Longitudinal history of mammographic breast density and breast cancer risk by familial risk, menopausal status, and initial mammographic density level in a high risk cohort: a nested case-control study

Abstract

Background: Elevated mammographic density is associated with increased breast cancer risk. However, the contribution of longitudinal changes in mammographic density to breast cancer risk beyond initial mammographic density levels, considering familial breast cancer risk and menopausal status, remains uncertain but holds important clinical implications.

Methods: In a nested case-control study within the Sister Study (323 cases, 899 controls; 12,095 mammograms), a cohort enriched for family history of breast cancer, we examined case-control status in relation to the largest annual change in percent density and dense area using mammograms available spanning 5.4 years, on average, using multivariable logistic regression and to the rate of mammographic density change using linear mixed-effects models. We considered effect modification by: mammographic density level of the earlier mammogram, the extent of family history, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation (BOADICEA) risk strata, and menopausal status.

Results: Cases (diagnosed < 60 years) had greater initial percent density and dense area levels and a slower rate of decline in dense area than controls. Women with stable mammographic density (≤ 10% annual change) had an increased breast cancer risk as compared with women whose largest mammographic density change was > 10% annual decline (e.g., Odds Ratio (OR) 2.34, 95% Confidence Interval (CI) 1.63-3.37 for dense area). Increasing vs. decreasing dense area was also associated with elevated risk, especially in women with the highest dense area levels at the earlier mammogram (OR: 2.56, 95%CI 1.50-4.36). Although generally similar across menopausal and familial risk categories, the associations of MD change with risk appeared stronger in pre-menopausal and lower-risk women.

Conclusions: Women who maintain higher levels of mammographic density (i.e. do not decrease over time) or have increasing mammographic density over time have a higher risk of subsequent breast cancer than women with high mammographic density that decreases over time. These findings suggest potential for incorporating mammographic density trajectories in clinical risk assessment, and the importance of additional breast cancer monitoring in women not experiencing declines in mammographic density over time.

Keywords: Breast cancer; Mammographic breast density; Mammography; Risk prediction.

Fig. 1

Longitudinal change in mammographic density for cases and controls by risk and menopausal status. A Total sample. B by BOADICCEA 5-year cancer risk categories. C by menopausal status at baseline. Adjusted for age closest to baseline and BMI at baseline, follow-up time, case–control status and product term between follow-up time and case status

Fig. 2

Associations between the Largest Relative Annual Change in Percent Density and Breast Cancer by risk. Associations presented by 5-year BOADICEA risk category. Models adjusted for age at earlier mammogram, BMI at baseline, percent density at earlier mammogram, 5-year BOADICEA breast cancer risk score and interaction with BOADICEA score (p_int = 0.005)

Fig. 3

Associations between the largest Relative Annual Change in Density and breast cancer by Menopausal Status. Menopausal status is based on the timing of the largest relative annual change in dense area. Models are presenting change in dense area, adjusted for age at earlier mammogram, BMI at baseline, dense area at earlier mammogram, first and second degree family history of breast cancer, menopause status of MD change and interaction with menopause status of MD change (p_int = 0.049). Excluded cases where age of menopause fell between mammograms for largest change in MD