The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density.

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 (ß√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (ß√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (ß√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (ß√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.

Dietary Fiber, Insulin and Breast Tissue Composition at Age 15-18: A Cross-Sectional Study.

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.

Correlation between cumulative mammographic density and age-specific incidence of breast cancer: A biethnic study in Israel.

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.

The origins of breast cancer associated with mammographic density: a testable biological hypothesis.

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.

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk.

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.

The Association between Alcohol Consumption and Breast Density: A Systematic Review and Meta-analysis.

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 [ß = 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.

Associations of Serum Levels of Sex Hormones in Follicular and Luteal Phases of the Menstrual Cycle with Breast Tissue Characteristics in Young Women.

BACKGROUND: In 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. METHODS: In 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. RESULTS: SHBG 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. CONCLUSIONS: Our 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.

Serum lipids, lipoproteins, and risk of breast cancer: a nested case-control study using multiple time points.

BACKGROUND: There is strong evidence that breast cancer risk is influenced by environmental factors. Blood lipid and lipoprotein levels are also influenced by environmental factors and are associated with some breast cancer risk factors. We examined whether serial measures of serum lipids and lipoproteins were associated with breast cancer risk. METHODS: We carried out a nested case-control study within a randomized long-term dietary intervention trial with 4690 women with extensive mammographic density followed for an average of 10 years for breast cancer incidence. We measured lipids in an average of 4.2 blood samples for 279 invasive breast cancer case subjects and 558 matched control subjects. We calculated subaverages of lipids for each subject based on menopausal status and use of hormone replacement therapy (HRT) at blood collection and analyzed their association with breast cancer using generalized estimating equations. All statistical tests were two-sided. RESULTS: High-density lipoprotein-cholesterol (HDL-C) (P = .05) and apoA1 (P = .02) levels were positively associated with breast cancer risk (75(th) vs 25(th) percentile: HDL-C, 23% higher; apoA1, 28% higher) and non-HDL-C (P = .03) and apoB (P = .01) levels were negatively associated (75(th) vs 25(th) percentile: non-HDL-C, 19% lower; apoB, 22% lower). These associations were observed only when lipids were measured when HRT was not used. Total cholesterol and triglyceride levels were not statistically significantly associated with breast cancer risk. CONCLUSIONS: These results demonstrate that serum lipids are associated with breast cancer risk in women with extensive mammographic density. The possibility that interventions for heart disease prevention, which aim to reduce non-HDL-C or raise HDL-C, may have effects on breast cancer risk merits examination.

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk.

Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5 × 10(-8)) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease-susceptibility loci.

Mammographic features associated with interval breast cancers in screening programs.

INTRODUCTION: Percent mammographic density (PMD) is associated with an increased risk of interval breast cancer in screening programs, as are younger age, pre-menopausal status, lower body mass index and hormone therapy. These factors are also associated with variations in PMD. We have examined whether these variables influence the relative frequency of interval and screen-detected breast cancer, independently or through their associations with PMD. We also examined the association of tumor size with PMD and dense and non-dense areas in screen-detected and interval breast cancers. METHODS: We used data from three case-control studies nested in screened populations. Interval breast cancer was defined as invasive breast cancer detected within 12 months of a negative mammogram. We used a computer-assisted method of measuring the dense and total areas of breast tissue in the first (baseline) mammogram taken at entry to screening programs and calculated the non-dense area and PMD. We compared these mammographic features, and other risk factors at baseline, in women with screen-detected (n = 718) and interval breast cancer (n = 125). RESULTS: In multi-variable analysis, the baseline characteristics of younger age, greater dense area and smaller non-dense mammographic area were significantly associated with interval breast cancer compared to screen-detected breast cancer. Compared to screen-detected breast cancers, interval cancers had a larger maximum tumor diameter within each mammographic measure. CONCLUSIONS: Age and the dense and non-dense areas in the baseline mammogram were independently associated with interval breast cancers in screening programs. These results suggest that decreased detection of cancers caused by the area of dense tissue, and more rapid growth associated with a smaller non-dense area, may both contribute to risk of interval breast cancer. Tailoring screening to individual mammographic characteristics at baseline may reduce the number of interval cancers.

Evidence that breast tissue stiffness is associated with risk of breast cancer.

BACKGROUND: Evidence from animal models shows that tissue stiffness increases the invasion and progression of cancers, including mammary cancer. We here use measurements of the volume and the projected area of the compressed breast during mammography to derive estimates of breast tissue stiffness and examine the relationship of stiffness to risk of breast cancer. METHODS: Mammograms were used to measure the volume and projected areas of total and radiologically dense breast tissue in the unaffected breasts of 362 women with newly diagnosed breast cancer (cases) and 656 women of the same age who did not have breast cancer (controls). Measures of breast tissue volume and the projected area of the compressed breast during mammography were used to calculate the deformation of the breast during compression and, with the recorded compression force, to estimate the stiffness of breast tissue. Stiffness was compared in cases and controls, and associations with breast cancer risk examined after adjustment for other risk factors. RESULTS: After adjustment for percent mammographic density by area measurements, and other risk factors, our estimate of breast tissue stiffness was significantly associated with breast cancer (odds ratio = 1.21, 95% confidence interval = 1.03, 1.43, p = 0.02) and improved breast cancer risk prediction in models with percent mammographic density, by both area and volume measurements. CONCLUSION: An estimate of breast tissue stiffness was associated with breast cancer risk and improved risk prediction based on mammographic measures and other risk factors. Stiffness may provide an additional mechanism by which breast tissue composition is associated with risk of breast cancer and merits examination using more direct methods of measurement.

Mammographic density phenotypes and risk of breast cancer: a meta-analysis.

BACKGROUND: Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. METHODS: We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. RESULTS: Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. CONCLUSIONS: The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.

Lifetime physical activity in postmenopausal Caucasian and Chinese-Canadian women.

Physical activity is recognized as a modifiable lifestyle risk factor that may prevent breast cancer. The aim of this cross-sectional study was to compare the physical activity patterns in two populations with different risks for breast cancer. We collected physical activity information from two groups of postmenopausal Canadian women with substantially different risks of developing breast cancer - Caucasians (N=372) and recent Chinese migrants from urban China (N=352). The frequency, duration, and intensity of occupational, household, and recreational activities were measured throughout the lifetime using the interviewer-administered Lifetime Total Physical Activity Questionnaire. Compared with Caucasians, Chinese migrants reported lower average total physical activity over their lifetime and for each age period (0-21, 21-29, 30-39, 40-49, and ≥ 50 years). Compared with Caucasians, Chinese migrants reported greater lifetime occupational activity, but lower levels of lifetime activity for both household and recreation activity. Among Chinese migrants, reported levels of occupational, household, and recreational activities were all greater in migrants from Mainland China than in migrants from Hong Kong. In conclusion, our results show that total activity was greater amongst Caucasians than Chinese migrants, suggesting that the lower breast cancer risk in urban Chinese women is not likely to be explained by greater total physical activity.

Longitudinal changes in IGF-I and IGFBP-3, and mammographic density among postmenopausal women.

A relation between the breast cancer risk factors, insulin-like growth factor-I (IGF-I) and mammographic density, is biologically plausible, but results from cross-sectional epidemiologic studies have been mixed. Our objective was to examine the relation in a longitudinal manner, that is, between the change in circulating IGF-I concentrations and the change in mammographic measures over one year. Data from an exercise intervention trial conducted in 302 postmenopausal women ages 50 to 74 years were used. Blood drawn at baseline and postintervention was assessed for IGF-I and its binding protein (IGFBP-3) by direct chemiluminscent immunoassay. Area and volumetric measurements of mammographic dense fibroglandular and nondense fatty tissue were made. Statistical analyses were based on multiple linear regression. A one SD (20.2 ng/mL) change in IGF-I over one year was associated with small changes in percent dense area [mean: 0.8%; 95% confidence interval (CI), 0.1-1.4] and dense area (mean: 1.2 cm(2); 95% CI, 0.2-2.1). Change in IGFBP-3 was also associated with percent and absolute dense area. Absolute and percent dense volume, and mammographic measures representing fatty tissue (nondense area and volume) were not associated with changes in IGF-I and IGFBP-3. Longitudinal associations may be more detectable than cross-sectional associations due to the absence of confounding by invariant personal factors. Absolute and percent dense area, measures that are related to breast cancer risk, may be affected by IGF-I. Confirmation should be sought in further longitudinal studies in which larger changes in the IGF system are evoked.

Relationship of mammographic density and gene expression: analysis of normal breast tissue surrounding breast cancer.

PURPOSE: Previous studies of breast tissue gene expression have shown that the extratumoral microenvironment has substantial variability across individuals, some of which can be attributed to epidemiologic factors. To evaluate how mammographic density and breast tissue composition relate to extratumoral microenvironment gene expression, we used data on 121 patients with breast cancer from the population-based Polish Women's Breast Cancer Study. EXPERIMENTAL DESIGN: Breast cancer cases were classified on the basis of a previously reported, biologically defined extratumoral gene expression signature with two subtypes: an Active subtype, which is associated with high expression of genes related to fibrosis and wound response, and an Inactive subtype, which has high expression of cellular adhesion genes. Mammographic density of the contralateral breast was assessed using pretreatment mammograms and a quantitative, reliable computer-assisted thresholding method. Breast tissue composition was evaluated on the basis of digital image analysis of tissue sections. RESULTS: The Inactive extratumoral subtype was associated with significantly higher percentage mammographic density (PD) and dense area (DA) in univariate analysis (PD: P = 0.001; DA: P = 0.049) and in multivariable analyses adjusted for age and body mass index (PD: P = 0.004; DA: P = 0.049). Inactive/higher mammographic density tissue was characterized by a significantly higher percentage of stroma and a significantly lower percentage of adipose tissue, with no significant change in epithelial content. Analysis of published gene expression signatures suggested that Inactive/higher mammographic density tissue expressed increased estrogen response and decreased TGF-ß signaling. CONCLUSIONS: By linking novel molecular phenotypes with mammographic density, our results indicate that mammographic density reflects broad transcriptional changes, including changes in both epithelia- and stroma-derived signaling.

Mammographic density and breast cancer: a comparison of related and unrelated controls in the Breast Cancer Family Registry.

INTRODUCTION: Percent mammographic density (PMD) is a strong and highly heritable risk factor for breast cancer. Studies of the role of PMD in familial breast cancer may require controls, such as the sisters of cases, selected from the same 'risk set' as the cases. The use of sister controls would allow control for factors that have been shown to influence risk of breast cancer such as race/ethnicity, socioeconomic status and a family history of breast cancer, but may introduce 'overmatching' and attenuate case-control differences in PMD. METHODS: To examine the potential effects of using sister controls rather than unrelated controls in a case-control study, we examined PMD in triplets, each comprised of a case with invasive breast cancer, an unaffected full sister control, and an unaffected unrelated control. Both controls were matched to cases on age at mammogram. Total breast area and dense area in the mammogram were measured in the unaffected breast of cases and a randomly selected breast in controls, and the non-dense area and PMD calculated from these measurements. RESULTS: The mean difference in PMD between cases and controls, and the standard deviation (SD) of the difference, were slightly less for sister controls (4.2% (SD = 20.0)) than for unrelated controls (4.9% (SD = 25.7)). We found statistically significant correlations in PMD between cases (n = 228) and sister controls (n = 228) (r = 0.39 (95% CI: 0.28, 0.50; P <0.0001)), but not between cases and unrelated controls (n = 228) (r = 0.04 (95% CI: -0.09, 0.17; P = 0.51)). After adjusting for other risk factors, square root transformed PMD was associated with an increased risk of breast cancer when comparing cases to sister controls (adjusted odds ratio (inter-quintile odds ratio (IQOR) = 2.19, 95% CI = 1.20, 4.00) or to unrelated controls (adjusted IQOR = 2.62, 95% CI = 1.62, 4.25). CONCLUSIONS: The use of sister controls in case-control studies of PMD resulted in a modest attenuation of case-control differences and risk estimates, but showed a statistically significant association with risk and allowed control for race/ethnicity, socioeconomic status and family history.

Mammographic density and risk of breast cancer.

The radiographic appearance of the breast on mammography varies among women, and reflects variations in breast tissue composition and the different X-ray attenuation characteristics of these tissues. Fat is radiologically lucent and appears dark on a mammogram. Connective and epithelial tissues are radiologically dense and appear light. These variations in appearance are commonly described as the percentage of the breast image that is radiologically dense, or as percent mammographic density (PMD). There is now extensive evidence that PMD is a risk factor for breast cancer, with a 4- to 6-fold gradient in risk between women with 75% or more PMD compared with those with 10% or less. However, the accuracy of risk prediction in individual women is modest. The extent of PMD is associated inversely with greater age, parity, and weight, and is reduced by the menopause and by tamoxifen. PMD is positively associated with greater height, a family history of breast cancer, and is increased by combined hormone therapy. The relative risk associated with density is substantially larger than the relative risk of breast cancer associated with a family history of the disease or any of the menstrual and reproductive risk factors. It is estimated that the risks of breast cancer attributable to density of 50% or more may be 16% for all breast cancers. Although combined hormone therapy and tamoxifen respectively increase a decrease both PMD and breast cancer risk, there is as yet insufficient evidence to use PMD as a surrogate marker for breast cancer.