Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Abstract

Background: Mammographic 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 findings: We 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.

Conclusions: Declines 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.

Fig 1. Polynomial smoothed curves of the crude association of percent mammographic density with age, for each population group within broad ethnic groups.

The broad ethnic groups are organised from largest (black women) to smallest (East Asian women) average breast area for BMI. Full names and details of studies/population groups presented in this figure are provided in S1 Text). Adjustments: none. PD, percent mammographic density.

Fig 2. Association of square-root percent mammographic density with menopausal status and age.

Associations of square-root percent density, by population group, with (a) menopausal status, (b) age among premenopausal women, and (c) age among postmenopausal women, meta-analysed overall and by ASR in source population (low, medium, high). Associations are adjusted for age (for [a] only), BMI, BMI2, parity, age at first birth, HRT use (never, current, former, ever, unknown), mammography view, and MD reader. Full names and details of studies/population groups presented in this figure are provided in S1 Text. Chile is excluded from (a) and (c) as all women were premenopausal. Norway, Australia (Greek), and Australia (Italian) were not included in (a) and (b) as all women were postmenopausal. Turkey was excluded from (a) as selection of women implied that age completely determined menopausal status. ASR, age-standardised incidence rate; BMI, body mass index; CI, confidence interval; HRT, hormone replacement therapy; MD, mammographic density; PD, percent mammographic density.

Fig 3. Modelled associations of square-root percent density, dense area, and total breast area with age and menopausal status, overall and by subgroups.

Square-root dense/breast area is the width of a square representing the dense/breast area; square-root PD is the width of a dense-area square within a 10 cm × 10 cm square. All models are adjusted for age, BMI, BMI2, parity, age at first birth, HRT use (never, ever, past, current, not known), MD reader, image type, and mammography view. BMI, body mass index; CI, confidence interval; ICMD, International Consortium on Mammographic Density;HRT, hormone replacement therapy; MD, mammographic density.