Percent Dense Volume Research Articles

Associations between quantitative measures of mammographic density and terminal ductal lobular unit involution in Chinese breast cancer patients

BackgroundHigher mammographic density (MD), a radiological measure of the proportion of fibroglandular tissue in the breast, and lower terminal duct lobular unit (TDLU) involution, a histological measure of the amount of epithelial tissue in the breast, are independent breast cancer risk factors. Previous studies among predominantly white women have associated reduced TDLU involution with higher MD.MethodsIn this cohort of 611 invasive breast cancer patients (ages 23–91 years [58.4% ≥ 50 years]) from China, where breast cancer incidence rates are lower and the prevalence of dense breasts is higher compared with Western countries, we examined the associations between TDLU involution assessed in tumor-adjacent normal breast tissue and quantitative MD assessed in the contralateral breast obtained from the VolparaDensity software. Associations were estimated using generalized linear models with MD measures as the outcome variables (log-transformed), TDLU measures as explanatory variables (categorized into quartiles or tertiles), and adjusted for age, body mass index, parity, age at menarche and breast cancer subtype.ResultsWe found that, among all women, percent dense volume (PDV) was positively associated with TDLU count (highest tertile vs. zero: Expbeta = 1.28, 95% confidence interval [CI] 1.08–1.51, ptrend = < .0001), TDLU span (highest vs. lowest tertile: Expbeta = 1.23, 95% CI 1.11–1.37, ptrend = < .0001) and acini count/TDLU (highest vs. lowest tertile: Expbeta = 1.22, 95% CI 1.09–1.37, ptrend = 0.0005), while non-dense volume (NDV) was inversely associated with these measures. Similar trend was observed for absolute dense volume (ADV) after the adjustment of total breast volume, although the associations for ADV were in general weaker than those for PDV. The MD-TDLU associations were generally more pronounced among breast cancer patients ≥ 50 years and those with luminal A tumors compared with patients < 50 years and with luminal B tumors.ConclusionsOur findings based on quantitative MD and TDLU involution measures among Chinese breast cancer patients are largely consistent with those reported in Western populations and may provide additional insights into the complexity of the relationship, which varies by age, and possibly breast cancer subtype.

Association of area- and volumetric-mammographic density and breast cancer risk in women of Asian descent: a case control study

BackgroundMammographic density (MD) has been shown to be a strong and independent risk factor for breast cancer in women of European and Asian descent. However, the majority of Asian studies to date have used BI-RADS as the scoring method and none have evaluated area and volumetric densities in the same cohort of women. This study aims to compare the association of MD measured by two automated methods with the risk of breast cancer in Asian women, and to investigate if the association is different for premenopausal and postmenopausal women.MethodsIn this case–control study of 531 cases and 2297 controls, we evaluated the association of area-based MD measures and volumetric-based MD measures with breast cancer risk in Asian women using conditional logistic regression analysis, adjusting for relevant confounders. The corresponding association by menopausal status were assessed using unconditional logistic regression.ResultsWe found that both area and volume-based MD measures were associated with breast cancer risk. Strongest associations were observed for percent densities (OR (95% CI) was 2.06 (1.42–2.99) for percent dense area and 2.21 (1.44–3.39) for percent dense volume, comparing women in highest density quartile with those in the lowest quartile). The corresponding associations were significant in postmenopausal but not premenopausal women (premenopausal versus postmenopausal were 1.59 (0.95–2.67) and 1.89 (1.22–2.96) for percent dense area and 1.24 (0.70–2.22) and 1.96 (1.19–3.27) for percent dense volume). However, the odds ratios were not statistically different by menopausal status [p difference = 0.782 for percent dense area and 0.486 for percent dense volume].ConclusionsThis study confirms the associations of mammographic density measured by both area and volumetric methods and breast cancer risk in Asian women. Stronger associations were observed for percent dense area and percent dense volume, and strongest effects were seen in postmenopausal individuals.

The Associations between Intakes of One-Carbon Metabolism-Related Vitamins and Breast Density among Young Women.

Folate is the primary methyl donor and B vitamins are cofactors for one-carbon metabolism that maintain DNA integrity and epigenetic signatures implicated in carcinogenesis. Breast tissue is particularly susceptible to stimuli in early life. Only limited data are available on associations of one-carbon metabolism-related vitamin intake during youth and young adulthood with breast density, a strong risk factor for breast cancer. Over 18 years in the DISC and DISC06 Follow-up Study, diets of 182 young women were assessed by three 24-hour recalls on five occasions at ages 8 to 18 years and once at 25 to 29 years. Multivariable-adjusted linear mixed-effects regression was used to examine associations of intakes of one-carbon metabolism-related vitamins with MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at ages 25 to 29 years. Folate intake in youth was inversely associated with %DBV (Ptrend = 0.006) and ADBV (Ptrend = 0.02). These inverse associations were observed with intake during post-, though not premenarche. In contrast, premenarche vitamin B2 intake was positively associated with ADBV (Ptrend < 0.001). Young adult folate and vitamin B6 intakes were inversely associated with %DBV (all Ptrend ≤ 0.04), whereas vitamins B6 and B12 were inversely associated with ADBV (all Ptrend ≤ 0.04). Among these DISC participants intakes of one-carbon metabolism-related vitamins were associated with breast density. Larger prospective studies among diverse populations are needed to replicate these findings. Our results suggest the importance of one-carbon metabolism-related vitamin intakes early in life with development of breast density and thereby potentially breast cancer risk later in life.

Untargeted serum metabolomic profiles and breast density in young women.

Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

Childhood adiposity, serum metabolites and breast density in young women

BackgroundChildhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density.MethodsLongitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography–tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25–29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation.ResultsOf the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity–%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV.ConclusionsAdditional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

Hormone and receptor activator of NF-\u03baB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women

BackgroundHormones impact breast tissue proliferation. Studies investigating the associations of circulating hormone levels with mammographic breast density have reported conflicting results. Due to the limited number of studies, we investigated the associations of hormone gene expression as well as their downstream mediators within the plasma with mammographic breast density in postmenopausal women.MethodsWe recruited postmenopausal women at their annual screening mammogram at Washington University School of Medicine, St. Louis. We used the NanoString nCounter platform to quantify gene expression of hormones (prolactin, progesterone receptor (PGR), estrogen receptor 1 (ESR1), signal transducer and activator of transcription (STAT1 and STAT5), and receptor activator of nuclear factor-kB (RANK) pathway markers (RANK, RANKL, osteoprotegerin, TNFRSF18, and TNFRSF13B) in plasma. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. Linear regression models, adjusted for confounders, were used to evaluate associations between gene expression (linear fold change) and mammographic breast density.ResultsOne unit increase in ESR1, RANK, and TNFRSF18 gene expression was associated with 8% (95% CI 0–15%, p value = 0.05), 10% (95% CI 0–20%, p value = 0.04) and % (95% CI 0–9%, p value = 0.04) higher volumetric percent density, respectively. There were no associations between gene expression of other markers and volumetric percent density. One unit increase in osteoprotegerin and PGR gene expression was associated with 12% (95% CI 4–19%, p value = 0.003) and 7% (95% CI 0–13%, p value = 0.04) lower non-dense volume, respectively.ConclusionThese findings provide new insight on the associations of plasma hormonal and RANK pathway gene expression with mammographic breast density in postmenopausal women and require confirmation in other studies.

Coffee, Tea, and Mammographic Breast Density in Premenopausal Women.

Studies have investigated the associations of coffee and tea with mammographic breast density (MBD) in premenopausal women with inconsistent results. We analyzed data from 375 premenopausal women who attended a screening mammogram at Washington University School of Medicine, St. Louis, MO in 2016, and stratified the analyses by race (non-Hispanic White (NHW) vs. Black/African American). Participants self-reported the number of servings of coffee, caffeinated tea, and decaffeinated tea they consumed. Volpara software was used to determine volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV). We used generalized linear regression models to quantify the associations of coffee and tea intake with MBD measures. Coffee: ≥1 time/day (β = 1.06; 95% CI = 0.93–1.21; p-trend = 0.61) and caffeinated tea: ≥1 time/day (β = 1.01; 95% CI = 0.88–1.17; p-trend = 0.61) were not associated with VPD. Decaffeinated tea (≥1 time/week) was positively associated with VPD in NHW women (β = 1.22; 95% CI = 1.06–1.39) but not in African American women (β = 0.93; 95% CI = 0.73–1.17; p-interaction = 0.02). Coffee (≥1 time/day) was positively associated with DV in African American women (β = 1.52; 95% CI = 1.11–2.07) but not in NHW women (β = 1.10; 95% CI = 0.95–1.29; p-interaction = 0.02). Our findings do not support associations of coffee and caffeinated tea intake with VPD in premenopausal women. Positive associations of decaffeinated tea with VPD, with suggestions of effect modification by race, require confirmation in larger studies with diverse study populations.

Abstract 1158: Hormone gene expression and mammographic breast density in postmenopausal women

Abstract Introduction: Mammographic breast density (MBD), which reflects the amount of epithelial and stromal tissues relative to adipose tissue in the breast, is a strong risk factor for breast cancer. MBD declines with menopause, highlighting the role of endogenous hormones. Nevertheless, studies evaluating the associations of circulating hormone levels with MBD report conflicting results. Only a limited number of studies have addressed the genomic signatures of MBD, which may better capture the broader transcriptional changes associated with MBD and more accurately quantify hormonal exposure than circulating hormone levels. We therefore investigated the associations of hormonal gene expression with MBD in postmenopausal women. Methods: We recruited 368 mid-life postmenopausal women (ages 50-64 years) who had annual screening mammogram at Washington University School of Medicine, St. Louis, MO between October 2017 and September 2018. Each participant completed a blood draw and a questionnaire on breast cancer risk factors. We used Volpara software to measure volumetric percent density (VPD, %), dense volume (VD, cm3) and non-dense volume (NDV, cm3). Prolactin (PRL), progesterone (PGR), estrogen receptor 1 (ESR1), signal transducer and activator of transcription (STAT1), and STAT5 gene expression were measured in total RNA isolated from plasma using NanoString nCounter system. Statistical analyses were performed with the NanoString nSolver Analysis Software. Fold changes in gene expression and p-values were calculated using nCounter default settings. Analyses were adjusted for body mass index (BMI), age, age at menarche, parity/age at first birth, race, and menopausal hormone use. VPD, DV, and NDV were log10 transformed to ensure the normality of the residuals. Results: The mean age of study participants was 57.9 years. The mean BMI was 31.3kg/m2. The average VPD, DV, and NDV were 6.2%, 121.2 cm3, and 2134.4 cm3, respectively. There were strong correlations between STAT1 and STAT5 gene expression (r=0.59, p-value&amp;lt;0.0001), and moderate correlations between ESR1 and PGR gene expression (r=0.43, p-value&amp;lt;0.0001). ESR1 gene expression was associated with VPD, while PGR and STAT5 were marginally associated with NDV. One unit increase in ESR1 gene expression was associated with a 29% (95% CI 2-64%) increase in VPD (p-value=0.03). One unit increase in STAT5 gene expression was associated with an 8% (p-value=0.05) increase in NDV, while one unit increase in PGR gene expression was associated with a 20% (p-value=0.06) decrease in NDV. Hormone gene expression was not associated with DV. Conclusions: We provide novel data on the associations of endogenous hormone gene expression with MBD in postmenopausal women. Future studies characterizing transcriptomic changes in hormone signaling and MBD are needed, as targeting these pathways could be used to reduce MBD for breast cancer prevention. Citation Format: Rachel L. Mintz, Mei Wang, Shuai Xu, Chris Markovic, Adetunji T. Toriola. Hormone gene expression and mammographic breast density in postmenopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1158.

Mammographic density changes during neoadjuvant breast cancer treatment: NeoDense, a prospective study in Sweden

ObjectivesTo assess if mammographic density (MD) changes during neoadjuvant breast cancer treatment and is predictive of a pathological complete response (pCR). MethodsWe prospectively included 200 breast cancer patients assigned to neoadjuvant chemotherapy (NACT) in the NeoDense study (2014–2019). Raw data mammograms were used to assess MD with a fully automated volumetric method and radiologists categorized MD using the Breast Imaging-Reporting and Data System (BI-RADS), 5th Edition. Logistic regression was used to calculate odds ratios (OR) for pCR comparing BI-RADS categories c vs. a, b, and d as well as with a 0.5% change in percent dense volume adjusting for baseline characteristics. ResultsThe overall median age was 53.1 years, and 48% of study participants were premenopausal pre-NACT. A total of 23% (N = 45) of the patients accomplished pCR following NACT. Patients with very dense breasts (BI-RADS d) were more likely to have a positive axillary lymph node status at diagnosis: 89% of the patients with very dense breasts compared to 72% in the entire cohort. A total of 74% of patients decreased their absolute dense volume during NACT. The likelihood of accomplishing pCR following NACT was independent of volumetric MD at diagnosis and change in volumetric MD during treatment. No trend was observed between decreasing density according to BI-RADS and the likelihood of accomplishing pCR following NACT. ConclusionsThe majority of patients decreased their MD during NACT. We found no evidence of MD as a predictive marker of pCR in the neoadjuvant setting.

Abstract P5-08-02: Association of daily alcohol intake, volumetric density and breast cancer risk

Abstract Background: Alcohol intake and breast density are established risk factors for breast cancer (BC). A few studies suggest breast density is on the causal pathway between alcohol and BC but the literature is not consistent. We examine the interrelationship between alcohol, volumetric breast density and BC risk, specifically whether there is a stronger alcohol and BC association among women with dense breasts and/or whether breast density mediates the alcohol and BC association. Methods: We conducted a nested case-control study within the San Francisco Mammography Registry consisting of four breast screening centers. From 2006-2013, through linkages with the California cancer registry, we identified 2572 women diagnosed with BC who had screening mammograms performed at least six months prior to diagnosis. Controls (5119) were matched to cases on age, date of earliest mammogram, race/ethnicity, facility, and mammography machine. We obtained the raw format of digital mammograms on average 3.1 (standard deviation (SD) =1.7) years prior to diagnosis or corresponding date for controls. We ascertained usual daily alcohol intake and other risk factors from a clinical questionnaire at time of mammography. We obtained BI-RADS density from clinical records and used VolparaTM to assess volumetric percent density, dense volume and non-dense volume from the mammogram. We examined the associations of daily alcohol intake (none, one or less, two or more drinks per day) and volumetric density phenotypes (per 1 SD) with BC risk using logistic regression (odds ratios, OR; 95% confidence intervals, CI; and trend tests). We examined deviation from multiplicative interaction using chi-squared tests. We evaluated mediation of the alcohol and BC association by volumetric density measures using logistic regression to estimate the association between alcohol use and BC with and without adjustment for density measures. Percent mediation was estimated using the differences in the log OR estimates from the two models. All models were adjusted for age, 1/BMI and menopause and matching factors. Analyses were also stratified by menopausal status. Results: Alcohol intake was available on 2233 cases and 4562 controls, 88% of those eligible. BC cases and controls had similar age (57.2 years (SD=11.5) vs. 57.1 years (SD=11.5)), BMI (25.3 kg/m2 (SD=5.3) vs. 24.9 kg/ m2 (SD=5.1)) and race (69.0% vs. 68.2% Caucasian). Cases were more likely to drink alcohol daily than controls (52.1% vs. 49.0%), in particular two or more drinks per day (14.8% vs. 13.2%). Alcohol was associated with increased BC risk (OR=1.14, 95% CI:1.02-1.27, for one or less drinks per day and OR=1.22, 95% CI:1.05-1.42 for 2 or more drinks per day) compared to non-drinkers (p-trend=0.004). Percent volumetric density (OR=1.45 per SD, 95%CI: 1.36-1.56,) and dense volume (OR=1.30, 95% CI: 1.24-1.37) were also positively associated with BC risk; non-dense volume was inversely associated (OR=0.93, 95%CI: 0.86-1.01). Associations were similar by menopausal subgroup. There was no evidence for a differential association of alcohol and breast cancer risk by dense breasts assessed using any of the density phenotypes examined (all P’s&amp;gt;0.1). However, the association between alcohol and overall risk of BC was partially mediated by dense volume among all women (percent mediated=25%, P=0.01) and postmenopausal women (percent mediated=19%, P=0.03). Conclusions: The association of daily alcohol intake and breast cancer risk was similar among women with dense and non-dense breasts. However, dense volume partially mediated the association between alcohol and risk of breast cancer, particularly among postmenopausal women, suggesting that alcohol partially influences breast cancer risk through changes in breast tissue composition. Citation Format: Celine Marie Vachon, Christopher G. Scott, Stacey J Winham, John A Shepherd, Kathleen R Brandt, Matthew R Jensen, Carrie B Hruska, John J Heine, V. Shane Pankratz, Karla Kerlikowske. Association of daily alcohol intake, volumetric density and breast cancer risk [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-02.

Pubertal timing and breast density in young women: a prospective cohort study

BackgroundEarlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk.MethodsFrom 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006–2008, 182 participants then aged 25–29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV.ResultsThe mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2–86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2–26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9–17.5%)).ConclusionsOur results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

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.

Abstract P4-10-08: Family history of breast cancer and mammographic density in premenopausal women

Abstract Introduction: Mammographic density and family history of breast cancer (FHBC) are independent risk factors for breast cancer. Women with dense breasts have a 4-6-fold increased risk of breast cancer and women with FHBC have a 1.5-3-fold increased risk of breast cancer. However, there is little data on the associations of FHBC with mammographic density, especially in premenopausal women. To address this, we investigated the associations of FHBC in first-degree relatives with mammographic density in premenopausal women. Methods: We used data from 375 cancer-free premenopausal women who were during routine screening mammography at Washington University in St. Louis in 2016. We used Volpara to measure volumetric measures of density including volumetric percent density, dense volume, and non-dense volume. We collected data on first-degree relatives (mother, sister) and numbers of first degree relatives (0, 1, ≥2) with a positive FHBC. We used multivariable linear regression model, adjusted for age, BMI, parity, race, age at menarche, and alcohol consumption, to determine the associations of FHBC and log-transformed volumetric percent density, dense volume, and non-dense volume. Beta coefficients (β) were evaluated and back transformed for easier interpretation. Results: The mean age of participants was 47.5 years (range=32-58). The mean BMI was 30.8 kg/m2 (range =17.9-63.1). Volumetric percent density was 25% (p-value&amp;lt;0.001) higher in women who had a FHBC compared with women who had no FHBC. The associations appeared confined to women with a positive family history in mothers but not those with a positive family history in sisters. Volumetric percent density was 31% higher (p-value&amp;lt;0.001) among women with a positive FHBC in mothers compared to those without a positive FHBC in mothers, but 8% higher (p-value=0.45) among women with a positive FHBC in sisters compared to those without a positive FHBC in sisters. The associations of FHBC with dense volume were similar to those of volumetric percent density in all the analyses. For instance, dense volume was 16% (p-value=0.006) higher in women who had a FHBC compared with women who had no FHBC. Table 1.Associations of family history of breast cancer (FHBC) and volumetric percent density (VPD), and dense volume (DV) in 375 premenopausal women*.FHBCNVPD (%) DV (cm3 ) Beta (95% CI)P-valueBeta (95% CI)P-valueNo275Ref Ref Yes871.25 (1.12,1.41)&amp;lt;0.0011.16 (1.04,1.29)0.007Unknown131.00 (0.76,1.30)0.990.74 (0.58,0.95)0.017*Adjusted for age, BMI, parity, race, age at menarche, and alcohol consumption. Conclusions: Premenopausal women with a first-degree FHBC have higher volumetric percent density. Our findings could help identify high-risk women who may benefit from targeted screening. Citation Format: Han Y, Zong X, Colditz GA, Toriola AT. Family history of breast cancer and mammographic density in premenopausal women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-08.

Abstract 3226: Overweight and obese women with high volumetric breast density at high breast cancer risk

Abstract Purpose: Volumetric breast density and body mass index (BMI) are increasingly used for breast cancer risk stratification. We examine if the effect of volumetric breast density on breast cancer risk increases with increasing BMI. Methods: Participants were from two case-control studies within mammography practices, the San Francisco Mammography Registry and the Mayo Clinic Rochester, Breast Screening Practice. Breast cancers were included if diagnosed between January 2007 and 2015 and with a screening full-field digital mammogram at least 6 months prior to diagnosis; the earliest mammogram within 5 years of diagnosis was selected. Up to three controls were matched to each case on age, race, date, mammography machine, and state of residence. Volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV) were measured using VolparaTM software. Breast cancer risk was assessed using logistic regression stratified by menopause status and adjusted for matching factors, family history of breast cancer, parity/age at first birth, and postmenopausal hormone therapy. Models for DV were additionally adjusted for NDV, and NDV models for DV. Multiplicative interactions were fit between BMI categories [&amp;lt;25 (underweight), 25-30 (normal weight) and &amp;gt;30 (overweight/obese) kg/m2] and VPD, DV, and NDV, and trend tests assessed for increasing odds ratios (OR) with increasing BMI. Results: A total of 781 premenopausal and 1850 postmenopausal breast cancers and 3535 controls were included in the analysis. Median age of premenopausal women was 45 years (IQR: 6.1) and 63.3 years (IQR: 14) for postmenopausal women. Cases vs. controls had greater VPD and DV for both premenopausal (VPD: 14.9% vs. 12.0%, DV: 74.1 cm3 vs. 64.4 cm3) and postmenopausal women (VPD: 6.8% vs. 6.1%, DV: 53.4 cm3 vs. 48.0 cm3)(all p's&amp;lt;0.001). Trends between increasing BMI and VPD were evident for both pre (ptrend=0.0007) and postmenopausal (ptrend=0.0005) women. Among premenopausal women, the odds ratio (OR) for breast cancer associated with a 10% increase in VPD was of 1.39, 2.19 and 2.88 for BMI &amp;lt;25, 25-30 and &amp;gt;30 kg/m2 (p-trend=0.0007), respectively. For DV, OR's were 1.39, 1.33 and 1.51 for a 1 SD increase in DV, respectively, though the interaction with DV was not significant (ptrend=0.68). Among postmenopausal women, a 10% increase in VPD was associated with OR's of 1.35, 2.03, 3.6 for BMI &amp;lt;25, 25-29, &amp;gt;30-kg/m2 (ptrend =0.0001), respectively, and 1.31, 1.34 and 1.65 for a 1 SD increase in DV (ptrend =0.01), respectively. Associations between NDV and breast cancer risk did not differ by BMI category for premenopausal (ptrend =0.52) or postmenopausal (ptrend =0.07) women. Conclusions: The effect of VPD on breast cancer risk is strongest in overweight/obese women. As volumetric breast density and BMI are commonly used in clinical risk stratification, these differences in risk have high clinical relevance for informing prevention decisions. Citation Format: Natalie J. Engmann, Christopher G. Scott, Matthew R. Jensen, Stacey J. Winham, Lin Ma, Kathleen R. Brandt, Amir Mahmoudzadeh, Serghei Malkov, Dana Whaley, Carrie Hruska, Fang Fang Wu, Diana L. Miglioretti, Aaron D. Norman, John Heine, John Shepherd, Vernon S. Pankratz, Celine M. Vachon, Karla Kerlikowske. Overweight and obese women with high volumetric breast density at high breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3226.

Intake of dietary carbohydrates in early adulthood and adolescence and breast density among young women.

Carbohydrateintake increases postprandial insulin secretion and may affect breast density, a strong risk factor for breast cancer, early in life. We examined associations of adolescent and early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars with breast density among 182 young women. Diet was assessed using three 24-h recalls at each of five Dietary Intervention Study in Children (DISC) clinic visits when participants were age 10-19years and at the DISC06 Follow-Up Study clinic visit when participants were age 25-29years. Associations between energy-adjusted carbohydrates and MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at 25-29years were quantified using multivariable-adjusted mixed-effects linear models. Adolescent sucrose intakes and premenarcheal total carbohydrates intakes were modestly associated with higher %DBV (mean %DBVQ1 vs Q4, 16.6 vs 23.5% for sucrose; and 17.2 vs 22.3% for premenarcheal total carbohydrates, all Ptrend ≤ 0.02), but not with ADBV. However, adolescent intakes of fiber and fructose were not associated with %DBV and ADBV. Early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars were not associated with %DBV and ADBV. Insulinemic carbohydrate diet during puberty may be associated with adulthood breast density, but our findings need replication in larger studies. Clinical Trials Registration ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

The combined effect of mammographic texture and density on breast cancer risk: a cohort study

BackgroundTexture patterns have been shown to improve breast cancer risk segregation in addition to area-based mammographic density. The additional value of texture pattern scores on top of volumetric mammographic density measures in a large screening cohort has never been studied.MethodsVolumetric mammographic density and texture pattern scores were assessed automatically for the first available digital mammography (DM) screening examination of 51,400 women (50–75 years of age) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. The texture assessment method was developed in a previous study and validated in the current study. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. All screen-detected breast cancers diagnosed at the first available digital screening examination were excluded. During a median follow-up period of 4.2 (interquartile range (IQR) 2.0–6.2) years, 301 women were diagnosed with breast cancer. The associations between texture pattern scores, volumetric breast density measures and breast cancer risk were determined using Cox proportional hazard analyses. Discriminatory performance was assessed using c-indices.ResultsThe median age of the women at the time of the first available digital mammography examination was 56 years (IQR 51–63). Texture pattern scores were positively associated with breast cancer risk (hazard ratio (HR) 3.16 (95% CI 2.16–4.62) (p value for trend <0.001), for quartile (Q) 4 compared to Q1). The c-index of texture was 0.61 (95% CI 0.57–0.64). Dense volume and percentage dense volume showed positive associations with breast cancer risk (HR 1.85 (95% CI 1.32–2.59) (p value for trend <0.001) and HR 2.17 (95% CI 1.51–3.12) (p value for trend <0.001), respectively, for Q4 compared to Q1). When adding texture measures to models with dense volume or percentage dense volume, c-indices increased from 0.56 (95% CI 0.53–0.59) to 0.62 (95% CI 0.58–0.65) (p < 0.001) and from 0.58 (95% CI 0.54–0.61) to 0.60 (95% CI 0.57–0.63) (p = 0.054), respectively.ConclusionsDeep-learning-based texture pattern scores, measured automatically on digital mammograms, are associated with breast cancer risk, independently of volumetric mammographic density, and augment the capacity to discriminate between future breast cancer and non-breast cancer cases.

Common genetic variation and novel loci associated with volumetric mammographic density

BackgroundMammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained.MethodsWe conducted a genetic association study of volumetric MD in a Swedish mammography screening cohort (n = 9498) to identify novel MD loci. Associations with volumetric MD phenotypes (percent dense volume, absolute dense volume, and absolute nondense volume) were estimated using linear regression adjusting for age, body mass index, menopausal status, and six principal components. We also estimated the proportion of MD variance explained by additive contributions from single-nucleotide polymorphisms (SNP-based heritability [h2SNP]) in 4948 participants of the cohort.ResultsIn total, three novel MD loci were identified (at P < 5 × 10− 8): one for percent dense volume (HABP2) and two for the absolute dense volume (INHBB, LINC01483). INHBB is an established locus for ER-negative breast cancer, and HABP2 and LINC01483 represent putative new breast cancer susceptibility loci, because both loci were associated with breast cancer in available meta-analysis data including 122,977 breast cancer cases and 105,974 control subjects (P < 0.05). h2SNP (SE) estimates for percent dense, absolute dense, and nondense volume were 0.29 (0.07), 0.31 (0.07), and 0.25 (0.07), respectively. Corresponding ratios of h2SNP to previously observed narrow-sense h2 estimates in the same cohort were 0.46, 0.72, and 0.41, respectively.ConclusionsThese findings provide new insights into the genetic basis of MD and biological mechanisms linking MD to breast cancer risk. Apart from identifying three novel loci, we demonstrate that at least 25% of the MD variance is explained by common genetic variation with h2SNP/h2 ratios varying between dense and nondense MD components.

Abstract P4-01-01: Adiposity at age 10 and mammographic density among premenopausal women

Abstract Background: Higher mammographic breast density is a strong risk factor for breast cancer. Early-life factors may influence breast development and subsequent breast density in adulthood. Although childhood adiposity is inversely associated with breast cancer risk, the association of childhood adiposity with mammographic breast density in premenopausal women has not been adequately studied. This knowledge could provide insight into pathways linking mammographic density and breast cancer risk. We investigated the associations between adiposity at age 10 and mammographic density. Methods: We collected data from 370 premenopausal women during their routine screening mammograms at Washington University in St. Louis, MO from December 2015 to October 2016. Body size at age 10 was self-reported using the Stunkard 9-figure Somatotype pictogram. For these analyses, the Stunkard pictogram was collapsed into 4 groups: (i) body size 1 or 2, (ii) body size 3 or 4, (iii) body size 5, (iv) body size 6 or higher. Body mass index (BMI) at age 10 was imputed using BMI and Stunkard data from the Growing Up Today Study. Trained personnel collected womens' height and weight, which were used to calculate current BMI. We used the Volpara software to evaluate the following volumetric mammographic density measures: volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV). Age-adjusted Pearson correlations and multivariable linear regression models (adjusted for age, age at each given birth, family history, race, education, oral contraceptive use, and breast feeding history) were used to evaluate the associations between adiposity at age 10 and volumetric mammographic density measures. Results: The mean age at the time of screening mammogram was 47.1 years. The majority of the women (43.8%) reported having body size 1 or 2, followed by body size 3 or 4 (34.9%), body size 5 (13.8%) and body size 6 (7.6%) at age 10. We observed a negative correlation between BMI at age 10 (r= -0.28, p-value&amp;lt;0.001) and VPD, and a positive correlation between BMI at age 10 (r= 0.27, p-value&amp;lt;0.001) and NDV. In multivariable regression models, adiposity at age 10 was significantly inversely associated with VPD, and positively associated with NDV. A 1kg/m2 increase in BMI at age 10 was associated with a 6.3% decrease in VPD (p-value &amp;lt;0.001), and a 6.7% increase in NDV (p-value &amp;lt;0.001). Compared to women whose body sizes were 1 and 2 at age 10, women with body size 3 or 4 had a 17.6% decrease in VPD, and a 28.5% increase in NDV; women with body size 5 had a 32.3% decrease in VPD, and a 58.1% increase in NDV, and women with body sizes ≥6 had a 46.6% decrease in VPD, and a 75.1% increase in NDV (all p-values &amp;lt;0.05). The associations of body size at age 10 and VPD were attenuated, but still statistically significant when we adjusted for current BMI. No statistically significant associations were found between adiposity at age 10 and DV. Conclusions: Our findings of an inverse association between adiposity at age 10 and percent density suggest that adiposity at age 10 could impact breast cancer development via its effect on mammographic density. Mechanistic studies to understand how childhood adiposity reduces mammographic density and breast cancer development in premenopausal women are needed. Citation Format: Alimujiang A, Imm KR, Appleton CM, Colditz GA, Berkey CS, Toriola AT. Adiposity at age 10 and mammographic density among premenopausal women [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-01-01.

Influence of breast compression pressure on the performance of population-based mammography screening

BackgroundIn mammography, breast compression is applied to reduce the thickness of the breast. While it is widely accepted that firm breast compression is needed to ensure acceptable image quality, guidelines remain vague about how much compression should be applied during mammogram acquisition. A quantitative parameter indicating the desirable amount of compression is not available. Consequently, little is known about the relationship between the amount of breast compression and breast cancer detectability. The purpose of this study is to determine the effect of breast compression pressure in mammography on breast cancer screening outcomes.MethodsWe used digital image analysis methods to determine breast volume, percent dense volume, and pressure from 132,776 examinations of 57,179 women participating in the Dutch population-based biennial breast cancer screening program. Pressure was estimated by dividing the compression force by the area of the contact surface between breast and compression paddle. The data was subdivided into quintiles of pressure and the number of screen-detected cancers, interval cancers, false positives, and true negatives were determined for each group. Generalized estimating equations were used to account for correlation between examinations of the same woman and for the effect of breast density and volume when estimating sensitivity, specificity, and other performance measures. Sensitivity was computed using interval cancers occurring between two screening rounds and using interval cancers within 12 months after screening. Pair-wise testing for significant differences was performed.ResultsPercent dense volume increased with increasing pressure, while breast volume decreased. Sensitivity in quintiles with increasing pressure was 82.0%, 77.1%, 79.8%, 71.1%, and 70.8%. Sensitivity based on interval cancers within 12 months was significantly lower in the highest pressure quintile compared to the third (84.3% vs 93.9%, p = 0.034). Specificity was lower in the lowest pressure quintile (98.0%) compared to the second, third, and fourth group (98.5%, p < 0.005). Specificity of the fifth quintile was 98.4%.ConclusionResults suggest that if too much pressure is applied during mammography this may reduce sensitivity. In contrast, if pressure is low this may decrease specificity.

Breast compression parameters and mammographic density in the Norwegian Breast Cancer Screening Programme.

To investigate possible associations between breast compression parameters, including compression force, pressure and compressed breast thickness, and mammographic density assessed by an automated software. We obtained data on breast compression parameters, breast volume, absolute and percentage dense volume, and body mass index for 14,698 women screened with two-view (craniocaudal, CC, and mediolateral oblique, MLO) digital mammography, in the Norwegian Breast Cancer Screening Programme, 2014-2015. The Spearman correlation coefficient (ρ) was used to measure correlation between breast compression parameters, breast volume and absolute and percentage dense volume. Linear regression was used to examine associations between breast compression parameters and absolute and percentage dense volume, adjusting for breast volume, age and BMI. A fair negative correlation was observed between compression pressure and absolute dense volume (ρ = - 0.37 for CC and ρ = - 0.34 for MLO). A moderate negative correlation was identified for compressed breast thickness and percentage dense volume (ρ = - 0.56 for CC and ρ = - 0.62 for MLO). These correlations were corroborated by the corresponding associations obtained in the adjusted regression analyses. Results from this study indicate that breast compression parameters may influence absolute and percentage dense volume measured by the automated software. • A fair correlation was identified between compression pressure and absolute dense volume • A moderate correlation was identified between compressed breast thickness and percentage dense volume • Breast compression may influence automated density estimates.