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.

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.

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.

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.

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 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.

Biomarkers of exposure to endogenous oxidative and aldehyde stress.

We observed an unexpectedly strong association of three different endogenous aldehydes and noted that the association could be explained by multiple reactions in which oxidative stress increased the formation of endogenous aldehydes and endogenous aldehydes increased oxidative stress. These interactions make it reasonable to assess multiple exposures to endogenous oxidative and aldehyde stress with less specific measures such as advanced glycation end-products or protein carbonyls.

Mammographic density, response to hormones, and breast cancer risk.

BACKGROUND: Percent mammographic density (PMD) is a strong risk factor for breast cancer that changes in response to changes in hormone exposure. We have examined the magnitude of the association of hormone exposure with PMD according to subsequent breast cancer risk. METHODS: In three case-control studies, with 1,164 patient cases and 1,155 controls nested in cohorts of women screened with mammography, we examined the association of PMD measured in the baseline mammogram with risk of breast cancer in the following 1 to 8 years (mean, 3 years), according to use of oral contraceptives (OCs) in premenopausal women, menopause, and hormone therapy (HT) in postmenopausal women. All statistical comparisons are adjusted for age and other risk factors. RESULTS: In premenopausal women who later developed breast cancer (patient cases), PMD was 5.3% greater in past users of OCs than in nonusers (P = .06). In controls, OC users had 2% less density than nonusers (P = .44; test for interaction P = .06). The difference in PMD between premenopausal and postmenopausal women for patient cases was 8.5% (P < .001) and for controls, 3.9% (P = .01; test for interaction P = .03). In postmenopausal women, PMD was 6% greater in patients who used HT than in never users (P < .001). Controls who used HT had 1.6% greater PMD (P = .26) than never users (test for interaction P = .001). Differences in PMD resulted mainly from differences in the dense area of the mammogram. CONCLUSION: Differences in PMD associated with differences in hormone exposure were greater in women who later developed breast cancer than in controls in each of the hormone exposures examined.

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.

A randomized trial of dietary intervention for breast cancer prevention.

Epidemiologic data and animal experiments suggest that dietary fat may influence risk of breast cancer. To determine whether intervention with a low-fat, high-carbohydrate diet would reduce breast cancer incidence in women at increased risk of the disease, we carried out a randomized controlled trial in Canada. We recruited 4,690 women with extensive mammographic density and randomized them to an intervention group or a comparison group. The intervention group received intensive dietary counseling to reduce fat intake to a target of 15% of calories and increase carbohydrate to 65% of calories. Dietary intakes were assessed throughout using food records. Subjects were followed for at least 7 years and for an average of 10 years. The main outcome was invasive breast cancer. Percentage of calories from fat in the intervention group decreased from 30% at baseline to 20% after randomization and remained 9% to 10% lower than the comparison group throughout. There were 118 invasive breast cancers in the intervention group and 102 in the comparison group [adjusted hazard ratio = 1.19 (95% CI: 0.91-1.55)]. Analysis of food records showed that fat intake at baseline and after randomization was not associated with total breast cancer incidence. Greater weight and lower carbohydrate intake at baseline and after randomization were associated with an increased risk of estrogen receptor (ER)-positive breast cancer. Our findings suggest that a sustained reduction in dietary fat intake did not reduce risk of breast cancer in women with extensive mammographic density. Weight and carbohydrate intakes were associated with risk of ER-positive breast cancer.

Breast tissue composition and susceptibility to breast cancer.

Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate x-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography.

Family history, mammographic density, and risk of breast cancer.

PURPOSE: Mammographic density is a strong and highly heritable risk factor for breast cancer. The purpose of this study was to examine the extent to which mammographic density explains the association of family history of breast cancer with risk of the disease. SUBJECTS AND METHODS: We carried out three nested case-control studies in screening programs that included in total 2,322 subjects (1,164 cases and 1,158 controls). We estimated the independent and combined associations of family history and percent mammographic density at baseline with subsequent breast cancer risk. RESULTS: After adjustment for age and other risk factors, compared with women with no affected first-degree relatives, percent mammographic density was 3.1% greater for women with one affected first-degree relative, and 7.0% greater for women with two or more affected relatives (P = 0.001 for linear trend across family history categories). The odds ratios for breast cancer risk were 1.37 [95% confidence interval (95% CI), 1.10-1.72] for having one affected relative, and 2.45 (95% CI, 1.30-4.62) for having two or more affected relatives (P for trend = 0.0002). Adjustment for percent mammographic density reduced these odds ratios by 16% and 14%, respectively. Percent mammographic density explained 14% (95% CI, 4-39%) of the association of family history (at least one affected first-degree relative) with breast cancer risk. CONCLUSIONS: Percent mammographic density has features of an intermediate marker for breast cancer, and some of the genes that explain variation in percent mammographic density might be associated with familial risk of breast cancer.

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.

Hormone therapy, mammographic density, and breast cancer risk.

Percent mammographic density (PMD) is a strong independent risk factor for breast cancer. The effects of age, parity and menopause on PMD are consistent with it being a marker of susceptibility to breast cancer. In this review, we describe the association of PMD with breast cancer, the biological plausibility of this association, and discuss the extent to which PMD meets the criteria for a surrogate marker for the effects of exogenous hormones on risk of breast cancer. Combined hormone therapy is associated with a small increase in both PMD and the risk of breast cancer. However there is evidence that the associations of blood estradiol levels and HRT with breast cancer risk are independent of the association of PMD with risk, suggesting that different biological pathways may be involved. Tamoxifen, an anti-estrogenic drug, reduces both the risk of breast cancer and PMD, but the potential mediation of the effects of anti-estrogens on breast cancer risk by their effects on PMD has not yet been examined. Given the evidence that estradiol and PMD are independently associated with breast cancer risk, it seems unlikely that an effect of these agents on PMD mediates their effects on risk. We thus find that the available evidence is insufficient to conclude that PMD can be used as a surrogate marker for the effect of exogenous hormones on breast cancer. Further research to examine the potential role of PMD as a mediator of the effects of other risk factors is required.