Abstract
BackgroundMammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known.Methods and findingsWe examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature.ConclusionsDeclines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.
Highlights
Mammographic density (MD), a measure of the amount of radiopaque fibroglandular as opposed to fat tissue in the breast, is amongst the strongest of breast cancer risk factors [1,2,3]
If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction
MD declines during the menopausal transition and with ageing; MD may be a tissue-specific marker of the biological processes underlying the rate of breast tissue ageing and, the shape of the breast cancer incidence–age curve [2,7,8]
Summary
Mammographic density (MD), a measure of the amount of radiopaque fibroglandular as opposed to fat tissue in the breast, is amongst the strongest of breast cancer risk factors [1,2,3]. Parallels have been drawn between life-course trajectories of MD and Pike’s model for the rate of breast tissue ageing [1,2,3,4] The latter model hypothesizes that Clemmesen’s hook (the slowing of the rate of increase of age-specific breast cancer incidence rates after menopause, S1 Fig) is due to a reduction in the rate of breast tissue ageing in postmenopausal women [4,5,6]. Many found non-linear declines with increasing age [8,10,11,12], often steepest during the perimenopausal period, and some suggested that MD plateaus by age 65 years [11,12] The majority of these studies were conducted at screening ages (predominantly 50–70 years) and in countries with high breast cancer incidence rates. Its agerelated characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known
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