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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Summary 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.
Mammographic density has been found to be strongly associated with risk of breast cancer. We have assessed a novel method of assessing breast tissue that is fully automated, does not require an ...observer, and measures the volume, rather than the projected area, of the relevant tissues in digitized screen-film mammogram.
Sixteen mammography machines in seven locations in Toronto were calibrated to allow the estimation of the proportion of radiologically dense (stromal and epithelial tissue) and nondense (fatty) tissue represented in each pixel of the mammographic image. This information was combined with a measurement of breast thickness to calculate the volumes of these tissues. Women with newly diagnosed breast cancer (cases) identified on these mammography machines during the years 2000 to 2003 were compared with other women of the same age who did not have breast cancer (controls).
Three hundred sixty-four cases and 656 controls were recruited, epidemiologic data were collected, screen-film mammograms were digitized and measured using both a computer-assisted thresholding method, and the new measure of the volume of density. After adjustment for other risk factors, the odds ratio for those in the 5th quintile compared with the 1st quintile was 1.98 (95% confidence interval, 1.3-3.1) for the volume measure and 1.86 (95% CI, 1.1-3.0) for the area measurement. After inclusion of the volume and area measures in a predictive model, the volume measure lost significance, whereas the area measure remained significant.
Contrary to our expectations, measurement of the volume of breast tissue did not improve prediction of breast cancer risk.
Greater weight and body mass index (BMI) are negatively correlated with mammographic density, a strong risk factor for breast cancer, and are associated with an increased risk of breast cancer in ...postmenopausal women, but with a reduced risk in premenopausal women. We have examined the associations of body size and mammographic density on breast cancer risk.
We examined the associations of body size and the percentage of mammographic density at baseline with subsequent risk of breast cancer among 1,114 matched case-control pairs identified from three screening programs. The effect of each factor on risk of breast cancer was examined before and after adjustment for the other, using logistic regression.
In all subjects, before adjustment for mammographic density, breast cancer risk in the highest quintile of BMI, compared with the lowest, was 1.04 95% confidence interval (CI), 0.8-1.4. BMI was associated positively with breast cancer risk in postmenopausal women, and negatively in premenopausal women. After adjustment for density, the risk associated with BMI in all subjects increased to 1.60 (95% CI, 1.2-2.2), and was positive in both menopausal groups. Adjustment for BMI increased breast cancer risk in women with 75% or greater density, compared with 0%, increased from 4.25 (95% CI, 1.6-11.1) to 5.86 (95% CI, 2.2-15.6).
BMI and mammographic density are independent risk factors for breast cancer, and likely to operate through different pathways. The strong negative correlated between them will lead to underestimation of the effects on risk of either pathway if confounding is not controlled.
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.
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.
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.
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.
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.
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.
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.
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.
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