affected by age. This finding is important because the risk of breast cancer increases with age. Because increased density is associated with decreased mammographic accuracy, HRT use could have particularly deleterious effects among older, higher-risk women.

We were able to examine changes in HRT use and breast density changes in a relatively large group of women because of automated data collection. Previous studies of initiators have also used detailed HRT-dose information, though the source of these data is sometimes unclear. Two studies appear to rely on a combination of medical records and self-report for HRT-dose information,^1- 2,5 while others used information from randomization within a treatment study.^3- 4 Automated pharmacy data allow broad capture of information, but these data have limitations. Women who filled prescriptions but do not subsequently take HRT may be misclassified as users. Women who filled HRT prescriptions at outside pharmacy facilities may have been misclassified as nonusers. Timing information is especially sensitive since we cannot determine when a woman actually begins to take her prescription. To overcome these limitations, we used relatively stringent requirements for categorization into use and nonuse groups, resulting in the exclusion of women who had intermediate use patterns. We also examined a subset of women whose self-reported current HRT use was consistent with pharmacy-estimated HRT use and found virtually identical results. Overall, only 5.1% of women's self-reported HRT use differed from pharmacy records. Thus, there is little evidence of misclassification of HRT use and such misclassification would result in attenuation of the effect of HRT use on density change.

Like all previous studies of HRT use, the current observational study is subject to bias. Women chose whether and when to initiate, continue, or discontinue HRT use, and these choices may be related to unmeasured factors that affect study findings. Randomized trials that include a placebo control⁴ come closest to avoiding this potential bias since all women, including the placebo group, were willing to initiate HRT. Although a recent study of HRT users suggests that there are fewer differences between users and nonusers than previously expected,²¹ our results must be viewed in light of their observational nature.

Finally, these data did not allow us to address several important factors that may influence the effect of HRT on breast density. While this is perhaps the largest study of HRT and density conducted to date, our sample sizes were moderate, particularly for the groups of women who initiated or discontinued use during the study period. Although sample sizes were sufficiently large to show main effects of HRT use on breast density, we may not have had power to find some interactions between age, BMI, and HRT use. We were unable to examine the effects of opposed vs unopposed estrogen and the effects of type of drug prescribed because there was not enough variability in these factors within our sample, reflecting the selection of naturally postmenopausal (ie, nonhysterectomized) women. In addition, automated pharmacy data did not allow us to distinguish between cyclical and combination estrogen and progestin. We also lacked information about women's overall duration of use.

This study shows strong associations between patterns of HRT use and changes in breast density. Our findings suggest that in some women, HRT increases breast density but these increases are potentially reversible with cessation of HRT. This result has important implications for breast cancer screening. Increased density adversely affects the accuracy of screening mammography and is a strong, if not the strongest, risk factor for cancer missed at screening.⁶ Hormone replacement therapy is associated with decreases in both the sensitivity and specificity of mammography.^7- 10 Observed decreases in mammographic accuracy among women using HRT are a likely result of corresponding increases in density.