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Background: Night-shift work (NSW) has been suggested as a possible cause of breast cancer, and its association with mammographic density (MD), one of the strongest risk factors for breast cancer, has been scarcely addressed. This study examined NSW and MD in Spanish women.Methods: The study covered 2,752 women aged 45–68 years recruited in 2007–2008 in 7 population-based public breast cancer screening centers, which included 243 women who had performed NSW for at least one year. Occupational data and information on potential confounders were collected by personal interview. Two trained radiologist estimated the percentage of MD assisted by a validated semiautomatic computer tool (DM-scan). Multivariable mixed linear regression models with random screening center–specific intercepts were fitted using log-transformed percentage of MD as the dependent variable and adjusting by known confounding variables.Results: Having ever worked in NSW was not associated with MD [{e^\beta }$:0.96; 95% confidence interval (CI), 0.86–1.06]. However, the adjusted geometric mean of the percentage of MD in women with NSW for more than 15 years was 25% higher than that of those without NSW history (MD>15 years:20.7% vs. MDnever:16.5%;{e^\beta }$:1.25; 95% CI,1.01–1.54). This association was mainly observed in postmenopausal participants ({e^\beta }$:1.28; 95% CI, 1.00–1.64). Among NSW-exposed women, those with ≤2 night-shifts per week had higher MD than those with 5 to 7 nightshifts per week ({e^\beta }$:1.42; 95% CI, 1.10–1.84).Conclusions: Performing NSW was associated with higher MD only in women with more than 15 years of cumulated exposure. These findings warrant replication in futures studies.Impact: Our findings suggest that MD could play a role in the pathway between long-term NSW and breast cancer. Cancer Epidemiol Biomarkers Prev; 26(6); 905–13. ©2017 AACR.

Supplementary table S1. Association of current or recent (stopped NSW

Supplementary Figure 1. Graphic esqueme summarizing the proposed pathways of the association between night-shift work and mammographic density.

[EN] Objectives: Mammographic density (MD) is a strong risk factor for breast cancer. The present study evaluates the association between relative caloric intake and MD in Spanish women. Study design: We conducted a cross-sectional study in which 3517 women were recruited from seven breast cancer screening centers. MD was measured by an experienced radiologist using craniocaudal mammography and Boyd's semi-quantitative scale. Information was collected through an epidemiological survey. Predicted calories were calculated using linear regression models, including the basal metabolic rate and physical activity as explanatory variables. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using center-specific mixed ordinal logistic regression models, adjusted for age, menopausal status, body mass index, parity, tobacco use, family history of breast cancer, previous biopsies, age at menarche and adherence to a Western diet. Main outcome measure: Mammographic density. Results: Those women with an excessive caloric intake ( > 40% above predicted) presented higher MD (OR = 1.41, 95%CI = 0.97-2.03; p = 0.070). For every 20% increase in relative caloric consumption the probability of having higher MD increased by 5% (OR = 1.05, 95%CI = 0.98-1.14; p = 0.178), not observing differences between the categories of explanatory variables. Caloric restriction was not associated with MD in our study. Conclusions: This is the first study exploring the association between MD and the effect of caloric deficit or excessive caloric consumption according to the energy requirements of each woman. Although caloric restriction does not seem to affect breast density, a caloric intake above predicted levels seems to increase this phenotype, This study was supported by the Research Grant FIS PI060386 from Spanish Public Health Research Fund (Fondo de Investigacion Sanitaria); the Carlos III Institute of Health (Institute de Salud Carlos III)PI15CIII/0029 and PI15CIII/00013; the EPY 1306/06Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health; and a grant from the Spanish Federation of Breast Cancer Patients (FECMA EPY 1169/10).

[EN] Objectives: The association between breast cancer (BC) and thyroid disorders has been widely explored with unclear results. Mammographic density (MD) is one of the strongest risk factor for BC. This study explores the relationship between thyroid diseases and MD in Spanish women. Materials & methods: This cross-sectional study covered 2883 women aged 47-71 years participating in 7 BC screening programs in 2010. They allowed access to their mammograms, had anthropometrical-measures taken, and answered a telephonic epidemiological interview which included specific questions on thyroid diseases. Percentage of MD was assessed with a semiautomatic-computer tool (DM-scan) by two trained radiologists. We calculated the geometric mean of MD percentages (mean MD). Multivariable mixed linear regression models with random screening-center-specific intercepts were fitted, using log-transformed percentage of MD as dependent variable and adjusting for age, body mass index, menopausal status and other confounders. e(beta) represents the relative increase of mean MD. Results: 13.9% of the participants reported personal history of thyroid disease. MD was not associated to hyperthyroidism (e(beta): 1.05, 95%CI: 0.82-1.36), hypothyroidism (e(beta):1.02, 95%CI: 0.75-1.38), thyroid nodules (e(beta):1.01, 95%CI: 0.85-1.19) or thyroid cancer (e(beta):1.03, 95%CI: 0.56-1.92). However, women with goiter had lower MD (mean MDno-goiter: 13.4% vs mean MDgoiter: 10.6%; e(beta):0.79, 95%CI: 0.64-0.98) and those with Hashimoto thyroiditis had higher MD (mean MDno-thyroiditis: 13.3% vs mean MDthyroidits: 25.8%; e(beta) 95%CI: 1.00-3.77). Conclusion: Functional thyroid disorders were not related to MD. However, MD was lower in women with goiter and higher in those reporting Hashimoto's thyroiditis. These relationships should be confirmed in future studies. (C) 2017 Elsevier Ltd. All rights reserved., This work was supported by the Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (ISCIII) (FI14CIII/00013, FIS PI060386 & PS09/0790); the Spanish Federation of Breast Cancer Patients (FECMA 485 EPY 1170-10); the Gent per Gent Fund (EDEMAC Project); and the EPY1306/06 collaboration agreement between Astra-Zeneca and the ISCIII and partially funded by the European Regional Development Fund. None of these funding sources had any role in the study design, in the collection, analysis or interpretation of data. Other members of DDM-Spain/Var-DDM: María Casals, Inmaculada Martínez, María Ederra and Jesús Vioque.

OBJECTIVE: To examine the association between two dietary patterns (Western and Mediterranean), previously linked to breast cancer risk, and mammographic density. METHODS: This cross-sectional study included 3,584 women attending population-based breast cancer screening programs and recruited between October 7, 2007, and July 14, 2008 (participation rate 74.5%). Collected data included anthropometric measurements; demographic, obstetric, and gynecologic characteristics; family and personal health history; and diet in the preceding year. Mammographic density was blindly assessed by a single radiologist and classified into four categories: less than 10%, 10-25%, 25-50%, and greater than 50%. The association between adherence to either a Western or a Mediterranean dietary pattern and mammographic density was explored using multivariable ordinal logistic regression models with random center-specific intercepts. Models were adjusted for age, body mass index, parity, menopause, smoking, family history, hormonal treatment, and calorie and alcohol intake. Differences according to women's characteristics were tested including interaction terms. RESULTS: Women with a higher adherence to the Western dietary pattern were more likely to have high mammographic density (n=242 [27%]) than women with low adherence (n=169 [19%]) with a fully adjusted odds ratio (ORQ4vsQ1) of 1.25 (95% confidence interval [CI] 1.03-1.52). This association was confined to overweight-obese women (adjusted ORQ4vsQ1 [95% CI] 1.41 [1.13-1.76]). No association between Mediterranean dietary pattern and mammographic density was observed. CONCLUSION: The Western dietary pattern was associated with increased mammographic density among overweight-obese women. Our results might inform specific dietary recommendations for women with high mammographic density. Sí

Mammographic density (MD) is regarded as an intermediate phenotype in breast cancer development. This association study investigated the influence of 14 breast cancer susceptibility loci identified through previous genome-wide association studies on MD among the participants in the "Determinants of Density in Mammographies in Spain" (DDM-Spain) study.Our study covered a total of 3348 Caucasian women aged 45-68years, recruited from seven Spanish breast cancer screening centres having DNA available. Mammographic density was blindly assessed by a single reader using a semiquantitative scale. Ordinal logistic models, adjusted for age, body mass index and menopausal status, were used to estimate the association between each genotype and MD.Evidence of association with MD was found for variant rs3803662 (TOX3) (Odds Ratio (OR)=1.13, 95% Confidence Interval (CI)=1.03-1.25), and marginal evidence of association for susceptibility loci rs3817198 (LSP1) (OR=1.09, 95% CI=1.00-1.20) and rs2981582 (FGFR2) (OR=0.92, 95% CI=0.84-1.01). Two other loci were associated with MD solely among pre-menopausal women, namely, rs4973768 (SLC4A7) (OR=0.83, 95% CI=0.70-1.00) and rs4415084 (MEPS30) (OR=1.22, 95% CI=1.00-1.49).Our findings lend some support to the hypothesis which links these susceptibility loci to MD.

The objective of the present study was to assess the reproducibility of data-driven dietary patterns in different samples extracted from similar populations. Dietary patterns were extracted by applying principal component analyses to the dietary information collected from a sample of 3550 women recruited from seven screening centres belonging to the Spanish breast cancer (BC) screening network (Determinants of Mammographic Density in Spain (DDM-Spain) study). The resulting patterns were compared with three dietary patterns obtained from a previous Spanish case-control study on female BC (Epidemiological study of the Spanish group for breast cancer research (GEICAM: grupo Español de investigación en cáncer de mama)) using the dietary intake data of 973 healthy participants. The level of agreement between patterns was determined using both the congruence coefficient (CC) between the pattern loadings (considering patterns with a CC≥0·85 as fairly similar) and the linear correlation between patterns scores (considering as fairly similar those patterns with a statistically significant correlation). The conclusions reached with both methods were compared. This is the first study exploring the reproducibility of data-driven patterns from two studies and the first using the CC to determine pattern similarity. We were able to reproduce the EpiGEICAM Western pattern in the DDM-Spain sample (CC=0·90). However, the reproducibility of the Prudent (CC=0·76) and Mediterranean (CC=0·77) patterns was not as good. The linear correlation between pattern scores was statistically significant in all cases, highlighting its arbitrariness for determining pattern similarity. We conclude that the reproducibility of widely prevalent dietary patterns is better than the reproducibility of more population-specific patterns. More methodological studies are needed to establish an objective measurement and threshold to determine pattern similarity. This study was supported by Carlos III Institute of Health FIS(Spanish Public Health Research Fund: PI060386 FIS; PS09/00790 and PI15CIII/0029 research grants), the Spanish Ministryof Health (EC11-273), the Spanish Ministry of Economyand Competitiveness (IJCI-2014-20900), the Spanish Federationof Breast Cancer Patients (FECMA: EPY 1169-10) and theAssociation of Women with Breast Cancer from Elche (AMAC-MEC: EPY 1394/15). None of the funders had any role in thedesign, analysis or writing of this article.V.L.,N.A.,B.P.-G.andM.P.designedthestudy;A.C.,J.V.,C.S.,C.P.-P.,S.A.,M.E.,D.S.-T.,C.V.andC.S.-C.collectedthedataand/or prepared the database. A. C. performed statistical analysisand wrote the initial version of the manuscript that M. P. revised andcorrected in its different versions. All the authors have read andapproved thefinal version of the manuscript.The authors declare that there are no conflicts of interest. Sí

OBJECTIVE The use of some forms of hormone therapy (HT) is associated with an increase in mammographic density-a major risk factor for breast cancer. The role of isoflavones, however, is unclear. Here, we quantify the prevalence of HT and isoflavone use among postmenopausal Spanish women, determine associated risk factors, and explore the relationship between these therapies and mammographic density. METHODS This cross-sectional study included 2,754 postmenopausal women who underwent breast cancer screening in seven geographical areas. Mammographic density was evaluated using Boyd's semiquantitative scale. Multinomial logistic regression models were adjusted to assess risk factors associated with both therapies. Ordinal regression models were fitted to study the association between HT and isoflavone consumption with mammographic density. RESULTS The prevalence of ever-use of HT was 12%, whereas that of the current use was 2.3%. Isoflavone lifetime prevalence was 3.7%, and current use was 1.7%. The most common HT types were tibolone and estrogens. Surgical menopause, oral contraceptive use, educational level, population density, and years since menopause were positively associated with HT, whereas body mass index and parity were inversely associated. Mammographic density was not associated with current or past HT use. However, women who reported having consumed isoflavones in the past and those who started their use after menopause had a higher mammographic density when compared with never-users (odds ratio 1.98, 95% CI 1.21-3.25, P = 0.007; and odds ratio 1.60, 95% CI 1.01-2.53, P = 0.045 respectively). CONCLUSIONS Our results show a low prevalence of HT and isoflavone use in postmenopausal Spanish women. In this population, HT use was not associated with mammographic density, whereas some categories of isoflavone users had higher density.

Growth and development factors could contribute to the development of breast cancer associated with an increase in mammographic density. This study examines the influence of certain childhood-related, socio-demographic and anthropometric variables on mammographic density in adult woman. The study covered 3574 women aged 45-68 years, participating in breast cancer-screening programmes in seven Spanish cities. Based on a craniocaudal mammogram, blind, anonymous measurement of mammographic density was made by a single radiologist, using Boyd's semiquantitative scale. Data associated with the early stages of life were obtained from a direct survey. Ordinal logistic regression and generalised linear models were employed to estimate the association between mammographic density and the variables covered by the questionnaire. Screening programme was introduced as a random effects term. Age, number of children, body mass index (BMI) and other childhood-related variables were used as adjustment variables, and stratified by menopausal status. A total of 811 women (23%) presented mammographic density of over 50%, and 5% of densities exceeded 75%. Our results show a greater prevalence of high mammographic density in women with low prepubertal weight (OR: 1.18; 95% CI: 1.02-1.36); marked prepubertal height (OR: 1.25; 95% CI: 0.97-1.60) and advanced age of their mothers at their birth (>39 years: OR: 1.28; 95% CI: 1.03-1.60); and a lower prevalence of high mammographic density in women with higher prepubertal weight, low birth weight and earlier menarche. The influence of these early-life factors may be explained by greater exposure to hormones and growth factors during the development of the breast gland, when breast tissue would be particularly susceptible to proliferative and carcinogenic stimulus.

Introduction Mammographic density (MD) is considered a strong predictor of Breast Cancer (BC). The objective of the present study is to explore the association between MD and the compliance with the World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) recommendations for cancer prevention. Methods Data of 3584 women attending screening from a population-based multicenter cross-sectional study (DDM-Spain) collected from October 7, 2007 through July 14, 2008, was used to calculate a score that measures the level of compliance with the WCRF/AICR recommendations: R1)Maintain adequate body weight; R2)Be physically active; 3R)Limit the intake of high density foods; R4)Eat mostly plant foods; R5)Limit the intake of animal foods; R6)Limit alcohol intake; R7)Limit salt and salt preserved food intake; R8)Meet nutritional needs through diet. The association between the score and MD (assessed by a single radiologist using a semi-quantitative scale) was evaluated using ordinal logistic models with random center-specific intercepts adjusted for the main determinants of MD. Stratified analyses by menopausal status and smoking status were also carried out. Results A higher compliance with the WCRF/AICR recommendations was associated with lower MD (OR1-unit increase = 0.93 95%CI:0.86;0.99). The association was stronger in postmenopausal women (OR = 0.91 95%CI:0.84;0.99) and nonsmokers (OR = 0.87;95%CI:0.80;0.96 for nonsmokers, OR = 1.01 95%CI:0.91;1.12 for smokers, P-interaction = 0.042). Among nonsmokers, maintaining adequate body weight (OR = 0.81 95%CI:0.65;1.01), practicing physical activity (OR = 0.68 95%CI:0.48;0.96) and moderating the intake of high-density foods (OR = 0.58 95%CI:0.40;0.86) and alcoholic beverages (OR = 0.76 95%CI:0.55;1.05) were the recommendations showing the strongest associations with MD. Conclusions postmenopausal women and non-smokers with greater compliance with the WCRF/AICR guidelines have lower MD. These results may provide guidance to design specific recommendations for screening attendants with high MD and therefore at higher risk of developing BC., This study was supported by FIS PI060386 FIS (Health Research Fund) Research Grant; EC11-273 Research Grant from the Spanish Ministy of Health; CD110/00018 FIS Sara Borrell contract; FECMA 485 EPY 1170-10 grant from the Spanish Federation of Breast Cancer Patients.

High mammographic density (MD) is one of the main risk factors for development of breast cancer. To date, however, relatively few studies have evaluated the association between MD and diet. In this cross-sectional study, we assessed the association between MD (measured using Boyd's semiquantitative scale with five categories: 75%) and diet (measured using a food frequency questionnaire validated in a Spanish population) among 3,548 peri- and postmenopausal women drawn from seven breast cancer screening programs in Spain. Multivariate ordinal logistic regression models, adjusted for age, body mass index (BMI), energy intake and protein consumption as well as other confounders, showed an association between greater calorie intake and greater MD [odds ratio (OR) = 1.23; 95% confidence interval (CI) = 1.10-1.38, for every increase of 500 cal/day], yet high consumption of olive oil was nevertheless found to reduce the prevalence of high MD (OR = 0.86;95% CI = 0.76-0.96, for every increase of 22 g/day in olive oil consumption); and, while greater intake of whole milk was likewise associated with higher MD (OR = 1.10; 95%CI 1.00-1.20, for every increase of 200 g/day), higher consumption of protein (OR = 0.89; 95% CI 0.80-1.00, for every increase of 30 g/day) and white meat (p for trend 0.041) was found to be inversely associated with MD. Our study, the largest to date to assess the association between diet and MD, suggests that MD is associated with modifiable dietary factors, such as calorie intake and olive oil consumption. These foods could thus modulate the prevalence of high MD, and important risk marker for breast cancer. Grant sponsor: Spain’s Health Research Fund (Fondo de Investigación Sanitaria);Grant numbers:FIS PI060386 & FIS PIS09/01006; Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health (Instituto de Salud Carlos III);Grant number: EPY 1306/06; Spanish Federation of Breast Cancer patients; Grant number: FECMA 485 EPY 1170-10 Sí

High mammographic density (MD) is used as a phenotype risk marker for developing breast cancer. During pregnancy and lactation the breast attains full development, with a cellular-proliferation followed by a lobular-differentiation stage. This study investigates the influence of obstetric factors on MD among pre- and post-menopausal women. We enrolled 3,574 women aged 45-68 years who were participating in breast cancer screening programmes in seven screening centers. To measure MD, blind anonymous readings were taken by an experienced radiologist, using craniocaudal mammography and Boyd's semiquantitative scale. Demographic and reproductive data were directly surveyed by purpose-trained staff at the date of screening. The association between MD and obstetric variables was quantified by ordinal logistic regression, with screening centre introduced as a random effect term. We adjusted for age, number of children and body mass index, and stratified by menopausal status. Parity was inversely associated with density, the probability of having high MD decreased by 16% for each new birth (P value < 0.001). Among parous women, a positive association was detected with duration of lactation [>9 months: odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.02-1.72] and weight of first child (>3,500 g: OR = 1.32; 95% CI = 1.12-1.54). Age at first birth showed a different effect in pre- and post-menopausal women (P value for interaction = 0.030). No association was found among pre-menopausal women. However, in post-menopausal women the probability of having high MD increased in women who had their first child after the age of 30 (OR = 1.53; 95% CI = 1.17-2.00). A higher risk associated with birth of twins was also mainly observed in post-menopausal women (OR = 2.02; 95% CI = 1.18-3.46). Our study shows a greater prevalence of high MD in mothers of advanced age at first birth, those who had twins, those who have breastfed for longer periods, and mothers whose first child had an elevated birth weight. These results suggest the influence of hormones and growth factors over the proliferative activity of the mammary gland. This study was supported by the Research Grant FIS PI060386 from Spain’s Health Research Fund (Fondo de Investigación Sanitaria); the EPY 1306/06 Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health (Instituto de Salud Carlos III); and a grant from the Spanish Federation of Breast Cancer patients (FECMA 485 EPY 1170-10). Sí