Elevated mammographic density (MD) for a woman’s age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35–85 years from 22 countries, capturing 40 country- ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. Among 10,988 women included in these analyses, 90.1

PDF file, 133KB, Supplemental Table 6a. Per-Allele Association (SE) of Breast Cancer Susceptibility Variants with Mammographic Percent Density Stratifying by Case Status, BMI, Menopausal Status and PMH Use. Supplemental Table 6b. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use. Supplemental Table 6c. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use.

PDF file, 120KB, Supplemental Table 1. Study Descriptions, Design and Sample Size for 19 DENSNP Studies. Caucasian Women Only. Supplemental Table 2. Source and Timing of Reproductive and Anthropometric Variable Collection. Supplemental Table 3. Description of Mammogram View, Side, Film Digitizer and Density Estimation Software for DENSNP Studies. Supplemental Table 4. Genotyping Platform and SNP Call Rates Performed by Each Study.

PDF file - 275K, Significance of the mammographic breast density polygenic risk score (PRS) for the prediction of breast cancer risk, according to percent cut-off of SNPs used in the PRS: sensitivity analysis using imputed case:control genotype dosages.

PDF file, 20KB, Supplemental Table 5a. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Percent Mammographic Density. Supplemental Table 5b. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area. Supplemental Table 5c. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area.

Selected characteristics of all studies included in the meta-analysis

Background Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. Methods Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. Results In pooled analyses, later age at menarche was associated with higher per cent density ( β √PD = 0.023 SE = 0.008, P = 0.003) and larger dense area ( β √DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area ( β √DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density ( β √PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. Conclusions In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Background Risk of breast cancer in adult life is influenced by body size and height in childhood, but the mechanisms responsible for these associations are currently unknown. We carried out research to determine if, at age 15-18, measures of dietary intake were associated with body size, hormones, and with variations in breast tissue composition that in adult life are associated with risk of breast cancer. Methods In a cross-sectional study of 766 healthy Caucasian women aged 15-18, we measured percent breast water (PBW), total breast water and fat by magnetic resonance (MR), and assessed dietary intake using a validated food frequency questionnaire. We also measured height, weight, skin-fold thicknesses and waist-to-hip ratio, and in fasting blood assayed glucose and insulin. Results After adjustment for age, measures of body size, and energy intake, dietary fiber (insoluble and total fiber) and insulin were associated positively and significantly with PBW. Conclusions Dietary fiber and fasting insulin were associated with breast tissue measures. These data suggest a potential approach to breast cancer prevention.

Women with the most extensive breast density, have a 4- to 6-fold higher cancer risk than women with the lowest density. This cross-sectional study evaluated associations of cumulative mammographic density in two distinct ethnic groups with the respective age-specific breast cancer incidences in the population. The study compared four cohorts of 200 women each aged 35 to 49 and 50 to 74, representing Jewish and Arab ethnicity. Breast density measures were calculated from screening mammograms, using a thresholding software (Cumulus). Breast cancer specific incidence values were obtained from the National Cancer Registry. The percent mammographic density was lower for women aged 50 to 74 than 35 to 49 years, both for Jews: 11.7 vs 23.1 and for Arabs: 11.6 vs 18.3. In contrast, the cumulative density increased with age, from 37.30 to 181.24 in Jews, compared to 21.26 to 108.03 in Arabs. Similar trends in breast cancer incidence rates per 100 000 in the Israeli population were apparent, with an increase from 92.95 to 381.91 in Jews, compared to 48.6 to 244.44 in Arabs. Comparing cumulative density of the cohort with respective age-specific breast cancer incidence in the population yielded a highly significant correlation: Jews; r = .97, P < .0001 and Arabs: r = .86, P = .007. A strong association was found between the log of cumulative density and the log of cancer incidence, as well. Our study identified correlations between cumulative mammographic density and breast cancer incidence in two distinct populations. The findings should prompt research to enhance our understanding of the pathogenesis of breast cancer, and lead to novel insights into measures of prevention.

Background. Risk of breast cancer in adult life is influenced by body size and height in childhood. The mechanisms responsible for these associations are currently unknown. The present research was carried out to determine if, at age 15-18, measures of dietary intake were associated with body size, hormones and growth factors, and with variations in breast tissue composition that in adult life are strongly associated with risk of breast cancer. Methods. We carried out a cross-sectional study in 766 healthy young Caucasian women aged 15-18. Percent breast water (PBW), total breast water and fat were measured by magnetic resonance (MR). Dietary intake at age 15-18 was assessed using a validated food frequency questionnaire. We also measured height, weight, skin-fold thicknesses and waist-to-hip ratio, and obtained fasting blood to assay glucose and insulin, and calculated an estimate of insulin sensitivity (HOMA2-S). Results. After adjustment for age, measures of body size, and energy intake, dietary fiber (insoluble and total fiber) was associated positively with PBW with the HOMA2-S estimate of insulin sensitivity, and inversely with fasting serum insulin. Insulin sensitivity was also significantly and positively associated with PBW and inversely with total breast fat. The association of dietary fiber with breast tissue composition was no longer statistically significant after adjustment for fasting insulin or insulin sensitivity. Conclusions. These results show an association of dietary fiber with breast tissue measures and suggest that this association may be mediated, at least in part, by insulin or insulin sensitivity. These findings suggest a potential approach to breast cancer prevention in early life.

Background: Our purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases. Methods: We used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population. Results: Extensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population. Conclusions: These findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions.

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. 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.

Abstract Background: Percent breast density (PBD) is a strong risk factor for breast cancer that is influenced by several other risk factors for the disease. Alcohol consumption is associated with an increased risk of breast cancer with an uncertain association with PBD. We have carried out a systematic review and meta-analysis to examine the association of alcohol consumption with PBD. Methods: We searched nine databases to identify all relevant studies on the association between alcohol intake and breast density. Two independent investigators evaluated and selected 20 studies that were included in our analyses. We divided the studies into three groups according to the methods used to measure and analyze the association of breast density with alcohol consumption. Results: Meta-analysis of the 11 studies that used quantitative methods to measure and analyze PBD as a continuous variable found a statistically significant difference in PBD when comparing the highest with the lowest alcohol level [β = 0.84; 95% confidence interval (CI), 0.12–1.56]. Three studies that used quantitative methods to measure PBD and categories of PBD for analysis had a summary OR = 1.81 (95% CI, 1.07–3.04). Five studies that used categories to classify PBD and analyze their association with alcohol intake had a summary OR = 1.78 (95% CI, 0.90–3.51). Conclusions: These results suggest that there is a positive association between alcohol intake and PBD. Impact: Alcohol may increase the risk of breast cancer associated with PBD. Cancer Epidemiol Biomarkers Prev; 26(2); 170–8. ©2016 AACR.

Background: Estrogen plus progestin therapy increases both mammographic density and breast cancer incidence. Whether mammographic density change associated with estrogen plus progestin initiation predicts breast cancer risk is unknown. Methods: We conducted an ancillary nested case-control study within the Women’s Health Initiative trial that randomly assigned postmenopausal women to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. Mammographic density was assessed from mammograms taken prior to and one year after random assignment for 174 women who later developed breast cancer (cases) and 733 healthy women (controls). Logistic regression analyses included adjustment for confounders and baseline mammographic density when appropriate. Results: Among women in the estrogen plus progestin arm (97 cases/378 controls), each 1% positive change in percent mammographic density increased breast cancer risk 3% (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01 to 1.06). For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased 3.6-fold (95% CI = 1.52 to 8.56). The effect of estrogen plus progestin use on breast cancer risk (OR = 1.28, 95% CI = 0.90 to 1.82) was eliminated in this study, after adjusting for change in mammographic density (OR = 1.00, 95% CI = 0.66 to 1.51). Conclusions: We found the one-year change in mammographic density after estrogen plus progestin initiation predicted subsequent increase in breast cancer risk. All of the increased risk from estrogen plus progestin use was mediated through mammographic density change. Doctors should evaluate changes in mammographic density with women who initiate estrogen plus progestin therapy and discuss the breast cancer risk implications.

BackgroundIn previous work in young women aged 15-30 years we measured breast water and fat using MR and obtained blood for hormone assays on the same day in the follicular phase of the menstrual cycle. Only serum growth hormone levels and sex hormone binding globulin (SHBG) were significantly associated with percent breast water after adjustment for covariates. The sex hormones estradiol, progesterone and testosterone were not associated with percent water in the breast in the follicular phase of the menstrual cycle. In the present study we have examined the association of percent breast water with serum levels of sex hormones in both follicular and luteal phase of the menstrual cycle.MethodsIn 315 healthy white Caucasian young women aged 15-30 with regular menstrual cycles who had not used oral contraceptives or other hormones in the previous 6 months, we used MR to determine percent breast water, and obtained blood samples for hormone assays within 10 days of the onset of the most recent menstrual cycle (follicular phase) of the cycle on the same day as the MR scan, and a second blood sample on days 19-24 of the cycle. Serum progesterone levels of > = 5 mmol/L in days 19-24 were used to define the 225 subjects with ovulatory menstrual cycles, whose data are the subject of the analyses shown here.ResultsSHBG was positively associated with percent water in both follicular and luteal phases of the menstrual cycle. Total and free estradiol and total and free testosterone were not associated with percent water in the follicular phase, but in young women with ovulatory cycles, were all negatively associated with percent water in the luteal phase.ConclusionsOur results from young women aged 15-30 years add to the evidence that the extent of fibroglandular tissue in the breast that is reflected in both mammographic density and breast water is associated positively with higher serum levels of SHBG, but not with higher levels of sex hormones.

Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

Lindström, Sara ; Thompson, Deborah J. ; Paterson, Andrew D. ; Li, Jingmei ; Gierach, Gretchen L. ; Scott, Christopher ; Stone, Jennifer ; Douglas, Julie A. ; Dos-Santos-Silva, Isabel ; Fernandez-Navarro, Pablo ; Verghase, Jajini ; Smith, Paula ; Brown, Judith ; Luben, Robert ; Wareham, Nicholas J. ; Loos, Ruth JF ; Heit, John A. ; Pankratz, V. Shane ; Norman, Aaron ; Goode, Ellen L ; Cunningham, Julie M ; De Andrade, Mariza ; Vierkant, Robert A. ; Czene, Kamila ; Fasching, Peter A. ; Baglietto, Laura ; Southey, Melissa C. ; Giles, Graham G. ; Shah, Kaanan P. ; Chan, Heang Ping ; Helvie, Mark A. ; Beck, Andrew H. ; Knoblauch, Nicholas W. ; Hazra, Aditi ; Hunter, David J. ; Kraft, Peter ; Pollan, Marina ; Figueroa, Jonine D. ; Couch, Fergus …

Background Mammographic density (MD) is a strong intermediate risk factor for breast cancer (BC) and, having both genetic and environmental determinants, may account for the over 6-fold international variations in BC incidence rates. The International Pooling Project of Mammographic Density is a worldwide collaborative project of MD targeting populations spanning the BC incidence range. The aims of the project are to (i) describe international variations in overall and age-specific distributions of MD, (ii) assess whether international variations in MD are explained by variations in the distributions of individual-level determinants of this marker and (iii) examine whether international variations in MD correlate with corresponding BC incidence rates. Methods Each contributing study provided comparable data on MD risk factors and mammographic images from a random sample of ˜ 400 general population women, who had undergone screening mammography. Images were transferred in digitised screen-film, full-field or computed radiography digital DICOM format (raw or processed). Images were randomly allocated into batches for MD reading using the Cumulus 6 thresholding software, by experienced readers who were blinded to study and individual-level factors. Data on MD determinants were pooled and linked with MD readings. Results are calibrated according to type of digital image (raw to processed), and adjusted for image type. Results 22 countries and approximately 12,000 women are included, spanning populations with age-standardised BC incidence rates (ASR) of 25.8 (India) to 99 (The Netherlands) per 100,000 woman-years. To date, for 9,635 participants data have been pooled (results will be updated). The MD risk factors vary greatly across populations, for example: mean age at menarche (in years) was 14.3 (95% CI 14.1–14.5) in Korean women and 12.6 (12.5–12.8) in Mexican women; mean parity was 3.8 (3.6–4.1) in Egyptian women and 1.3 (1.1–1.4) in those from Hong Kong; and mean BMI (in kg/m2) was 33.7 (33.1–34.3) in Egyptian women compared to 22.3 (21.6–22.9) in those from India. Differences in MD according to these distributions will be presented. Discussion The international perspective of this study generated large exposure heterogeneity enabling a wider investigation of MD determinants and the extent to which MD is an intermediate marker of BC risk, both within and between populations.