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.

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.

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.

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 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.

Identification of a novel percent mammographic density locus at 12q24.

Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta-analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 × 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 × 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition.

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.

Association between sex hormones, glucose homeostasis, adipokines, and inflammatory markers and mammographic density among postmenopausal women.

The biological mechanisms underlying the relationship between mammographic density and breast cancer risk are unknown. Our objective was to examine the association between mammographic density and circulating factors that are putative breast cancer intermediate endpoints. Biologic data from a year-long aerobic exercise intervention trial conducted in 302 postmenopausal women aged 50-74 years were analyzed. Sex hormones, markers of glucose homeostasis, inflammatory markers, and adipokines were assayed in fasting blood drawn at baseline and after 1 year. Area and volumetric measurements of mammographic dense fibroglandular and nondense fatty tissue were made. Multiple linear regression was used to examine the association between the circulating factors and mammographic measures and partial correlations were estimated. Mammographic nondense volume was positively correlated with concentrations of estradiol (r = 0.28), estrone (r = 0.13), insulin (r = 0.41), glucose (r = 0.15), leptin (r = 0.49), and C-reactive protein (r = 0.22), and negatively correlated with sex hormone binding globulin (r = -0.30) and adiponectin (r = -0.12) but correlations became null after adjustment for overall body adiposity as represented by body mass index and waist circumference. With adjustment for overall adiposity, mammographic dense volume, a measure that represents fibroglandular tissue, was negatively correlated with leptin (r = -0.19) and C-reactive protein (r = -0.19). As expected, circulating factors originating from or correlated with adipose tissue were also correlated with mammographic measures of breast adipose tissue, but not after adjustment for overall body adiposity. Interpreting correlations between adiposity-derived factors and mammographic measures whose validity may be affected by adiposity is problematic. To rectify this problem, future studies with very good measures of the volume of fibroglandular tissue in the breast will be necessary.

Mammographic density and breast cancer risk: current understanding and future prospects.

Variations in percent mammographic density (PMD) reflect variations in the amounts of collagen and number of epithelial and non-epithelial cells in the breast. Extensive PMD is associated with a markedly increased risk of invasive breast cancer. The PMD phenotype is important in the context of breast cancer prevention because extensive PMD is common in the population, is strongly associated with risk of the disease, and, unlike most breast cancer risk factors, can be changed. Work now in progress makes it likely that measurement of PMD will be improved in the near future and that understanding of the genetics and biological basis of the association of PMD with breast cancer risk will also improve. Future prospects for the application of PMD include mammographic screening, risk prediction in individuals, breast cancer prevention research, and clinical decision making.

A genome-wide linkage study of mammographic density, a risk factor for breast cancer.

INTRODUCTION: Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD). METHODS: Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel. RESULTS: Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study. CONCLUSIONS: The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer.

Associations of overall and abdominal adiposity with area and volumetric mammographic measures among postmenopausal women.

Whereas mammographic density and adiposity are positively associated with postmenopausal breast cancer risk, they are inversely associated with one another. To examine the association between these two risk factors, a secondary analysis of data from a randomized controlled trial of a year-long aerobic exercise intervention was done. Participants were 302 postmenopausal women aged 50-74 years. Dense fibroglandular and nondense fatty tissue were measured from mammograms using computer-assisted thresholding software for area measurements and a technique relying on the calibration of mammography machines with a tissue-equivalent phantom for volumetric measurements. Adiposity was measured by anthropometry (body mass index, waist circumference), whole-body dual x-ray absorptiometry scans (body fat) and computed tomography scans (abdominal adiposity). Correlations were estimated between and within women, the latter representing the association between the 1-year change in adiposity and mammographic measures. Adiposity was correlated with nondense area and volume (0.50 ≤ r ≤ 0.66 between women; 0.18 ≤ r ≤ 0.46 within women). Between women, adiposity was correlated with dense area and volume (-0.12 ≤ r ≤ -0.30) and with percent dense area and volume (-0.28 ≤ r ≤ -0.48). Because measurements made with scans explained at most only 3% more of the variation in absolute or percent density beyond that explained by anthropometric measurements, anthropometric measurements are likely sufficient for adjustment of the association between mammographic density and breast cancer risk. Adiposity is associated with breast fatty tissue and possibly weakly inversely associated with fibroglandular tissue.

Associations between mammographic density and serum and dietary cholesterol.

Although high mammographic density is a risk factor for postmenopausal breast cancer, its etiology remains unclear. We examined whether serum and dietary cholesterol, which increase breast cancer risk and are involved in endogenous estrogen formation, were associated with increased mammographic density. We conducted a cross-sectional analysis of 302 healthy, sedentary postmenopausal women, aged 50-74 years, enrolled in the Alberta Physical Activity and Breast Cancer Prevention Trial between 2003 and 2006. In multiple linear regression models, no significant associations were observed between serum lipids and percent density or dense tissue area (Percent density: b (change in square root percent density per unit change in cholesterol level) = -0.06 (95%CI = -0.26 to 0.13); b = 0.06 (95%CI = -0.48 to 0.61); and b = -0.11 (95%CI = -0.33 to 0.10) for total cholesterol, high-, and low-density lipoprotein, respectively; similar results found for dense area). Alcohol consumption modified the association between triglycerides and percent density (>1 drink/day: b = -0.94 (95%CI = -1.79 to -0.10); ≤ 1 drink/day: b = 0.19 (95%CI = -0.12 to 0.50); and no alcohol consumption: b = 0.15 (95%CI = -0.44 to 0.73). We found no evidence indicating any association between dietary and serum cholesterol levels and mammographic density.

Food, beverage, and macronutrient intakes in postmenopausal Caucasian and Chinese-Canadian women.

International differences in breast cancer rates and diet, and studies in migrants, suggest that diet may be a modifiable risk factor for breast cancer. The goal of this cross-sectional study was to examine the dietary intakes of women from populations considered to be at different risks for breast cancer. We collected four 24-h food recalls in 3 groups of postmenopausal Canadian women: Caucasians (n = 392), Chinese women born in the West or who migrated to the West before age 21 (n = 156), and recent Chinese migrants (n = 383). Compared to Caucasians, recent Chinese migrants had lower energy and fat intakes and higher protein and carbohydrate intakes. Recent Chinese migrants consumed higher amounts of grains, vegetables, fish, and soy and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western-born Chinese and early Chinese migrants had intakes intermediate between the other 2 groups. The differences in intake between the ethnic groups suggest foods and nutrients that may contribute to the differences in risk of breast cancer between women in Canada and China. Future work will examine whether these dietary differences are associated with biological markers of breast cancer risk.

Active smoking and secondhand smoke increase breast cancer risk: the report of the Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk (2009).

Four authoritative reviews of active smoking and breast cancer have been published since 2000, but only one considered data after 2002 and conclusions varied. Three reviews of secondhand smoke (SHS) and breast cancer (2004-2006) each came to different conclusions. With 30 new studies since 2002, further review was deemed desirable. An Expert Panel was convened by four Canadian agencies, the Ontario Tobacco Research Unit, the Public Health Agency of Canada, Physicians for a Smoke-Free Canada and the Canadian Partnership Against Cancer to comprehensively examine the weight of evidence from epidemiological and toxicological studies and understanding of biological mechanisms regarding the relationship between tobacco smoke and breast cancer. This article summarises the panel's full report (http://www.otru.org/pdf/special/expert_panel_tobacco_breast_cancer.pdf). There are 20 known or suspected mammary carcinogens in tobacco smoke, and recognised biological mechanisms that explain how exposure to these carcinogens could lead to breast cancer. Results from the nine cohort studies reporting exposure metrics more detailed than ever/never and ex/current smoker show that early age of smoking commencement, higher pack-years and longer duration of smoking increase breast cancer risk 15% to 40%. Three meta-analyses report 35% to 50% increases in breast cancer risk for long-term smokers with N-acetyltransferase 2 gene (NAT2) slow acetylation genotypes. The active smoking evidence bolsters support for three meta-analyses that each reported about a 65% increase in premenopausal breast cancer risk among never smokers exposed to SHS. The Panel concluded that: 1) the association between active smoking and breast cancer is consistent with causality and 2) the association between SHS and breast cancer among younger, primarily premenopausal women who have never smoked is consistent with causality.

Risk factors for breast cancer in postmenopausal Caucasian and Chinese-Canadian women.

INTRODUCTION: Striking differences exist between countries in the incidence of breast cancer. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The goal of this cross-sectional study was to examine breast cancer risk factors in populations with different risks for breast cancer. METHODS: We compared breast cancer risk factors among three groups of postmenopausal Canadian women at substantially different risk of developing breast cancer - Caucasians (N = 413), Chinese women born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants (N = 421). Information on risk factors and dietary acculturation were collected by telephone interviews using questionnaires, and anthropometric measurements were taken at a home visit. RESULTS: Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, less often had a family history of breast cancer or a benign breast biopsy, a higher Chinese dietary score, and a lower Western dietary score. For most of these variables, Western born Chinese and early Chinese migrants had values intermediate between those of Caucasians and recent Chinese migrants. We estimated five-year absolute risks for breast cancer using the Gail Model and found that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the risk factors in the Gail Model. CONCLUSIONS: Our results suggest that in addition to the risk factors in the Gail Model, there likely are other factors that also contribute to the large difference in breast cancer risk between Canada and China.

Mammographic density and the risk and detection of breast cancer.

BACKGROUND: Extensive mammographic density is associated with an increased risk of breast cancer and makes the detection of cancer by mammography difficult, but the influence of density on risk according to method of cancer detection is unknown. METHODS: We carried out three nested case-control studies in screened populations with 1112 matched case-control pairs. We examined the association of the measured percentage of density in the baseline mammogram with risk of breast cancer, according to method of cancer detection, time since the initiation of screening, and age. RESULTS: As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an increased risk of breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected by screening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram. CONCLUSIONS: Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.

Family-based association study of IGF1 microsatellites and height, weight, and body mass index.

Height, weight, and body mass index (BMI) are partly heritable, known to be associated with chronic diseases, and are linked to circulating insulin-like growth factor I (IGF-I) concentrations. IGF-I concentrations are also partly heritable and thus genetic variation at IGF1 could influence height, weight, BMI and the risk of developing chronic diseases. Our objective was to examine the association of genetic variation at IGF1 with height, weight and BMI using a sample of premenopausal women. A family-based study design was used to investigate the association of three IGF1 CA repeat variants at 5' (5'CA), intron 2 (In2CA) and 3' (3'CA) with these anthropometric measures. We analyzed the data for 827 families of different sizes and configurations, which included 1520 premenopausal women. Nominally significant associations (P

Breast-tissue composition and other risk factors for breast cancer in young women: a cross-sectional study.

BACKGROUND: Mammographic density is a heritable quantitative trait and is a strong risk factor for breast cancer in middle-aged and older women. However, little is known about the development of mammographic density in early life. We used MRI to measure the water content of the breast, which provides a measurement of the fibro-glandular content of breast tissue with similar accuracy to mammography, but without the attendant exposure to radiation. METHODS: Between December, 2003, and December, 2007, we recruited 400 young women, aged 15-30 years, and their mothers. We used MRI scans to measure daughters' breast water and fat, and on the same day obtained blood for hormone assays in the follicular phase of the menstrual cycle for each young woman. Mothers underwent mammography (n=356), and a random sample (n=100) also consented to have a breast MRI scan. FINDINGS: In mothers, per cent water-as measured by MRI-was strongly correlated with per cent mammographic density (r=0.85). Per cent water in daughters (median 44.8%) was significantly higher than in mothers (median 27.8%; p<0.0001), and was independently inversely associated with both their age (p=0.04) and weight (p<0.0001), and positively associated with their height (p<0.0001) and their mothers' per cent mammographic density (p<0.0001). Serum growth hormone concentrations, adjusted for covariates, were positively associated with per cent breast water (p=0.001) in a subgroup of young women (n=280) who had not used oral contraceptives within 6 months. INTERPRETATION: Per cent breast water was greatest during the ages when women are most susceptible to breast carcinogens, and was associated with weight, height, and mother's breast-tissue characteristics, and with serum concentrations of growth hormone: a breast mitogen that also mediates postnatal somatic growth. Mammographic density in middle age might partly be the result of genetic factors that affect growth and development in early life. FUNDING: Canadian Breast Cancer Research Alliance.

Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women.

BACKGROUND: Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density. METHODS: Percentage density, amounts of dense and non-dense (fat) tissue, IGF-I levels, and BMI were measured in 163 premenopausal women. Three CA repeat polymorphisms were genotyped, one each at the 5' and 3' ends of IGF1 and one in intron 2. RESULTS: The number of 19 alleles at the 5' polymorphism was associated with lower circulating levels of IGF-I (P = 0.02), whereas the number of 185 alleles at the 3' polymorphism was associated with higher percentage density (P = 0.03) and a smaller amount of non-dense tissue (P = 0.02). The strength of the effect of the 185 allele at 3' on percentage density was greatly reduced and statistical significance lost when BMI was included in regression models. CONCLUSIONS: Our results suggest an association between the number of 185 alleles at 3' with percentage density. This association appears to be mediated by body composition and particularly body fat, as indicated by the association of 3' IGF1 genotype with non-dense (fat) tissue and the mediating effect of BMI on the association of 3' genotype with percentage density.

Columnar cell lesions, mammographic density and breast cancer risk.

BACKGROUND: Mammographic density is the third largest risk factor for ductal carcinoma in-situ (DCIS) and invasive breast cancer. However, the question of whether risk-mediating precursor histological changes, such as columnar cell lesions (CCLs), can be found in dense but non-malignant breast tissues has not been systematically addressed. We hypothesized that CCLs may be related to breast composition, in particular breast density, in non-tumour containing breast tissue. PATIENTS AND METHODS: We examined randomly selected tissue samples obtained by bilateral subcutaneous mastectomy from a forensic autopsy series, where tissue composition was assessed, and in which there had been no selection of subjects or histological specimens for breast disease. We reviewed H&E slides for the presence of atypical and non-atypical CCLs and correlated with histological features measured using quantitative microscopy. RESULTS: CCLs were seen in 40 out of 236 cases (17%). The presence of CCLs was found to be associated with several measures of breast tissue composition, including radiographic density: high Faxitron Wolfe Density (P = 0.037), high density estimated by percentage non-adipose tissue area (P = 0.037), high percentage collagen (P = 9.2E-05) and high percentage glandular area (P = 2E-05). DCIS was identified in two atypical CCL cases. The extent of CCL was not associated with any of the examined variables. CONCLUSION: Our study is the first to report a possible association between CCLs and breast tissue composition, including mammographic density. Our data suggest that prospective elucidation of the strength and nature of the clinicopathological correlation may lead to an enhanced understanding of mammographic density and evidence based management strategies.