Reproductive and hormonal factors associated with mammographic breast density by age (United States)

Objectives: We determined the association of certain reproductive and hormonal factors with breast density over decades of life. Methods: Subjects were women age 20–79 years who had a screening mammogram between 1 June 1996 and 1 August 1997, in Seattle, Washington. Women with increased breast density (upper two categories of BI-RADS terminology) (n = 14,432) were compared to those with fatty breasts (lower two categories (n = 14,552). Unconditional logistic regression was used with adjustment for age at mammogram, parity, age at first birth, menopausal status, current use of hormone replacement therapy (HRT), and body mass index. Results: The association of nulliparity with density was evident for women at all ages (odds ratio (OR) and 95% confidence interval (CI) = 1.5 (1.3–1.7) and 1.6 (1.4–1.9) for women age 45 and >65, respectively). Older age at first birth was more strongly associated with density among women >55 than among younger women. The association of current use of HRT with density, but not of former use, increased with age when compared to never users (OR = 1.4 (1.2–1.7) and 2.2 (2.0–2.5) for women age 46–55 and >65, respectively). Conclusions: Results suggest that pregnancy at an early age has a permanent beneficial association with density, while HRT has a transitory adverse association.     

Childhood factors associated with mammographic density in adult women

Growth and development factors could contribute to the development of breast cancer associated with an increase in mammographic density. This study examines the influence of certain childhood-related, socio-demographic and anthropometric variables on mammographic density in adult woman. The study covered 3574 women aged 45-68 years, participating in breast cancer-screening programmes in seven Spanish cities. Based on a craniocaudal mammogram, blind, anonymous measurement of mammographic density was made by a single radiologist, using Boyd's semiquantitative scale. Data associated with the early stages of life were obtained from a direct survey. Ordinal logistic regression and generalised linear models were employed to estimate the association between mammographic density and the variables covered by the questionnaire. Screening programme was introduced as a random effects term. Age, number of children, body mass index (BMI) and other childhood-related variables were used as adjustment variables, and stratified by menopausal status. A total of 811 women (23%) presented mammographic density of over 50%, and 5% of densities exceeded 75%. Our results show a greater prevalence of high mammographic density in women with low prepubertal weight (OR: 1.18; 95% CI: 1.02-1.36); marked prepubertal height (OR: 1.25; 95% CI: 0.97-1.60) and advanced age of their mothers at their birth (>39 years: OR: 1.28; 95% CI: 1.03-1.60); and a lower prevalence of high mammographic density in women with higher prepubertal weight, low birth weight and earlier menarche. The influence of these early-life factors may be explained by greater exposure to hormones and growth factors during the development of the breast gland, when breast tissue would be particularly susceptible to proliferative and carcinogenic stimulus.     

The relationship between bone mineral density and mammographic density in Korean women: the Healthy Twin study

Mammographic density is one of the strong risk factors for breast cancer. A potential mechanism for this association is that cumulative exposure to mammographic density may reflect cumulative exposure to hormones that stimulate cell division in breast stroma and epithelium, which may have corresponding effects on breast cancer development. Bone mineral density (BMD), a marker of lifetime estrogen exposure, has been found to be associated with breast cancer. We examined the association between BMD and mammographic density in a Korean population. Study subjects were 730 Korean women selected from the Healthy Twin study. BMD (g/cm²) was measured with dual-energy X-ray absorptiometry. Mammographic density was measured from digital mammograms using a computer-assisted thresholding method. Linear mixed model considering familial correlations and a wide range of covariates was used for analyses. Quantitative genetic analysis was completed using SOLAR. In premenopausal women, positive associations existed between absolute dense area and BMD at ribs, pelvis, and legs, and between percent dense area and BMD at pelvis and legs. However, in postmenopausal women, there was no association between BMD at any site and mammographic density measures. An evaluation of additive genetic cross-trait correlation showed that absolute dense area had a weak-positive additive genetic cross-trait correlation with BMD at ribs and spines after full adjustment of covariates. This finding suggests that the association between mammographic density and breast cancer could, at least in part, be attributable to an estrogen-related hormonal mechanism.     

Genetic influences on mammographic density in Korean twin and family: the Healthy Twin study

Higher mammographic density is a strong risk factor for breast cancer. This study was conducted to determine the role of genetic factors on mammographic density measurements in Korean women. Study subjects were 730 women (122 monozygotic (MZ) twin pairs, 28 dizygotic (DZ) twin pairs, and 430 first degree relatives) from the Healthy Twin study. Mammographic density was measured using a computer-assisted method. Pairwise correlations of residual variance of each component of mammographic density were calculated within each pair of twins and family members. Quantitative genetic analysis was completed using SOLAR. Age and measured covariates accounted for 50% of the variation in dense area, 70% of non-dense area, and 67% of percent dense area. Fully adjusted heritability coefficients for dense area, non-dense area, and percent dense area were 0.76 (SE = 0.04), 0.69 (SE = 0.04) and 0.68 (SE = 0.04), respectively. Pairwise correlation coefficients of the adjusted residual variance of the mammographic density measures within MZ pairs and within DZ and sibling pairs combined were, respectively, 0.70 and 0.28 for dense area, 0.52 and 0.31 for non-dense area, and 0.58 and 0.24 for percent dense area. Covariance between dense and non-dense area had a significant genetic basis (correlation coefficient = −0.25, SE = 0.06). The same high heritability of mammographic density in Korean women as found in Western women supports a significant role of genetic determinants in breast cancer development. Genes that are responsible for familial correlation in mammographic density and have opposite effects on dense and non-dense mammographic areas need to be elucidated.     

Regular physical activity and mammographic density: a cohort study

Purpose

Physical activity is a modifiable lifestyle risk factor in prevention of breast cancer. Mammographic density (MD) is a strong risk factor for breast cancer. We investigate the association of regular physical activity with MD.

Methods

For 5,703 women who participated in the Danish Diet, Cancer and Health cohort (1993–1997) and attended mammographic screening in Copenhagen (1993–2001), MD was assessed at the first screening after cohort entry. MD was defined as a binary measure equivalent to Breast Imaging Report and Data System (BI-RADS) to either mixed/dense or fatty. Participation and duration in physical activities (hours/week) and confounders were assessed by questionnaire at cohort baseline. Logistic regression was used to estimate associations [odds ratios (OR), 95% confidence intervals (CI)] between physical activities and MD.

Results

56.3% of women had mixed/dense MD and 47.6% participated in sports. We found a significant positive association between participation in sports (OR 1.15; 95% CI 1.03–1.28) and do-it-yourself work (1.17; 1.05–1.31) and odds of having mixed/dense MD, which attenuated (1.08; 0.96–1.22 and 1.11; 0.98–1.25, respectively) in a fully adjusted model. No associations were found for time spent on physical activities or total metabolic equivalent of task scores with MD, in fully adjusted models. There was no effect modification of association between any physical activities and MD by obesity (BMI?≥?30 kg/m²) and menopause status.

Conclusions

Physical activity is not a determinant of MD.

     

Reproductive and menstrual factors and mammographic density in African American,Caribbean, and white women

Objective  

We investigated the associations between reproductive and menstrual risk factors for breast cancer and mammographic density, a strong risk factor for breast cancer, in a predominantly ethnic minority and immigrant sample.     

Early life factors and adult mammographic density

Purpose

Early life factors have shown to be related to breast cancer risk. The pathophysiological link could be mammographic density, a strong risk factor for breast cancer. Mammary gland development already starts in utero and early life factors might affect the number of mammary cells at risk. In this study, we investigated the association between early life factors and mammographic density in adulthood.

Methods

The study was conducted within 2,588, mainly postmenopausal women of the Prospect-European Prospective Investigation into Cancer and Nutrition cohort. This ongoing study recruited breast cancer screening participants who filled out extensive questionnaires. Information on the early life factors birth weight, gestational age, maternal and paternal age, multiple births, birth rank, exposure to parental smoking, and leg length as a proxy for growth at childhood was obtained using questionnaires. Generalized linear models and linear regression models were used to study the relation between early life factors and mammographic density. Analyses were adjusted for potential confounders.

Results

Women who had an older mother (p = 0.06) or father (p = 0.002) at birth tended to have a higher mammographic density. Furthermore, greater leg length seemed to be related to higher mammographic density, although not statistically significantly (p = 0.16). After adjustment for confounders, none of the early life factors showed any statistically significant relationship with mammographic density in adulthood.

Conclusion

Although we cannot exclude small effects that go undetected due to measurement error in recall of early life factors, the results suggest that mammographic density is not a major pathway in any observed relationship between these early life events and breast cancer risk.     

Aspirin use is associated with lower mammographic density in a large screening cohort

Background

Observational and biologic studies suggest that aspirin is a promising prevention therapy for breast cancer. However, clinical trials to date have not corroborated this evidence, potentially due to study design. We evaluated the effect of aspirin on mammographic density (MD), an established modifiable risk factor for breast cancer.

Methods

Electronic medical records from the University of Pennsylvania were evaluated for women who underwent screening mammography, saw their primary care provider, and had a confirmed list of medications during 2012–2013. Logistic regression was performed to test for associations between clinically recorded MD and aspirin use, after adjusting for age, body mass index (BMI), and ethnicity.

Results

We identified 26,000 eligible women. Mean age was 57.3, mean BMI was 28.9 kg/m², 41% were African American, and 19.7% reported current aspirin use. Aspirin users were significantly older and had higher BMI. There was an independent, inverse association between aspirin use and MD (P _trend < 0.001). Women with extremely dense breasts were less likely to be aspirin users than women with scattered fibroglandular density (OR 0.73; 95% CI 0.57–0.93). This association was stronger for younger women (P = 0.0002) and for African Americans (P = 0.011). The likelihood of having dense breasts decreased with aspirin dose (P _trend = 0.007), suggesting a dose response.

Conclusions

We demonstrate an independent association between aspirin use and lower MD in a large, diverse screening cohort. This association was stronger for younger and African American women: two groups at greater risk for ER? breast cancer. These results contribute to the importance of investigating aspirin for breast cancer prevention.

     

Alcohol, tobacco, and mammographic density: a population-based study

Mammographic density (MD), or the proportion of the breast with respect to its overall area that is composed of dense tissue, is a strong risk factor for breast cancer. Studies support a positive association of mammographic density and alcohol drinking. This was a cross-sectional multicenter study based on 3584 women, aged 45-68 years, recruited from seven screening centers within the Spanish breast cancer screening program network. The association between MD, alcohol consumption and tobacco use was evaluated by using ordinal logistic models with random center-specific intercepts. We found a weak positive association between current alcohol intake and higher MD, with current alcohol consumption increasing the odds of high MD by 13% (OR = 1.13; 95% CI 0.99-1.28) and high daily grams of alcohol being positively associated with increased MD (P for trend = 0.045). There were no statistically significant differences in MD between smokers and non-smokers. Nevertheless, increased number of daily cigarettes and increased number of accumulated lifetime cigarettes were negatively associated with high MD (P for trend 0.017 and 0.021). The effect of alcohol on MD was modified by menopausal status and tobacco smoking: whereas, alcohol consumption and daily grams of alcohol were positively associated with higher MD in postmenopausal women and in women who were not currently smoking, alcohol consumption had no effect on MD in premenopausal women and current smokers. Our results support an association between recent alcohol consumption and high MD, characterized by a modest increase in risk at low levels of current consumption and a decrease in risk among heavier drinkers. Our study also shows how the effects of alcohol in the breast can be modified by other factors, such as smoking.     

Reproductive factors associated with mastalgia.

Mastalgia has been classified as an aberration of the normal, rather than a disease. We present an age-matched, case-control study which compares the reproductive factors of patients with severe cyclical and noncyclical mastalgia with control groups of women who presented to a breast clinic but in whom no clinical abnormality was found and who did not later develop breast disease. There were few statistically significant differences in reproductive factors between the cases and controls, which lends some support to the concept that mastalgia can be considered to be an aberration of the normal.     

Associations of mammographic density with dietary factors in Japanese women.

BACKGROUND: A high percentage of mammographic dense area has been strongly associated with a risk of beast cancer. The present cross-sectional study evaluated the relations of percent density with dietary factors, such as fats, protein, dietary fiber, and soy isoflavones. METHODS: Study subjects were 601 (348 premenopausal and 253 postmenopausal) Japanese women who were recruited from a mammographic screening center. The size of the total breast area and the dense area were measured quantitatively using an automated mammographic mass detection method. Intakes of nutrients were estimated with a validated semiquantitative food-frequency questionnaire. RESULTS: The crude means of the percent density were 39.2% and 18.9% in premenopausal and postmenopausal women, respectively. There were no significant associations of any dietary factors with the percent density in premenopausal women. In postmenopausal women, percent density was significantly positively associated with intakes of protein, total fat, and saturated fat after controlling for covariates; the increase in the means of percent density were 7.2%, 5.6%, and 9.2% in the highest versus lowest quartile of intakes for protein, total fat, and saturated fat, respectively (P for linear trend were 0.006, 0.04, and 0.01, respectively). Carbohydrate intake was inversely associated with percent density; the mean of percent density was 6.0% lower in the highest versus the lowest quartile of intake (P(trend) = 0.03). The associations of dietary factors with dense area were very similar to those with percent density. CONCLUSION: These dietary factors may have implications for the risk of breast cancer in postmenopausal women.     

Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women

Introduction  

Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates.     

Serum prolactin levels are positively associated with mammographic density in postmenopausal women

Background Prolactin is a polypeptide hormone that promotes normal breast proliferation and differentiation, but it is also implicated in the development and growth of mammary tumors. Mammographic density is a strong, independent predictor of breast cancer and, therefore, a potential surrogate indicator of breast cancer risk. Methods To test the hypothesis that serum prolactin is positively related to mammographic density, we conducted a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Mammographic Density Study. Based on prior work, we further hypothesized that this association would be apparent only in women who had not recently used postmenopausal hormone therapy (HT). Results In linear regression models adjusted for age, body mass index, race, smoking, alcohol use, parity and physical activity, among the 400 women who were not recent users of HT, prolactin was positively and statistically significantly associated with mammographic density (Beta log base 2 prolactin 0.0369 [95% CI: 0.0094–0.0645]. Thus, for each doubling of serum prolactin, there was an absolute increase in mammographic density of 3.69%. Additional adjustment for serum levels of estradiol, progesterone, sex hormone binding globulin and age at first pregnancy did not affect this result. There was no association between prolactin and mammographic density among the 169 participants who had recently used HT. Conclusion The correspondence between higher prolactin and higher mammographic density is consistent with prolactin’s mitogenic properties and the associations between prolactin and breast tumor promotion. These results support the thesis that prolactin deserves investigation as a target for breast cancer risk reduction.     

Growth factors and stromal matrix proteins associated with mammographic densities.

Extensive radiologically dense breast tissue is associated with a marked increase in breast cancer risk. To explore the biological basis for this association, we have examined the association of growth factors and stromal matrix proteins in breast tissue with mammographic densities. Ninety-two formalin-fixed paraffin blocks of breast tissues surrounding benign lesions were obtained, half from breasts with little or no density and half from breasts with extensive density, matched for age at biopsy. Sections were stained for cell nuclei, total collagen, the stromal matrix regulatory protein tissue metalloproteinase-3 (TIMP-3), and the growth factors, transforming growth factor-alpha and insulin-like growth factor (IGF-I). The area of immunoreactive staining was measured using quantitative microscopy. Breast tissue from subjects with extensive densities had a greater nuclear area (P = 0.007), as well as larger stained areas of total collagen (P = 0.003), TIMP-3 (P = 0.08), and IGF-I (P = 0.02) when compared with subjects with little breast density. Differences were greater for subjects less than 50 years of age. These data indicate that increased tissue cellularity, greater amounts of collagen, and increased IGF-I and TIMP-3 expression are found in tissue from mammographically dense breasts and suggest mechanisms that may mediate the associated increased risk of breast cancer.     

Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence

There is now extensive evidence that mammographic density is an independent risk factor for breast cancer that is associated with large relative and attributable risks for the disease. The epidemiology of mammographic density, including the influences of age, parity and menopause, is consistent with it being a marker of susceptibility to breast cancer, in a manner similar to the concept of 'breast tissue age' described by the Pike model. Mammographic density reflects variations in the tissue composition of the breast. It is associated positively with collagen and epithelial and nonepithelial cells, and negatively with fat. Mammographic density is influenced by some hormones and growth factors as well as by several hormonal interventions. It is also associated with urinary levels of a mutagen. Twin studies have shown that most of the variation in mammographic density is accounted for by genetic factors. The hypothesis that we have developed from these observations postulates that the combined effects of cell proliferation (mitogenesis) and genetic damage to proliferating cells by mutagens (mutagenesis) may underlie the increased risk for breast cancer associated with extensive mammographic density. There is clearly a need for improved understanding of the specific factors that are involved in these processes and of the role played by the several breast tissue components that contribute to density. In particular, identification of the genes that are responsible for most of the variance in percentage density (and of their biological functions) is likely to provide insights into the biology of the breast, and may identify potential targets for preventative strategies in breast cancer.     

Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study

Introduction  

Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk.     

Active,but not passive cigarette smoking was inversely associated with mammographic density

Purpose  

The opposing carcinogenic and antiestrogenic properties of tobacco smoke may explain why epidemiologic studies have not consistently reported positive associations for active smoking and breast cancer risk. A negative relation between mammographic density, a strong breast cancer risk factor, and active smoking would lend support for an antiestrogenic mechanism.     

Association of mammographic density with hormone receptors in invasive breast cancers: Results from a case-only study

For many breast cancer (BC) risk factors, there is growing evidence concerning molecular subtypes for which the risk factor is specific. With regard to mammographic density (MD), there are inconsistent data concerning its association with estrogen receptor (ER) and progesterone receptor (PR) expression. The aim of our study was to analyze the association between ER and PR expression and MD. In our case-only study, data on BC risk factors, hormone receptor expression and MD were available for 2,410 patients with incident BC. MD was assessed as percent MD (PMD) using a semiautomated method by two readers for every patient. The association of ER/PR and PMD was studied with multifactorial analyses of covariance with PMD as the target variable and including well-known factors that are also associated with MD, such as age, parity, use of hormone replacement therapy, and body mass index (BMI). In addition to the commonly known associations between PMD and age, parity, BMI and hormone replacement therapy, a significant inverse association was found between PMD and ER expression levels. Patients with ER-negative tumors had an average PMD of 38%, whereas patients with high ER expression had a PMD of 35%. A statistical trend toward a positive association between PMD and PR expression was also seen. PMD appears to be inversely associated with ER expression and may correlate positively with PR expression. These effects were independent of other risk factors such as age, BMI, parity, and hormone replacement therapy, possibly suggesting other pathways that mediate this effect.     

Hormone replacement therapy,mammographic density,and breast cancer risk: a cohort study

Purpose

Hormone replacement therapy (HRT) use increases breast cancer risk and mammographic density (MD). We examine whether MD mediates or modifies the association of HRT with the breast cancer.

Methods

For the 4,501 participants in the Danish diet, cancer and health cohort (1993–1997) who attended mammographic screening in Copenhagen (1993–2001), MD (mixed/dense or fatty) was assessed at the first screening after cohort entry. HRT use was assessed by questionnaire and breast cancer diagnoses until 2012 obtained from the Danish cancer registry. The associations of HRT with MD and with breast cancer were analyzed separately using Cox’s regression. Mediation analyses were used to estimate proportion [with 95% confidence intervals (CI)] of an association between HRT and breast cancer mediated by MD.

Results

2,444 (54.3%) women had mixed/dense breasts, 229 (5.4%) developed breast cancer, and 35.9% were current HRT users at enrollment. Compared to never users, current HRT use was statistically significantly associated with having mixed/dense breasts (relative risk and 95% CI 1.24; 1.14–1.35), and higher risk of breast cancer (hazard ratio 1.87; 1.40–2.48). Association between current HRT use and breast cancer risk was partially mediated by MD (percent mediated?=?10%; 95% CI 4–22%). The current HRT use-related breast cancer risk was higher in women with mixed/dense (1.94; 1.37–3.87) than fatty (1.37; 0.80–2.35) breasts (p value for interaction?=?0.15).

Conclusions

MD partially mediates some of the association between HRT and breast cancer risk. The association between HRT and breast cancer seems to be stronger in women with dense breasts.