Predictors of Breast Density Change After Hormone Therapy Cessation: Results from a Randomized Trial

Mammographic density (MD) is a strong marker of breast cancer risk (1). Postmenopausal hormone therapy increases MD (2, 3), particularly combined hormone therapy (2), which also increases breast cancer risk (4). Postmenopausal hormone therapy cessation decreases MD in some women (5); reasons for this are not well understood. We examined whether the association between hormone therapy cessation and decrease in percentage MD (%MD) is modified by woman-level factors related to MD including age, race, body mass index (BMI), change in BMI between mammograms, baseline %MD, parity, and family history of breast cancer, as well as hormone therapy characteristics (type and duration of use; refs. 2, 3,5). The purpose of this study was to gain insight into the relationship between hormone therapy and mammographic density change and to identify subgroups of women whose %MD might be more likely to decrease due to hormone therapy cessation.

Methods used in the Radiological Evaluation and Breast Density (READ) randomized trial have been described previously (5). Briefly, we identified women aged 45 to 80 years who reported hormone therapy use at a screening (index) mammogram conducted at Group Health Cooperative within the past 24 months. Women due for another screening (study) mammogram who had filled 2 or more hormone therapy prescriptions in the 6 months before recruitment were eligible. Of those who completed the study mammogram (n = 1,471), we excluded women with a baseline %MD of less than 10% (n = 290), as well as women missing information on BMI (n = 13). Study methods were approved by the Institutional Review Boards of Group Health and the U.S. Department of Defense.

Women randomized to 1 month or 2 months of hormone therapy cessation were considered “exposed” (n = 738) and those randomized to continue hormone therapy were “unexposed” (n = 430). We gathered data on potential effect modifiers (age, race, BMI, change in BMI between mammograms, baseline %MD, parity, and family history of breast cancer, hormone therapy type, duration of hormone therapy use) from automated databases and study questionnaires (5). We defined change in BMI between mammograms as a change of 1.5 units or more (kg/m²), corresponding to a weight change of approximately 7 to 11 pounds for height 4′11′ to 6′0′. Buist and colleagues used Cumulus software to measure dense area and total breast area in digitized left breast craniocaudal projections; %MD was calculated as dense area divided by total area (5).

We report median change in %MD between mammograms with 95% CIs by woman-level characteristics, separately by exposure status. We used generalized linear models (GLM) with a log link and a robust variance estimator to estimate relative risks (RR) of decreasing %MD versus no change associated with hormone therapy cessation (see definitions of change below). We used GLM with an identity link to estimate attributable risks (AR). We report RRs and ARs with 95% CIs by subgroup of each potential effect modifier to assess whether certain women were more likely to experience a decrease in %MD due to cessation. To estimate RRs and ARs, we compared women who decreased ≥7.5% MD versus women with no change (defined as an absolute change of ≤3% MD). A 7.5% decrease in %MD was approximately the median level of decrease among women whose %MD decreased (>3%) and may represent a clinically relevant level of decrease. Studies suggest that women with a given %MD have a 15% to 20% higher risk of breast cancer than women whose %MD is lower by 10% (6,7). All analyses were conducted using STATA version 11.1 (StataCorp).

Women randomized to suspend hormone therapy had a greater median decrease in %MD between mammograms than continued users (−2.4% vs. −0.7%), and a greater proportion who decreased by ≥7.5% MD (21% vs. 15%; Table 1). Overall, hormone therapy cessation was associated with a 30% increased likelihood of a ≥7.5% MD decrease versus no change (RR = 1.3, 95% CI = 1.03–1.7) and an attributable risk of 9% (95% CI = 2–17). We found little evidence of effect modification by the factors studied on either a multiplicative or an additive scale (Table 2).

We did not observe strong evidence that the effect of hormone therapy cessation on %MD varies by woman-level characteristics. Our findings suggest that hormone therapy cessation may have a similar biological effect on %MD regardless of age, BMI, baseline %MD, and the other factors we examined. Although we used continuous measures of %MD, which are more precise than commonly used categorical measures, and a single trained reader interpreted all mammograms, measurement error of %MD remains a concern. Quality control sampling indicated that less than 10% of mammography rereads differed by ≥7.5% MD. We were unable to measure %MD immediately before hormone therapy cessation. However, our comparison of 2 large, randomized groups allowed us to infer this change with reasonable confidence. Additional strengths include a large sample size, randomization of exposure, high compliance with the intervention (8), and high-quality administrative data.

Our findings suggest that hormone therapy cessation–associated decrease in %MD is not predicted by woman-level factors. Other explanations for why subsets of women experience %MD decreases due to hormone therapy cessation, such as genetic factors, should be considered.

No potential conflicts of interest were disclosed.

This study could not have been completed without the assistance of Tammy Dodd, Linda Palmer, Dawn Fitzgibbons, Deborah Seger, Susan Reed, Katherine Newton, or Melissa Rabelhofer. The authors would further like to thank members of our advisory board: Hermien Watkins, Paula Hoffman, Deb Schiro, and Margrit Schubiger; members of the Data Safety and Monitoring Board: Susan Heckbert, MD, PhD, Chair, Department of Epidemiology, University of Washington; Ben Anderson, MD, University of Washington; Mary Anne Rossing, DVM, PhD, Fred Hutchinson Cancer Research Center; Robert D. Rosenberg, MD, University of New Mexico; Thomas Lumley, PhD, University of Washington Department of Biostatistics; and Elizabeth Lin, MD, Group Health Permanente medical monitor. They also thank Robert Karl, MD, Donna White, MD, and Jo Ellen Callahan for their support for implementing this trial at Group Health; Noel Weiss, MD, MPH, and Jessica Chubak, PhD, MBHL, for providing feedback on methods and analyses; Stephen Taplin, MD, MPH, for his collaboration in getting this study funded when he was an investigator at Group Health Cooperative.

The READ study was funded by the Department of Defense (principal investigator, D.S.M. Buist; DAMD17-03-1-0447). Registered clinical trial number: NCT00117663. Study participants were recruited from the Group Health Breast Cancer Screening Program funded by the National Cancer Institute (principal investigator: D.S.M. Buist, U01CA63731).