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.

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.

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.

Hormone 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.

Purpose: Hormone replacement therapy (HRT) is used to reduce climacteric symptoms of menopause and prevent osteoporosis; however, it increases risk of breast cancer. Mammographic density (MD) is also a strong risk factor for breast cancer. We conducted this review to investigate the association between HRT use and MD and to assess the effect of different HRT regimens on MD.Methods: Two of authors examined articles published between 2002 and 2019 from PubMed, Embase, and OVID using Covidence systematic review platform. Any disagreements were discussed until consensus was reached. The protocol used in this review was created in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Quality of each eligible study was assessed using the Oxford Center for Evidence-Based Medicine (OCEBM) hierarchy.Results: Twenty-two studies met the inclusion criteria. Six studies showed that using estrogen plus progestin (E + P) HRT was associated with higher MD than estrogen alone. Four studies reported that continuous estrogen plus progestin (CEP) users had higher MD than sequential estrogen plus progestin (SEP) and estrogen alone users. However, two studies showed that SEP users had slightly higher MD than CEP users and estrogen alone users.Conclusions: Epidemiological evidence is rather consistent suggesting that there is a positive association between HRT use and MD with the highest increase in MD among current users, and CEP users. Our results suggest that due to increase in MD and masking effect, current E + P users may require additional screening procedures, shorter screening intervals, or using advanced imaging techniques.

Background: Mammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm²) and annual MD change (cm²/year).Methods: This study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time.Results: Greater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm²per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm²), oesterone sulphate (+ 1.42 cm²), prolactin (+ 2.11 cm²) and SHBG (+ 4.18 cm²), and inversely associated with 11-deoxycortisol (− 1.33 cm²). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was − 0.8 cm². Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was − 0.96 cm²and − 1.16 cm²lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations.Conclusions: Our results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.