Background We examined the association between annual mammographic density change (MDC) and breast cancer (BC) risk, and how annual MDC influences the association between baseline mammographic density (MD) and BC risk. Methods We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort of Swedish women (N = 43 810) aged 30–79 years with full access to BC risk factors and mammograms. MD was measured as dense area (cm2) and percent MD using the STRATUS method. We used the contralateral mammogram for women with BC and randomly selected a mammogram from either left or right breast for healthy women. We calculated relative area MDC between repeated examinations. Relative area MDC was categorized as decreased (>10% decrease per year), stable (no change), or increased (>10% increase per year). We used Cox proportional hazards regression to estimate the association of BC with MDC and interaction analysis to investigate how MDC modified the association between baseline MD and BC risk. All tests of statistical significance were two-sided. Results In all, 563 women were diagnosed with BC. Compared with women with a decreased MD over time, no statistically significant difference in BC risk was seen for women with either stable MD or increasing MD (hazard ratio = 1.01, 95% confidence interval = 0.82 to 1.23, P = .90; and hazard ratio = 0.98, 95% confidence interval = 0.80 to 1.22, P = .90, respectively). Categorizing baseline MD and subsequently adding MDC did not seem to influence the association between baseline MD and BC risk. Conclusions Our results suggest that annual MDC does not influence BC risk. Furthermore, MDC does not seem to influence the association between baseline MD and BC risk.

Background Mammographic density (MD) is a strong risk factor for breast cancer. We examined how breast cancer risk factors are associated with MD area (cm2) change across age. Methods We conducted a cohort study of 31 782 Swedish women ages 40–70 years at time of baseline mammogram. Lifestyle and reproductive risk factors were assessed by a web-based questionnaire. MD was measured as dense area using the STRATUS method (mean over the left and right breast). Linear regression analyses with adjustments for age, body mass index (BMI), and menopausal status at baseline were performed to assess the association between breast cancer risk factors and mean baseline MD. To investigate mean MD change across age, linear regression analyses with adjustments for age, BMI, menopausal status, and age at last mammogram were performed. All tests of statistical significance were two-sided. Results Except for oral contraceptive use, established lifestyle and reproductive risk factors for breast cancer were associated with baseline mean MD. The overall average annual MD change was −1.0 cm2. BMI and physical activity were statistically significantly associated with MD change. Lean women (BMI <20 kg/m2) had a mean MD change of −1.13 cm2 per year (95% confidence interval = −1.25 to −1.02) compared with −0.46 cm2 per year (95% confidence interval = −0.57 to −0.35) for women with BMI 30 or higher. The annual MD change was −0.4 cm2 larger in women who were very physically active compared with less physically active women. Conclusions Our results indicate that all risk factors for breast cancer, except oral contraceptive use, are associated with baseline MD but that only age, BMI, and physical activity are determinants of MD change.

PurposeHormone replacement therapy (HRT) use increases breast cancer risk and mammographic density (MD). We examine whether MD mediates or modifies the association of HRT with the breast cancer.MethodsFor the 4,501 participants in the Danish diet, cancer and health cohort (1993–1997) who attended mammographic screening in Copenhagen (1993–2001), MD (mixed/dense or fatty) was assessed at the first screening after cohort entry. HRT use was assessed by questionnaire and breast cancer diagnoses until 2012 obtained from the Danish cancer registry. The associations of HRT with MD and with breast cancer were analyzed separately using Cox’s regression. Mediation analyses were used to estimate proportion [with 95% confidence intervals (CI)] of an association between HRT and breast cancer mediated by MD.Results2,444 (54.3%) women had mixed/dense breasts, 229 (5.4%) developed breast cancer, and 35.9% were current HRT users at enrollment. Compared to never users, current HRT use was statistically significantly associated with having mixed/dense breasts (relative risk and 95% CI 1.24; 1.14–1.35), and higher risk of breast cancer (hazard ratio 1.87; 1.40–2.48). Association between current HRT use and breast cancer risk was partially mediated by MD (percent mediated = 10%; 95% CI 4–22%). The current HRT use-related breast cancer risk was higher in women with mixed/dense (1.94; 1.37–3.87) than fatty (1.37; 0.80–2.35) breasts (p value for interaction = 0.15).ConclusionsMD partially mediates some of the association between HRT and breast cancer risk. The association between HRT and breast cancer seems to be stronger in women with dense breasts.

Background Mammographic microcalcifications are considered early signs of breast cancer (BC). We examined the association between microcalcification clusters and the risk of overall and subtype-specific BC. Furthermore, we studied how mammographic density (MD) influences the association between microcalcification clusters and BC risk. Methods We used a prospective cohort (n = 53,273) of Swedish women with comprehensive information on BC risk factors and mammograms. The total number of microcalcification clusters and MD were measured using a computer-aided detection system and the STRATUS method, respectively. Cox regressions and logistic regressions were used to analyse the data. Results Overall, 676 women were diagnosed with BC. Women with ≥3 microcalcification clusters had a hazard ratio [HR] of 2.17 (95% confidence interval [CI] = 1.57–3.01) compared to women with no clusters. The estimated risk was more pronounced in premenopausal women (HR = 2.93; 95% CI = 1.67–5.16). For postmenopausal women, microcalcification clusters and MD had a similar influence on BC risk. No interaction was observed between microcalcification clusters and MD. Microcalcification clusters were significantly associated with in situ breast cancer (odds ratio: 2.03; 95% CI = 1.13–3.63). Conclusions Microcalcification clusters are an independent risk factor for BC, with a higher estimated risk in premenopausal women. In postmenopausal women, microcalcification clusters have a similar association with BC as baseline MD.

Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features among women with a family history of breast cancer (N ¼ 49,674) and a polygenic risk score (PRS, N ¼ 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm 2 /year) was estimated using 1,940 sister pairs. Heritability was estimated at 58% [95% confidence interval (CI), 48%-67%) for MD, 23% (2%-45%) for microcalcifications, and 13% (1%-25%)] for masses. The estimated heritability for MDC was essentially null (2%; 95% CI, À8% to 12%).The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. In summary, we have confirmed previous findings of heritability in MD, and also established heritability of the number of microcalcifications and masses at baseline. Because these features are associated with breast cancer risk and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer.Significance: These findings provide novel data on the heritability of microcalcifications, masses, and density change, which are all associated with breast cancer risk and can indicate women at short-term risk.