Abstract 5741: Change in mammographic density with estrogen and progestin therapy: A measure of breast cancer risk in the Women's Health Initiative
Authors: Byrne Celia , Ursin Giske , Martin Christopher F. , Peck Jennifer D. , Cole Elodia B. , Heiss Gerardo , McTiernan Anne , Zeng Donglin , Chlebowski Rowan T. , Lane Dorothy S. , Manson JoAnn E. , Wactawski-Wende Jean , Yasmeen Shagufta , Boyd Norman F. , Yaffe Martin J. , Pisano Etta D. 
Published: February 2011

Abstract
Background: In 2002 the Women's Health Initiative (WHI) reported an increased rate of breast cancer with estrogen and progestin therapy (EPT). Percent mammographic density (MD) is one of the strongest predictors of breast cancer risk and may be a useful intermediate marker of change in breast cancer risk. We conducted a nested case-control study within the WHI to determine if change in MD with EPT could explain the increased breast cancer risk among these women.
Methods: We obtained and digitized the baseline (prior to randomization) and the 1 year post randomization follow-up mammograms from the contralateral breast of 97 women who developed invasive breast cancer after the date of their follow-up mammogram in the EPT and 77 in the placebo arms of the WHI as well as a mammogram from a random side from 733 healthy women (controls) matched to the cases on clinical center, age, and treatment arm (378 and 355 respectively). Four experienced readers blinded to treatment and outcome assessed MD, the proportion of the breast area appearing dense on the mammogram, using two different validated computer-assisted techniques (Cumulus and Madena). The four readers’ results were highly correlated (correlation coefficients &gt; 0.92) and averaged in this study. The risk associated with both baseline MD and change in MD was evaluated. Using logistic regression models controlling for confounders and baseline MD, we determined the degree to which change in MD after initiation of EPT predicted breast cancer risk in this group and potentially explained the breast cancer risk associated with EPT.
Results: Of the women in the placebo arm approximately half (57%) had a decline in MD and 47% had a modest increase in MD. In contrast, 84% of women in the EPT arm had increased MD while only 16% had a decrease. In the EPT arm both baseline and change in MD were significantly associated with breast cancer risk (baseline MD OR= 1.03; 95% CI 1.01-1.05 per 1% in MD and change in MD OR= 1.03; 95% CI 1.01-1.06 per 1% increase in MD). Among the 20% of women with the greatest increase in MD (&gt;19.3 %) in the EPT arm of the study, breast cancer risk increased 3.6-fold (95% CI 1.52-8.56) compared to the 20% with the lowest increase (&lt; 0.6 %) or decrease. The OR within this sub-study for the effect of EPT on breast cancer risk compared to placebo was 1.28 (95% CI 0.90-1.82) similar to that of the entire WHI where the HR for EPT was 1.24 (95% CI: 1.01-1.54). After adjusting for change in MD, EPT was no longer associated with breast cancer risk within this nested study population (adjusted OR=0.99; 95% CI: 0.66-1.51).
Conclusions: In this nested study within the WHI randomized trial of the effects of EPT, the associated change in MD was a significant predictor of breast cancer risk and statistically accounted for the increased breast cancer risk associated with EPT. Thus change in MD may be a useful intermediate marker of increased breast cancer risk with use of EPT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5741.