METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences.
RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p
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.
METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.
RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.
CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.
IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.
RESULTS: In European ancestry samples, 14 genes were significantly associated (q