Breast cancer risk factors and mammographic breast density in women over age 70

SummaryBackground Breast density is a strong risk factor for breast cancer, but little is known about factors associated with breast density in women over 70.Methods Percent breast density, sex hormone levels and breast cancer risk factor data were obtained on 239 women ages 70–92 recruited from 1986 to 1988 in the United States. Multivariable linear regression was used to develop a model to describe factors associated with percent density.Results Median (range) percent density among women was 23.7% (0–85%). Body mass index (β= −0.345, p<0.001 adjusted for age and parity) and parity (β= −0.277, p<0.001 adjusted for age and BMI) were significantly and inversely associated with percent breast density. After adjusting for parity and BMI, age was not associated with breast density (β=0.05, p=0.45). Parous women had lower percent density than nulliparous women (23.7 versus 34.7%, p=0.005). Women who had undergone surgical menopause had greater breast density than those who had had a natural menopause (33.4 versus 24.8%, p=0.048), as did women who were not current smokers (26.0 versus 17.3% for smokers, p=0.02). Breast density was not associated with age at menarche, age at menopause, age at first birth, breastfeeding, estrogen levels or androgen levels. In a multivariable model, 24% of the variance in percent breast density was explained by BMI (β= −0.35), parity (β=−0.29), surgical menopause (β=0.13) and current smoking (β= −0.12).Conclusion Factors associated with breast density in older, post-menopausal women differ from traditional breast cancer risk factors and from factors associated with breast density in pre-menopausal and younger post-menopausal women.     

Effects of mammographic density and benign breast disease on breast cancer risk (United States)

Background: Having either a history of benign breast disease, particularly atypical hyperplasia or extensive mammographic breast density, is associated with increased breast cancer risk. Previous studies have described an association between benign breast disease histology and breast density. However, whether these features measure the same risk, or are independent risk factors, has not been addressed. Methods: This case–control study, nested within the prospective follow-up of the Breast Cancer Detection Demonstration Project, evaluated both benign histologic and mammographic density information from 347 women who later developed breast cancer and 410 age- and race-matched controls without breast cancer. Multivariate logistic regression analyses provided maximum-likelihood estimates of the odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relative risk of breast cancer associated with each exposure. Results: Adjusting for mammographic density, the OR for atypical hyperplasia was 2.1 (95% CI: 1.3–3.6), and adjusting for benign breast histology, the OR for 75% density was 3.8 (95% CI: 2.0–7.2). Women with nonproliferative benign breast disease and 75% density had an OR of 5.8 (95% CI: 1.8–18.6), and women with <50% density and atypical hyperplasia had an OR of 4.1 (95% CI: 2.1–8.0). Conclusions: In this study, both benign breast disease histology and the percentage of the breast area with mammographic density were associated with breast cancer risk. However, women with both proliferative benign breast disease and 75% density were not at as high a risk of breast cancer due to the combination of effects (p = 0.002) as women with only one of these factors.     

Change of mammographic density predicts the risk of contralateral breast cancer - a case-control study

Introduction

Mammographic density is a strong risk factor for breast cancer, but it is unknown whether density at first breast cancer diagnosis and changes during follow-up influences risk of non-simultaneous contralateral breast cancer (CBC).

Methods

We collected mammograms for CBC-patients (cases, N = 211) and unilateral breast cancer patients (controls, N = 211), individually matched on age and calendar period of first breast cancer diagnosis, type of adjuvant therapy and length of follow-up (mean follow-up time: 8.25 years). The odds of CBC as a function of changes of density during follow-up were investigated using conditional logistic regression, adjusting for non-dense area at diagnosis.

Results

Patients who experienced ≥10% absolute decrease in percent density had a 55% decreased odds of CBC (OR = 0.45 95% CI: 0.24 to 0.84) relative to patients who had little or no change in density from baseline to first follow-up mammogram (mean = 1.6 (SD = 0.6) years after diagnosis), whereas among those who experienced an absolute increase in percent density we could not detect any effect on the odds of CBC (OR = 0.83 95% CI: 0.24 to 2.87).

Conclusion

Decrease of mammographic density within the first two years after first diagnosis is associated with a significantly reduced risk of CBC, this potential new risk predictor can thus contribute to decision-making in follow-up strategies and treatment.     

Comparison of fully and semi-automated area-based methods for measuring mammographic density and predicting breast cancer risk

Background:

Mammographic density is a strong risk factor for breast cancer but the lack of valid fully automated methods for quantifying it has precluded its use in clinical and screening settings. We compared the performance of a recently developed automated approach, based on the public domain ImageJ programme, to the well-established semi-automated Cumulus method.

Methods:

We undertook a case-control study within the intervention arm of the Age Trial, in which ∼54 000 British women were offered annual mammography at ages 40–49 years. A total of 299 breast cancer cases diagnosed during follow-up and 422 matched (on screening centre, date of birth and dates of screenings) controls were included. Medio-lateral oblique (MLO) images taken closest to age 41 and at least one year before the index case''s diagnosis were digitised for each participant. Cumulus readings were performed in the left MLO and ImageJ-based readings in both left and right MLOs. Conditional logistic regression was used to examine density–breast cancer associations.

Results:

The association between density readings taken from one single MLO and breast cancer risk was weaker for the ImageJ-based method than for Cumulus (age–body mass index-adjusted odds ratio (OR) per one s.d. increase in percent density (95% CI): 1.52 (1.24–1.86) and 1.61 (1.33–1.94), respectively). The ImageJ-based density–cancer association strengthened when the mean of left–right MLO readings was used: OR=1.61 (1.31–1.98).

Conclusions:

The mean of left–right MLO readings yielded by the ImageJ-based method was as strong a predictor of risk as Cumulus readings from a single MLO image. The ImageJ-based method, using the mean of two measurements, is a valid automated alternative to Cumulus for measuring density in analogue films.     

Background risk of breast cancer influences the association between alcohol consumption and mammographic density

Background:

Alcohol consumption has been suggested to increase risk of breast cancer through a mechanism that also increases mammographic density. Whether the association between alcohol consumption and mammographic density is modified by background breast cancer risk has, however, not been studied.

Methods:

We conducted a population-based cross-sectional study of 53 060 Swedish women aged 40–74 years. Alcohol consumption was assessed using a web-based self-administered questionnaire. Mammographic density was measured using the fully-automated volumetric Volpara method. The Tyrer–Cuzick prediction model was used to estimate risk of developing breast cancer in the next 10 years. Linear regression models were used to evaluate the association between alcohol consumption and volumetric mammographic density and the potential influence of Tyrer–Cuzick breast cancer risk.

Results:

Overall, increasing alcohol consumption was associated with higher absolute dense volume (cm³) and per cent dense volume (%). The association between alcohol consumption and absolute dense volume was most pronounced among women with the highest (⩾5%) Tyrer–Cuzick 10-year risk. Among high-risk women, women consuming 5.0–9.9, 10.0–19.9, 20.0–29.9, and 30.0–40.0 g of alcohol per day had 2.6 cm³ (95% confidence interval (CI), 0.2–4.9), 2.9 cm³ (95% CI, −0.6 to 6.3), 4.6 cm³ (95% CI, 1.5–7.7), and 10.8 cm³ (95% CI, 4.8–17.0) higher absolute dense volume, respectively, as compared with women abstaining from alcohol. A trend of increasing alcohol consumption and higher absolute dense volume was seen in women at low (⩽3%) risk, but not in women at moderate (3.0–4.9%) risk.

Conclusion:

Alcohol consumption may increase breast cancer risk through increasing mammographic density, particularly in women at high background risk of breast cancer.     

A case‐control study to assess the impact of mammographic density on breast cancer risk in women aged 40–49 at intermediate familial risk

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40–49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case‐control study nested with the FH01 cohort study of 6,710 women mostly aged 40–49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age‐matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm² = 1.07, 95% CI 1.00–1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer‐Cuzick 10‐year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high‐risk groups alongside the Tyrer‐Cuzick 10‐year relative risk estimate.     

Association of mammographically defined percent breast density with epidemiologic risk factors for breast cancer (United States)

Objective: Mammographically defined percent breast density is an important risk factor for breast cancer, but the epidemiology of this trait is poorly understood. Although several studies have investigated the associations between reproductive factors and density, few data are available on the associations of breast density and waist-to-hip ratio (WHR), physical activity, education, alcohol and smoking. Methods: We investigated the associations of known and suspected breast cancer risk factors with breast density in a large breast cancer family study. Information was collected on members of 426 families through telephone interviews, mailed questionnaires and mammography. Mammographic films on 1900 women were digitized and breast density was estimated in discrete five-unit increments by one radiologist. Analysis of covariance techniques were used and all analyses were performed stratified by menopausal status. Results: Similar to other reports, nulliparity, late age at first birth, younger age and lower body mass index were associated with increased percent density in both premenopausal and postmenopausal women, and hormone replacement therapy among postmenopausal women. Higher levels of alcohol consumption and low WHR were associated with increased percent density among both premenopausal and postmenopausal women (differences of 3–11% between high and low categories). However, smoking and education were inversely associated with percent density among premenopausal (p = 0.004 and p = 0.003, respectively) but not postmenopausal women (p = 0.52 and p = 0.90). Physical activity was not associated with percent density in either stratum (p values > 0.25). Combined, these factors explained approximately 37% of the variability in the percent density measure in premenopausal women and 19% in postmenopausal women. Conclusions: Many of these factors may potentially affect breast cancer risk through their effect on percent breast density.     

Mammographic density, lobular involution, and risk of breast cancer

In this review, we propose that age-related changes in mammographic density and breast tissue involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer. We propose that the reduction in mammographic density that occurs with increasing age, parity and menopause reflects the involution of breast tissue. We further propose that age-related changes in both mammographic density and breast tissue composition are observable and measurable phenomena that resemble Pike's theoretical construct of 'breast tissue ageing'. Extensive mammographic density and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypothesis of the Pike model that cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence.     

Relationship between breast cancer risk factors and mammographic breast density in the Fernald Community Cohort

Background:

We investigated associations of known breast cancer risk factors with breast density, a well-established and very strong predictor of breast cancer risk.

Methods:

This nested case–control study included breast cancer-free women, 265 with high and 860 with low breast density. Women were required to be 40–80 years old and should have a body mass index (BMI) <35 at the time of the index mammogram. Information on covariates was obtained from annual questionnaires.

Results:

In the overall analysis, breast density was inversely associated with BMI at mammogram (P for trend<0.001), and parity (P for trend=0.02) and positively associated with alcohol consumption (ever vs never: odds ratio 2.0, 95% confidence interval 1.4–2.8). Alcohol consumption was positively associated with density, and the association was stronger in women with a family history of breast cancer (P<0.001) and in women with hormone replacement therapy (HRT) history (P<0.001). Parity was inversely associated with density in all subsets, except premenopausal women and women without a family history. The association of parity with density was stronger in women with HRT history (P<0.001).

Conclusion:

The associations of alcohol and parity with breast density appear to be in reverse direction, but stronger in women with a family history of breast cancer and women who ever used HRT.     

Change in mammographic density across birth cohorts of Dutch breast cancer screening participants

High mammographic density is a well-known risk factor for breast cancer. This study aimed to search for a possible birth cohort effect on mammographic density, which might contribute to explain the increasing breast cancer incidence. We separately analyzed left and right breast density of Dutch women from a 13-year period (2003–2016) in the breast cancer screening programme. First, we analyzed age-specific changes in average percent dense volume (PDV) across birth cohorts. A linear regression analysis (PDV vs. year of birth) indicated a small but statistically significant increase in women of: 1) age 50 and born from 1952 to 1966 (left, slope = 0.04, p = 0.003; right, slope = 0.09, p < 0.0001); 2) age 55 and born from 1948 to 1961 (right, slope = 0.04, p = 0.01); and 3) age 70 and born from 1933 to 1946 (right, slope = 0.05, p = 0.002). A decrease of total breast volume seemed to explain the increase in PDV. Second, we compared proportion of women with dense breast in women born in 1946–1953 and 1959–1966, and observed a statistical significant increase of proportion of highly dense breast in later born women, in the 51 to 55 age-groups for the left breast (around a 20% increase in each age-group), and in the 50 to 56 age-groups for the right breast (increase ranging from 27% to 48%). The study indicated a slight increase in mammography density across birth cohorts, most pronounced for women in their early 50s, and more marked for the right than for the left breast.     

Mammographic density,plasma vitamin D levels and risk of breast cancer in postmenopausal women

Mammographic density is a strong risk factor for breast cancer, but the underlying biology for this association is unknown. Studies suggest that vitamin D may reduce breast cancer risk and dietary vitamin D intake has been associated with reduced breast density. We conducted a case–control study nested within the Nurses' Health Study cohort consisting of 463 and 497 postmenopausal cases and controls, respectively. We examined the association between mammographic density and plasma levels of 25‐hydroxyvitamin D [25(OH)D] and 1,25‐dihydroxyvitamin D [1,25(OH)₂D]. We assessed whether plasma vitamin D metabolites modify the association between breast density and breast cancer. Percent mammographic density was measured from digitized film mammograms. Generalized linear models were used to determine mean percent breast density per quartile of vitamin D metabolite. Logistic regression models were used to calculate relative risks and confidence intervals. All models were adjusted for matching variables and potential confounders. We found no cross‐sectional association between circulating levels of 25(OH)D or 1,25(OH)₂D with mammographic density. Women in the highest tertile of mammographic density and lowest tertile of plasma 25(OH)D had 4 times greater risk of breast cancer than women with the lowest mammographic density and highest plasma 25(OH)D levels (RR = 3.8; 95% CI: 2.0–7.3). The overall interaction between mammographic density and plasma 25(OH)D was nonsignificant (p‐het = 0.20). These results indicate that the association between mammographic density and breast cancer is independent of plasma vitamin D metabolites in postmenopausal women. Further research examining vitamin D, mammographic density and breast cancer risk is warranted.     

Circulating serum xenoestrogens and mammographic breast density

Introduction

Humans are widely exposed to estrogenically active phthalates, parabens, and phenols, raising concerns about potential effects on breast tissue and breast cancer risk. We sought to determine the association of circulating serum levels of these chemicals (reflecting recent exposure) with mammographic breast density (a marker of breast cancer risk).

Methods

We recruited postmenopausal women aged 55 to 70 years from mammography clinics in Madison, Wisconsin (N = 264). Subjects completed a questionnaire and provided a blood sample that was analyzed for mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, butyl paraben, propyl paraben, octylphenol, nonylphenol, and bisphenol A (BPA). Percentage breast density was measured from mammograms by using a computer-assisted thresholding method.

Results

Serum BPA was positively associated with mammographic breast density after adjusting for age, body mass index, and other potentially confounding factors. Mean percentage density was 12.6% (95% confidence interval (CI), 11.4 to 14.0) among the 193 women with nondetectable BPA levels, 13.7% (95% CI, 10.7 to 17.1) among the 35 women with detectable levels below the median (<0.55 ng/ml), and 17.6% (95% CI, 14.1 to 21.5) among the 34 women with detectable levels above the median (>0.55 ng/ml; P_trend = 0.01). Percentage breast density was also elevated (18.2%; 95% CI, 13.4 to 23.7) among the 18 women with serum mono-ethyl phthalate above the median detected level (>3.77 ng/ml) compared with women with nondetectable BPA levels (13.1%; 95% CI, 11.9 to 14.3; P_trend = 0.07). No other chemicals demonstrated associations with percentage breast density.

Conclusions

Postmenopausal women with high serum levels of BPA and mono-ethyl phthalate had elevated breast density. Further investigation of the impact of BPA and mono-ethyl phthalate on breast cancer risk by using repeated serum measurements or other markers of xenoestrogen exposure are needed.     

An investigation of mammographic density and gene variants in healthy women

This cross-sectional study examined if polymorphisms in genes that code for enzymes involved in the production and metabolism of estrogens are associated with mammographic density, a strong predictor of breast cancer risk. The study included 328 healthy women of different ethnicities who underwent mammographic screening and donated a blood or mouthwash sample for DNA analysis. After digitizing cranio-caudal views of the mammograms, we performed computer-assisted mammographic density assessment. Following DNA extraction, samples were analyzed for polymorphisms in the COMT (Val158Met), CYP1A1 (Ile462Val), CYP1B1 (Val432Leu), CYP1A2 (*1F) and CYP17 (T27C) genes using PCR-RFLP. Breast density was lower in Caucasians than in Asians. Caucasian women were less likely to carry the CYP1A1 variant allele and more likely to carry the variant alleles for CYP1B1 and COMT than women with Asian or Hawaiian ancestry. The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively). These relations were observed in premenopausal women only and were similar in direction and magnitude after stratification by ethnicity. We found no significant associations between breast density and the variant alleles for CYP1A1, CYP1B1 and CYP17. Our data suggest lower mammographic density for women carrying the COMT and CYP1A2 variant alleles than for women carrying the common alleles, though this is the opposite of what is commonly hypothesized from the enzyme function.     

Breast cancer risk factors and a novel measure of volumetric breast density: cross-sectional study

We conducted a cross-sectional study nested within a prospective cohort of breast cancer risk factors and two novel measures of breast density volume among 590 women who had attended Glasgow University (1948-1968), replied to a postal questionnaire (2001) and attended breast screening in Scotland (1989-2002). Volumetric breast density was estimated using a fully automated computer programme applied to digitised film-screen mammograms, from medio-lateral oblique mammograms at the first-screening visit. This measured the proportion of the breast volume composed of dense (non-fatty) tissue (Standard Mammogram Form (SMF)%) and the absolute volume of this tissue (SMF volume, cm3). Median age at first screening was 54.1 years (range: 40.0-71.5), median SMF volume 70.25 cm3 (interquartile range: 51.0-103.0) and mean SMF% 26.3%, s.d.=8.0% (range: 12.7-58.8%). Age-adjusted logistic regression models showed a positive relationship between age at last menstrual period and SMF%, odds ratio (OR) per year later: 1.05 (95% confidence interval: 1.01-1.08, P=0.004). Number of pregnancies was inversely related to SMF volume, OR per extra pregnancy: 0.78 (0.70-0.86, P<0.001). There was a suggestion of a quadratic relationship between birthweight and SMF%, with lowest risks in women born under 2.5 and over 4 kg. Body mass index (BMI) at university (median age 19) and in 2001 (median age 62) were positively related to SMF volume, OR per extra kg m(-2) 1.21 (1.15-1.28) and 1.17 (1.09-1.26), respectively, and inversely related to SMF%, OR per extra kg m(-2) 0.83 (0.79-0.88) and 0.82 (0.76-0.88), respectively, P<0.001. Standard Mammogram Form% and absolute SMF volume are related to several, but not all, breast cancer risk factors. In particular, the positive relationship between BMI and SMF volume suggests that volume of dense breast tissue will be a useful marker in breast cancer studies.     

Breast density and risk of breast cancer

Early studies reported a 4- to 6-fold risk of breast cancer between women with extremely dense and fatty breasts. As most early studies were case-control studies, we took advantage of a population-based screening program to study density and breast cancer incidence in a cohort design. In the Capital Region, Denmark, women aged 50 to 69 are invited to screening biennially. Women screened November 2012 to December 2017 were included, and classified by BI-RADS density code, version 4, at first screen after recruitment. Women were followed up for incident breast cancer, including ductal carcinoma in situ (DCIS), to 2020 in nationwide pathology data. Rate ratios (RRs) and 95% confidence intervals (CI) were compared across density groups using Poisson-regression. We included 189 609 women; 1 067 282 person-years; and 4110 incident breast cancers/DCIS. Thirty-three percent of women had BI-RADS density code 1; 38% code 2; 24% code 3; 4.7% code 4; and missing 0.3%. Using women with BI-RADS density code 1 as baseline; women with code 2 had RR 1.69 (95% CI 1.56-1.84); women with code 3, RR 2.06 (95% CI 1.89-2.25); and women with code 4, RR 2.37 (95% CI 1.05-2.74). Results differed between observations accumulated during screening and above screening age. Our results indicated less difference in breast cancer risk across level of breast density than normally stated. Translated into absolute risk of breast cancer after age 50, we found a 6.2% risk for the one-third of women with lowest density, and 14.7% for the 5% of women with highest density.     

乳腺密度、性激素和乳腺癌关系的研究进展

乳腺密度(mammographic breast density,BD)是乳腺癌危险性独立的预测指标,性激素也在乳腺癌的发展中扮演重要角色,而乳腺密度与性激素的关系仍不明确。本文将对乳腺密度,性激素,乳腺癌的关系进行综述。     

Alcohol intake in adolescence and mammographic density

Adolescent exposures may be important in the development of breast cancer later in life. We examined the association of adolescent alcohol consumption and adult mammographic density, a strong risk factor for breast cancer. Women within the Minnesota Breast Cancer Family Cohort with detailed mammogram and risk factor information (n = 1,893) formed our sample. Breast cancer cases were excluded. Adolescent alcohol consumption (before age 18) was solicited through a mailed questionnaire. Percent density (PD) was estimated using the computer-assisted thresholding program, Cumulus. Statistical analyses were performed using linear mixed effect models. Women who reported ever drinking alcohol before age 18 (n = 390; 21%) had a higher unadjusted PD than women who never drank during adolescence (mu(unadj) = 26.5% vs. 22.2%), but this difference disappeared with adjustment for risk factors for mammographic density (mu(adj) = 21.0% vs. 21.2%, p = 0.94). Adult PD was not associated with age at initiation, amount of alcohol consumed at one sitting or frequency of alcohol use before age 18. The lack of differences was seen across strata of menopausal status. There was suggestion of higher PD among heavy and more frequent drinkers (24.0%, 95% CI 21.1-26.8%) compared to lighter (21.3%, 95% CI 20.3-22.3%) and never drinkers (21.4%, 95% CI 20.9-21.9%) and also among regular adolescent drinkers who were daily or weekly adult drinkers (25.0%, 95% CI 23.0-27.0%) compared to less regular drinkers in these 2 time periods (23.0-23.4%). However, these associations were not statistically significant (p = 0.27 and p = 0.22, respectively). In summary, there was no evidence that adolescent alcohol use was associated with large and persistent effects on adult PD.     

Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change

Tamoxifen prevents recurrence of breast cancer and is also approved for preventive, risk-reducing, therapy. Tamoxifen alters the breast tissue composition and decreases the mammographic density. We aimed to test if baseline breast tissue composition influences tamoxifen-associated density change. This biopsy-based study included 83 participants randomised to 6 months daily intake of placebo, 20, 10, 5, 2.5, or 1 mg tamoxifen. The study is nested within the double-blinded tamoxifen dose-determination trial Karolinska Mammography Project for Risk Prediction of Breast Cancer Intervention (KARISMA) Study. Ultrasound-guided core-needle breast biopsies were collected at baseline before starting treatment. Biopsies were quantified for epithelial, stromal, and adipose distributions, and epithelial and stromal expression of proliferation marker Ki67, oestrogen receptor (ER) and progesterone receptor (PR). Mammographic density was measured using STRATUS. We found that greater mammographic density at baseline was positively associated with stromal area and inversely associated with adipose area and stromal expression of ER. Premenopausal women had greater mammographic density and epithelial tissue, and expressed more epithelial Ki67, PR, and stromal PR, compared to postmenopausal women. In women treated with tamoxifen (1–20 mg), greater density decrease was associated with higher baseline density, epithelial Ki67, and stromal PR. Women who responded to tamoxifen with a density decrease had on average 17% higher baseline density and a 2.2-fold higher PR expression compared to non-responders. Our results indicate that features in the normal breast tissue before tamoxifen exposure influences the tamoxifen-associated density decrease, and that the age-associated difference in density change may be related to age-dependant differences in expression of Ki67 and PR.     

Birth weight and mammographic density among postmenopausal women in Sweden

Birth weight is a significant predictor of breast cancer risk in adult life and mammary gland mass could be an intermediate stage in this long process. We have studied the association of birth size measurements with mammographic density, a marker of mammary gland mass. For a population‐based sample of 893 postmenopausal women without previous cancer in Sweden, we retrieved information on birth size from birth records and their most recent mammography. Film mammograms of the medio‐lateral oblique view were digitized and the Cumulus software was used for computer‐assisted semi‐automated thresholding of mammographic density. Results were analyzed using generalized linear models controlling for possible confounders. Mean percent mammographic density increased when comparing the extreme categories of birth weight (from 15.6% to 18.6%) and head circumference (from 15.5% to 20.4%), and the corresponding linear trends were statistically significant (p values 0.02 and 0.007, respectively). The associations were particularly strong when the cutoff for high versus low mammographic density was set at the relatively high value of 50%. Compared to women weighing 3001–3500 grams at birth, women with birth weights >4000g were at almost 3‐fold risk of developing high mammographic density (odds ratio: 2.9, 95% confidence interval 1.1 to 7.9). No association with mammographic density was evident with respect to birth length which, however, is known to be less accurately measured. These results indicate that adult breast density, a powerful predictor of breast cancer risk, has intrauterine roots, as reflected in birth size.     

Postmenopausal mammographic breast density and subsequent breast cancer risk according to selected tissue markers

Background:

This study aimed to determine if associations of pre-diagnostic percent breast density, absolute dense area, and non-dense area with subsequent breast cancer risk differ by the tumour''s molecular marker status.

Methods:

We included 1010 postmenopausal women with breast cancer and 2077 matched controls from the Nurses'' Health Study (NHS) and the Nurses'' Health Study II (NHS II) cohorts. Breast density was estimated from digitised film mammograms using computer-assisted thresholding techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires. Polychotomous logistic regression was used to assess associations of breast density measures with tumour subtypes by the status of selected tissue markers. All tests of statistical significance were two sided.

Results:

The association of percent density with breast cancer risk appeared to be stronger in ER− as compared with ER+ tumours, but the difference did not reach statistical significance (density ⩾50% vs <10% odds ratio (OR)=3.06, 95% confidence interval (CI) 2.17–4.32 for ER+ OR=4.61, 95% CI 2.36–9.03 for ER−, P_{heterogeneity}=0.08). Stronger positive associations were found for absolute dense area and CK5/6− and EGFR− as compared with respective marker-positive tumours (P_{heterogeneity}=0.002 and 0.001, respectively). Stronger inverse associations of non-dense area with breast cancer risk were found for ER− as compared with ER+ tumours (P_{heterogeneity}=0.0001) and for AR+, CK5/6+, and EGFR+ as compared with respective marker-negative tumours (P_{heterogeneity}=0.03, 0.005, and 0.009, respectively). The associations of density measures with breast cancer did not differ by progesterone receptor and human epidermal growth factor receptor 2 status.

Conclusions:

Breast density influences the risk of breast cancer subtypes by potentially different mechanisms.