Assessing breast arterial calcification in mammograms and its implications for atherosclerotic cardiovascular disease risk.

PURPOSE: Breast arterial calcifications (BAC) are incidentally observed on mammograms, yet their implications remain unclear. We investigated lifestyle, reproductive, and cardiovascular determinants of BAC in women undergoing mammography screening. Further, we investigated the relationship between BAC, coronary arterial calcifications (CAC) and estimated 10-year atherosclerotic cardiovascular (ASCVD) risk. METHODS: In this cross-sectional study, we obtained reproductive history and CVD risk factors from 215 women aged 18 or older who underwent mammography and cardiac computed tomographic angiography (CCTA) within a 2-year period between 2007 and 2017 at hospital. BAC was categorized as binary (present/absent) and semi-quantitatively (mild, moderate, severe). CAC was determined using the Agatston method and recorded as binary (present/absent). Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated, accounting for age as a confounding factor. ASCVD risk over a 10-year period was calculated using the Pooled Cohort Risk Equations. RESULTS: Older age, systolic and diastolic blood pressures, higher parity, and younger age at first birth (≤28 years) were significantly associated with greater odds of BAC. Women with both BAC and CAC had the highest estimated 10-year risk of ASCVD (13.30 %). Those with only BAC (8.80 %), only CAC (5.80 %), and no BAC or CAC (4.40 %) had lower estimated 10-year risks of ASCVD. No association was detected between presence of BAC and CAC. CONCLUSIONS: These findings support the hypothesis that BAC on a screening mammogram may help to identify women at potentially increased risk of future cardiovascular disease without additional cost and radiation exposure.

Long-term exposure to air pollution and mortality in a Danish nationwide administrative cohort study: Beyond mortality from cardiopulmonary disease and lung cancer.

BACKGROUND: The association between long-term exposure to air pollution and mortality from cardiorespiratory diseases is well established, yet the evidence for other diseases remains limited. OBJECTIVES: To examine the associations of long-term exposure to air pollution with mortality from diabetes, dementia, psychiatric disorders, chronic kidney disease (CKD), asthma, acute lower respiratory infection (ALRI), as well as mortality from all-natural and cardiorespiratory causes in the Danish nationwide administrative cohort. METHODS: We followed all residents aged ≥ 30 years (3,083,227) in Denmark from 1 January 2000 until 31 December 2017. Annual mean concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), and ozone (warm season) were estimated using European-wide hybrid land-use regression models (100 m × 100 m) and assigned to baseline residential addresses. We used Cox proportional hazard models to evaluate the association between air pollution and mortality, accounting for demographic and socioeconomic factors. We additionally applied indirect adjustment for smoking and body mass index (BMI). RESULTS: During 47,023,454 person-years of follow-up, 803,881 people died from natural causes. Long-term exposure to PM2.5 (mean: 12.4 µg/m3), NO2 (20.3 µg/m3), and/or BC (1.0 × 10-5/m) was statistically significantly associated with all studied mortality outcomes except CKD. A 5 µg/m3 increase in PM2.5 was associated with higher mortality from all-natural causes (hazard ratio 1.11; 95% confidence interval 1.09-1.13), cardiovascular disease (1.09; 1.07-1.12), respiratory disease (1.11; 1.07-1.15), lung cancer (1.19; 1.15-1.24), diabetes (1.10; 1.04-1.16), dementia (1.05; 1.00-1.10), psychiatric disorders (1.38; 1.27-1.50), asthma (1.13; 0.94-1.36), and ALRI (1.14; 1.09-1.20). Associations with long-term exposure to ozone (mean: 80.2 µg/m3) were generally negative but became significantly positive for several endpoints in two-pollutant models. Generally, associations were attenuated but remained significant after indirect adjustment for smoking and BMI. CONCLUSION: Long-term exposure to PM2.5, NO2, and/or BC in Denmark were associated with mortality beyond cardiorespiratory diseases, including diabetes, dementia, psychiatric disorders, asthma, and ALRI.

Mammographic features are associated with cardiometabolic disease risk and mortality.

AIMS: In recent years, microcalcifications identified in routine mammograms were found to be associated with cardiometabolic disease in women. Here, we aimed to systematically evaluate the association of microcalcifications and other mammographic features with cardiometabolic disease risk and mortality in a large screening cohort and to understand a potential genetic contribution. METHODS AND RESULTS: This study included 57 867 women from a prospective mammographic screening cohort in Sweden (KARMA) and 49 583 sisters. Cardiometabolic disease diagnoses and mortality and medication were extracted by linkage to Swedish population registries with virtually no missing data. In the cardiometabolic phenome-wide association study, we found that a higher number of microcalcifications were associated with increased risk for multiple cardiometabolic diseases, particularly in women with pre-existing cardiometabolic diseases. In contrast, dense breasts were associated with a lower incidence of cardiometabolic diseases. Importantly, we observed similar associations in sisters of KARMA women, indicating a potential genetic overlap between mammographic features and cardiometabolic traits. Finally, we observed that the presence of microcalcifications was associated with increased cardiometabolic mortality in women with pre-existing cardiometabolic diseases (hazard ratio and 95% confidence interval: 1.79 [1.24-2.58], P = 0.002) while we did not find such effects in women without cardiometabolic diseases. CONCLUSIONS: We found that mammographic features are associated with cardiometabolic risk and mortality. Our results strengthen the notion that a combination of mammographic features and other breast cancer risk factors could be a novel and affordable tool to assess cardiometabolic health in women attending mammographic screening.

Mammographic microcalcifications and risk of breast cancer.

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.

Predictors of mammographic microcalcifications.

We examined the association between established risk factors for breast cancer and microcalcification clusters and their asymmetry. A cohort study of 53 273 Swedish women aged 30 to 80 years, with comprehensive information on breast cancer risk factors and mammograms, was conducted. Total number of microcalcification clusters and the average mammographic density area were measured using a Computer Aided Detection system and the STRATUS method, respectively. A polygenic risk score for breast cancer, including 313 single nucleotide polymorphisms, was calculated for those women genotyped (N = 7387). Odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders, were estimated. Age was strongly associated with microcalcification clusters. Both high mammographic density (>40 cm2 ), and high polygenic risk score (80-100 percentile) were associated with microcalcification clusters, OR = 2.08 (95% CI = 1.93-2.25) and OR = 1.22 (95% CI = 1.06-1.48), respectively. Among reproductive risk factors, life-time breastfeeding duration >1 year was associated with microcalcification clusters OR = 1.22 (95% CI = 1.03-1.46). The association was confined to postmenopausal women. Among lifestyle risk factors, women with a body mass index ≥30 kg/m2 had the lowest risk of microcalcification clusters OR = 0.79 (95% CI = 0.73-0.85) and the association was stronger among premenopausal women. Our results suggest that age, mammographic density, genetic predictors of breast cancer, having more than two children, longer duration of breast-feeding are significantly associated with increased risk of microcalcification clusters. However, most lifestyle risk factors for breast cancer seem to protect against presence of microcalcification clusters. More research is needed to study biological mechanisms behind microcalcifications formation.

Hormonal determinants of mammographic density and density change.

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 cm2 per 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 cm2 and - 1.16 cm2 lesser, 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.

Hormone replacement therapy and mammographic density: a systematic literature review.

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.

Heritability of Mammographic Breast Density, Density Change, Microcalcifications, and Masses.

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 = 49,674) and a polygenic risk score (PRS, N = 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm2/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, -8% 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.

Mammographic Density Change and Risk of Breast Cancer.

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.

Determinants of Mammographic Density Change.

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.

Regular physical activity and mammographic density: a cohort study.

PURPOSE: Physical activity is a modifiable lifestyle risk factor in prevention of breast cancer. Mammographic density (MD) is a strong risk factor for breast cancer. We investigate the association of regular physical activity with MD. METHODS: For 5,703 women who participated in the Danish Diet, Cancer and Health cohort (1993-1997) and attended mammographic screening in Copenhagen (1993-2001), MD was assessed at the first screening after cohort entry. MD was defined as a binary measure equivalent to Breast Imaging Report and Data System (BI-RADS) to either mixed/dense or fatty. Participation and duration in physical activities (hours/week) and confounders were assessed by questionnaire at cohort baseline. Logistic regression was used to estimate associations [odds ratios (OR), 95% confidence intervals (CI)] between physical activities and MD. RESULTS: 56.3% of women had mixed/dense MD and 47.6% participated in sports. We found a significant positive association between participation in sports (OR 1.15; 95% CI 1.03-1.28) and do-it-yourself work (1.17; 1.05-1.31) and odds of having mixed/dense MD, which attenuated (1.08; 0.96-1.22 and 1.11; 0.98-1.25, respectively) in a fully adjusted model. No associations were found for time spent on physical activities or total metabolic equivalent of task scores with MD, in fully adjusted models. There was no effect modification of association between any physical activities and MD by obesity (BMI ≥ 30 kg/m2) and menopause status. CONCLUSIONS: Physical activity is not a determinant of MD.

Hormone replacement therapy, mammographic density, and breast cancer risk: a cohort study.

PURPOSE: 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. METHODS: For 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. RESULTS: 2,444 (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). CONCLUSIONS: MD 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.