Breast Density In Premenopausal Women Research Articles

Aspirin Metabolites and Mammographic Breast Density in Premenopausal Women.

Studies investigating the associations of self-reported aspirin use and mammographic breast density (MBD) have reported conflicting results. We, therefore, investigated the associations of aspirin metabolites, with MBD in premenopausal women. We performed this study on 705 premenopausal women who had fasting blood draw for metabolomic profiling. We performed covariate-adjusted linear regression models to calculate the least squares means of volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) by quartiles of aspirin metabolites (salicyluric glucuronide, 2-hydroxyhippurate (salicylurate), salicylate, and 2,6-dihydroxybenzoic acid). Approximately 13% of participants reported taking aspirin in the past 12 months. Aspirin users had higher levels of 2-hydroxyhippurate (salicylurate), salicylate, and salicyluric glucuronide (peak area) than non-users, but only mean peak area of salicyluric glucuronide increased by both dose (1-2 tabs per day=1,140,663.7, and ≥3 tabs per day=1,380,476.0) and frequency (days per week: 1 day=888,129.3, 2-3 days=1,199,897.9 and ≥4 days=1,654,637.0). Aspirin metabolites were not monotonically associated with VPD, DV, or NDV. Given the null results, additional research investigating the associations of aspirin metabolites in breast tissue and MBD is necessary. Elucidating the determinants of MBD, a strong risk factor for breast cancer, can play an important role in breast cancer prevention. Future studies should determine the associations of non-aspirin non-steroidal anti-inflammatory drug metabolites with MBD.

Abstract 4431: Steroid hormone metabolites and mammographic breast density in premenopausal women

Abstract Background: Steroid hormones influence breast tissue development and play a role in breast carcinogenesis. Their associations with mammographic breast density (MBD), an established risk factor for breast cancer, are less clear. We, therefore, investigated the associations of steroid hormone metabolites with MBD in premenopausal women. Methods: Our study population consists of 705 premenopausal women recruited during their annual screening mammogram at the Washington University School of Medicine, St. Louis, MO. We assessed volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV) using Volpara. We assayed 54 steroid hormone metabolites from fasting blood samples at Metabolon. Linear regression models were used, after adjusting for covariates, to estimate the least square means of VPD, DV, and NDV across tertiles (T) of each metabolite. Sensitivity analysis was performed among the subset of participants with a history of oral contraceptive use (OCP). We used the Benjamini-Hochberg procedure to correct for multiple tests to control the false discovery rate (FDR) at a 5% level. Results: Five androgen metabolites (androstenediol (3beta,17beta) monosulfate 2, androstenediol (3beta,17beta) disulfate 1, 5alpha-androstan-3alpha,17beta-diol monosulfate 2, 5alpha-androstan-3alpha,17beta-diol disulfate, and 5alpha-androstan-3beta,17beta-diol disulfate) and two corticosteroid metabolites (tetrahydrocortisone glucuronide 5, and cortolone glucuronide 1) were inversely associated with VPD. Androstenediol (3beta,17beta) disulfate 1, and 5alpha-androstan-3alpha,17beta-diol disulfate displayed the strongest associations with VPD. The mean VPD decreased across tertiles of androstenediol (3beta,17beta) disulfate 1 from 9.0% in T1 to 8.5% in T2, and 7.5% in T3 (FDR p-value=0.02). Similarly, the mean VPD decreased from 8.8% in T1 to 8.4% in T2, and 7.6% in T3 of 5alpha-androstan-3alpha,17beta-diol disulfate (FDR p-value=0.03). Progestin steroid metabolites appeared to be positively associated with VPD but only 5alpha-pregnan-3beta,20alpha-diol monosulfate 2 was marginally significant after FDR correction (7.5% in T1, 8.3% in T2, and 8.8% in T3; FDR p-value=0.06). Four metabolites (three corticosteroids and one androgenic steroid) were positively associated with NDV. No metabolite was associated with DV. In sensitivity analysis limited to OCP users, mean VPDs were lower but the directions of associations were similar to those observed in the overall analysis. Conclusion: We report novel associations of corticosteroids and androgen metabolites with breast density in premenopausal women. Our findings shed important new insights into hormonal biomarkers and MBD. Citation Format: Kayode A. Matthew, Girish K. Vanapali, Kayla R. Getz, Myung S. Jeon, Chongliang Luo, Xingyi Guo, Jingqin Luo, Adetunji T. Toriola. Steroid hormone metabolites and mammographic breast density in premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4431.

Abstract 3429: Using metabolomics to identify biomarkers mediating the associations of adiposity in childhood and early adulthood with mammographic breast density in premenopausal women

Abstract Introduction: Mammographic breast density (MBD), a strong predictor of breast cancer risk, is highly influenced by body mass index (BMI) in childhood and early adulthood, but the mechanisms elucidating this relationship are undetermined. To our knowledge, no study has explored the mediating role of biomarkers on the relationship between early-life adiposity and MBD. The goal of this study is to discover metabolites that mediate the relationship between BMI at ages 10 and 18 with MBD in premenopausal women. Methods: This study includes premenopausal women who had their screening mammogram at Washington University in St. Louis, MO, and provided a fasting blood sample. Metabolon performed untargeted metabolomic profiling, detecting 1,074 metabolites. Metabolites missing >300 observations were excluded, leaving 828 metabolites; the other missing values were imputed using the nearest neighbor method. To mitigate batch effect, we normalized the metabolite peak area data using ComBat. Volumetric percent density (VPD) was calculated in 700 women using Volpara software. BMI at age 10 was estimated using the Stunkard pictogram, and BMI at age 18 was calculated from self-reported weight at 18 and height at study initiation. To assess the mediating role of the 828 metabolites, we performed high dimensional mediation analysis using the hima R package adjusting for potential confounders. Missing values in the covariates and BMI measures included in the mediation analysis were imputed using multivariate imputation by chain equations. Associations were considered significant if FDR p-value <0.1. Results: Four metabolites (glutamate, beta-cryptoxanthin, phytanate, and cortolone glucuronide (1)) mediated the relationship between BMI at age 10 and VPD; and 2 metabolites (glutamate, beta-cryptoxanthin) mediated the relationship between BMI at age 18 and VPD. Glutamate and beta-cryptoxanthin significantly mediated the relationship between both BMI measures and VPD, but glutamate was the strongest mediator across both time points. Glutamate mediated 6.7% (FDR p-value=0.06) and 9.3% (FDR p-value=0.008) of the total effect between BMI at age 10 and 18, respectively, on VPD. Beta-cryptoxanthin mediated 4.1% (FDR p-value=0.06) and 6.3% (FDR p-value=0.04), of the total effect between BMI at age 10 and 18, respectively, on VPD. Additionally, phytanate mediated 2.6% (FDR p-value=0.06) and cortolone glucuronide (1) mediated 2.0% (FDR p-value=0.07) of the total effect between BMI at age 10 and VPD. Conclusion: Amino acid, lipid, cofactor/vitamin, and xenobiotic metabolites mediated the associations of BMI in early-life and VPD in premenopausal women. This innovative study offers insight into the biological mechanisms underlying the link between early-life adiposity and MBD, which can support future research into breast cancer prevention. Citation Format: Kayla R. Getz, Myung Sik Jeon, Lili Liu, Lei Liu, Chongliang Luo, Jingqin Luo, Adetunji T. Toriola. Using metabolomics to identify biomarkers mediating the associations of adiposity in childhood and early adulthood with mammographic breast density in premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3429.

Associations of Vitamins and Related Cofactor Metabolites with Mammographic Breast Density in Premenopausal Women

BackgroundIdentifying biological drivers of mammographic breast density (MBD), a strong risk factor for breast cancer, could provide insight into breast cancer etiology and prevention. Studies on dietary factors and MBD have yielded conflicting results. There are, however, very limited data on the associations of dietary biomarkers and MBD. ObjectiveWe aimed to investigate the associations of vitamins and related cofactor metabolites with MBD in premenopausal women. MethodsWe measured 37 vitamins and related cofactor metabolites in fasting plasma samples of 705 premenopausal women recruited during their annual screening mammogram at the Washington University School of Medicine, St. Louis, MO. Volpara was used to assess volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV). We estimated the least square means of VPD, DV, and NDV across quartiles of each metabolite, as well as the regression coefficient of a metabolite in continuous scale from multiple covariate-adjusted linear regression. We corrected for multiple testing using the Benjamini–Hochberg procedure to control the false discover rate (FDR) at a 5% level. ResultsParticipants’ mean VPD was 10.5%. Two vitamin A metabolites (β-cryptoxanthin and carotene diol 2) were positively associated, and one vitamin E metabolite (γ-tocopherol) was inversely associated with VPD. The mean VPD increased across quartiles of β-cryptoxanthin (Q1 = 7.2%, Q2 = 7.7%, Q3 = 8.4%%, Q4 = 9.2%; P-trend = 1.77E-05, FDR P value = 1.18E-03). There was a decrease in the mean VPD across quartiles of γ-tocopherol (Q1 = 9.4%, Q2 = 8.1%, Q3 = 8.0%, Q4 = 7.8%; P -trend = 4.01E-03, FDR P value = 0.04). Seven metabolites were associated with NDV: 3 vitamin E (γ-CEHC glucuronide, δ-CEHC, and γ-tocopherol) and 1 vitamin C (gulonate) were positively associated, whereas 2 vitamin A (carotene diol 2 and β-cryptoxanthin) and 1 vitamin C (threonate) were inversely associated with NDV. No metabolite was significantly associated with DV. ConclusionWe report novel associations of vitamins and related cofactor metabolites with MBD in premenopausal women.

Lipidome of mammographic breast density in premenopausal women

BackgroundHigh mammographic breast density (MBD) is a strong risk factor for breast cancer development, but the biological mechanisms underlying MBD are unclear. Lipids play important roles in cell differentiation, and perturbations in lipid metabolism are implicated in cancer development. Nevertheless, no study has applied untargeted lipidomics to profile the lipidome of MBD. Through this study, our goal is to characterize the lipidome of MBD in premenopausal women.MethodsPremenopausal women were recruited during their annual screening mammogram at the Washington University School of Medicine in St. Louis, MO. Untargeted lipidomic profiling for 982 lipid species was performed at Metabolon (Durham, NC®), and volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) was assessed using Volpara 1.5 (Volpara Health®). We performed multivariable linear regression models to investigate the associations of lipid species with MBD and calculated the covariate-adjusted least square mean of MBD by quartiles of lipid species. MBD measures were log10 transformed, and lipid species were standardized. Linear coefficients of MBD were back-transformed and considered significant if the Bonferroni corrected p-value was < 0.05.ResultsOf the 705 premenopausal women, 72% were non-Hispanic white, and 23% were non-Hispanic black. Mean age, and BMI were 46 years and 30 kg/m2, respectively. Fifty-six lipid species were significantly associated with VPD (52 inversely and 4 positively). The lipid species with positive associations were phosphatidylcholine (PC)(18:1/18:1), lysophosphatidylcholine (LPC)(18:1), lactosylceramide (LCER)(14:0), and phosphatidylinositol (PI)(18:1/18:1). VPD increased across quartiles of PI(18:1/18:1): (Q1 = 7.5%, Q2 = 7.7%, Q3 = 8.4%, Q4 = 9.4%, Bonferroni p-trend = 0.02). The lipid species that were inversely associated with VPD were mostly from the triacylglycerol (N = 43) and diacylglycerol (N = 7) sub-pathways. Lipid species explained some of the variation in VPD. The inclusion of lipid species increased the adjusted R2 from 0.45, for a model that includes known determinants of VPD, to 0.59.ConclusionsWe report novel lipid species that are associated with MBD in premenopausal women. Studies are needed to validate our results and the translational potential.

Abstract 4173: Lipidome of mammographic breast density in premenopausal women

Abstract Introduction: High mammographic breast density (MBD) is a strong risk factor for breast cancer, but the biological mechanisms underlying high MBD are not well understood. We, therefore, comprehensively investigated for the first time the associations of lipid species with volumetric measures of MBD to elucidate potential biological mechanisms of high MBD in premenopausal women. Methods: We performed lipidomic profiling on 705 premenopausal women recruited during their annual screening mammogram at Washington University School of Medicine, St. Louis, MO. Lipidomic profiling for 982 lipid species was completed at Metabolon (Durham, NC®). Lipid species with greater than 300 missing values (N=125) were excluded from the analysis. Using nearest neighbor methods, we imputed the lipid species missing less than 300 values. We used Volpara 1.5 (Volpara Health®) to quantify volumetric measures of MBD - volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV). We investigated the associations of the lipid species with MBD measures using multivariable linear regression models adjusting for age, age at menarche, body shape at age 10, race/ethnicity, body fat %, family history of breast cancer, oral contraceptive use, parity/age at first birth, and alcohol use. MBD measures were log10-transformed, and lipid species were standardized. Linear coefficients were back-transformed to the original scale and considered significant if the Bonferroni corrected p&amp;lt;0.05. Results: In multivariable linear regression models, 34 lipid species were inversely associated with VPD. The lipid species belong to the triacylglycerol (TAG, N=26), diacylglycerol (DAG, N=6), phosphatidylcholine (PC, N=1), and cholesterol ester (N=1) pathways. DAG(16:0/18:2) and TAG54:6-FA20:4 displayed the largest inverse associations with one standard deviation increase in DAG(16:0/18:2), and TAG54:6-FA20:4 corresponding to 9.9% (p=0.002), and 9.6% (p=0.007) decrease in VPD, respectively. Eleven lipid species were significantly associated with NDV, with 10 species (all TAG) having a positive association and 1 inverse association PC(18:1/18:1). The strongest positive association was observed with TAG54:6-FA20:4. One standard deviation increase in TAG54:6-FA20:4 was associated with a 9.8% increase in NDV (p=0.01). Several of the lipid species (N=8, 23.5%) that were associated with VPD were also associated with NDV, but in opposite directions. No lipid species were significantly associated with DV. Conclusions: Our study identified many lipid species, especially in TAG and DAG pathways, that were associated with VPD and NDV and offer new insights into the biological mechanisms underlying high MBD in premenopausal women. Future studies are needed to validate our results and the translational potential. Citation Format: Kayla R. Getz, Myung S. Jeon, Chongliang Luo, Jingqin Luo, Adetunji T. Toriola. Lipidome of mammographic breast density in premenopausal women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4173.

Family History of Breast Cancer and Mammographic Breast Density in Premenopausal Women

Family history of breast cancer (FHBC) and mammographic breast density are independent risk factors for breast cancer, but the association of FHBC and mammographic breast density in premenopausal women is not well understood. To investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements. This single-center cohort study examined 2 retrospective cohorts: a discovery set of 375 premenopausal women and a validation set of 14 040 premenopausal women. Data from women in the discovery set was collected between December 2015 and October 2016, whereas data from women in the validation set was collected between June 2010 and December 2015. Data analysis was performed between June 2018 and June 2020. Family history of breast cancer (FHBC). The primary outcomes were mammographic breast density measured quantitatively as volumetric percent density using Volpara (discovery set) and qualitatively using BI-RADS (Breast Imaging Reporting and Data System) breast density (validation set). Multivariable regressions were performed using a log-transformed normal distribution for the discovery set and a logistic distribution for the validation set. Of 14 415 premenopausal women included in the study, the discovery set and validation set had similar characteristics (discovery set with FHBC: mean [SD] age, 47.1 [5.6] years; 15 [17.2%] were Black or African American women and 64 [73.6%] were non-Hispanic White women; discovery set with no FHBC: mean [SD] age, 47.7 [4.5] years; 87 [31.6%] were Black or African American women and 178 [64.7%] were non-Hispanic White women; validation set with FHBC: mean [SD] age, 46.8 [7.3] years; 720 [33.4%] were Black or African American women and 1378 [64.0%] were non-Hispanic White women]; validation set with no FHBC: mean [SD] age, 47.5 [6.1] years; 4572 [38.5%] were Black or African American women and 6632 [55.8%] were non-Hispanic White women]). In the discovery set, participants who had FHBC were more likely to have a higher mean volumetric percent density compared with participants with no FHBC (11.1% vs 9.0%). In the multivariable-adjusted model, volumetric percent density was 25% higher (odds ratio [OR], 1.25 ;95% CI, 1.12-1.41) in women with FHBC compared with women without FHBC; and 24% higher (OR, 1.24; 95% CI, 1.10-1.40) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.40; 95% CI, 0.95-2.07) compared with women with no relatives affected. In the validation set, women with a positive FHBC were more likely to have dense breasts (BI-RADS 3-4) compared with women with no FHBC (BI-RADS 3: 41.1% vs 38.8%; BI-RADS 4: 10.5% vs 7.7%). In the multivariable-adjusted model, the odds of having dense breasts (BI-RADS 3-4) were 30% higher (OR, 1.30; 95% CI, 1.17-1.45) in women with FHBC compared with women without FHBC; and 29% higher (OR, 1.29; 95% CI, 1.14-1.45) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.38; 95% CI, 0.85-2.23) compared with women with no relatives affected. In this cohort study, having an FHBC was positively associated with mammographic breast density in premenopausal women. Our findings highlight the heritable component of mammographic breast density and underscore the need to begin annual screening early in premenopausal women with a family history of breast cancer.

Associations of Oral Contraceptives with Mammographic Breast Density in Premenopausal Women.

We investigated the associations of oral contraceptives (OC) with percent breast density (PD), absolute dense area (DA), nondense area (NDA), and a novel image intensity variation (V) measure in premenopausal women. This study included 1,233 controls from a nested case-control study within Nurses' Health Study II cohort. Information on OCs was collected in 1989 and updated biennially. OC use was defined from the questionnaire closest to the mammogram date. PD, DA, and NDA were measured from digitized film mammograms using a computer-assisted thresholding technique; the V measure was obtained with a previously developed algorithm measuring the SD of pixel values in the eroded breast region. Generalized linear regression was used to assess associations between OCs and density measures (square root-transformed PD, DA, and NDA, and -untransformed V). OC use was not associated with PD [current vs. never: β = -0.06; 95% confidence interval (CI), -0.37-0.24; past vs. never: β = 0.10; 95% CI, -0.09-0.29], DA (current vs. never: β = -0.20; 95% CI -0.59-0.18; past vs. never: β = 0.13; 95% CI, -0.12-0.39), and NDA (current vs. never: β = -0.19; 95% CI, -0.56-0.18; past vs. never: β = -0.01; 95% CI, -0.28-0.25). Women with younger age at initiation had significantly greater V-measure (<20 years vs. never: β = 26.88; 95% CI, 3.18-50.58; 20-24 years vs. never: β = 20.23; 95% CI, -4.24-44.71; 25-29 years vs. never: β = 2.61; 95% CI -29.00-34.23; ≥30 years vs. never: β = 0.28; 95% CI, -34.16-34.72, P trend = 0.03). Our findings suggest that an earlier age at first OC use was associated with significantly greater V. These findings could guide decisions about the age for OC initiation.

Does circulating progesterone mediate the associations of single nucleotide polymorphisms in progesterone receptor (PGR)-related genes with mammographic breast density in premenopausal women?

Progesterone is a proliferative hormone in the breast but the associations of genetic variations in progesterone-regulated pathways with mammographic breast density (MD) in premenopausal women and whether these associations are mediated through circulating progesterone are not clearly defined. We, therefore, investigated these associations in 364 premenopausal women with a median age of 44 years. We sequenced 179 progesterone receptor (PGR)-related single nucleotide polymorphisms (SNPs). We measured volumetric percent density (VPD) and non-dense volume (NDV) using Volpara. Linear regression models were fit on circulating progesterone or VPD/NDV separately. We performed mediation analysis to evaluate whether the effect of a SNP on VPD/NDV is mediated through circulating progesterone. All analyses were adjusted for confounders, phase of menstrual cycle and the Benjamini–Hochberg false discovery (FDR) adjusted p-value was applied to correct for multiple testing. In multivariable analyses, only PGR rs657516 had a direct effect on VPD (averaged direct effect estimate = − 0.20, 95%CI = − 0.38 ~ − 0.04, p-value = 0.02) but this was not statistically significant after FDR correction and the effect was not mediated by circulating progesterone (mediation effect averaged across the two genotypes = 0.01, 95%CI = − 0.02 ~ 0.03, p-value = 0.70). Five SNPs (PGR rs11571241, rs11571239, rs1824128, rs11571150, PGRMC1 rs41294894) were associated with circulating progesterone but these were not statistically significant after FDR correction. SNPs in PGR-related genes were not associated with VPD, NDV and circulating progesterone did not mediate the associations, suggesting that the effects, if any, of these SNPs on MD are independent of circulating progesterone.

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.

RE: Chemopreventive Agents to Reduce Mammographic Breast Density in Premenopausal Women: A Systematic Review of Clinical Trials.

RE: Chemopreventive Agents to Reduce Mammographic Breast Density in Premenopausal Women: A Systematic Review of Clinical Trials.

Chemoprevention Agents to Reduce Mammographic Breast Density in Premenopausal Women: A Systematic Review of Clinical Trials.

BackgroundHigher mammographic breast density (MBD) is associated with an increased risk of breast cancer when compared with lower MBD, especially in premenopausal women. However, little is known about the effectiveness of chemoprevention agents in reducing MBD in premenopausal women without a history of breast cancer. Findings from this review should provide insight on how to target MBD in breast cancer prevention in premenopausal women with dense breasts.MethodsWe searched 9 electronic databases for clinical trials in English, Spanish, French, or German published until January 2020. Articles evaluating the association of pharmacological agents and MBD were included. Data were extracted on methods, type and dose of intervention, outcomes, side effects, and follow up. Quality of the studies was assessed using the US Preventive Services Task Force criteria.ResultsWe identified 7 clinical trials evaluating the associations of 6 chemoprevention agents with changes in MBD in premenopausal women without history of breast cancer. The studies evaluated selective estrogen-receptor modulators (n = 1); gonadotropin-releasing hormone agonists (n = 2); isoflavones (n = 1); vitamin D (n = 1); and Boswellia, betaine, and mayo-inositol compound (n = 1). Hormonal interventions were associated with net reductions in percent density (tamoxifen [13.4%], leuprolide acetate [8.9%], and goserelin [2.7%]), whereas nonhormonal (vitamin D and isoflavone) interventions were not. However, MBD returned to preintervention baseline levels after cessation of gonadotropin-releasing hormone agonists.ConclusionsA limited number of chemoprevention agents have been shown to reduce MBD in premenopausal women. Identification of new and well-tolerated chemoprevention agents targeting MBD and larger studies to confirm agents that have been studied in small trials are urgent priorities for primary breast cancer prevention in premenopausal women with dense breasts.

Pre-Menopausal Breast Fat Density Might Predict MACE During 10 Years of Follow-Up: The BRECARD Study

ObjectivesThis study sought to determine whether the breast gland adipose tissue is associated with different rates of major adverse cardiac events (MACEs) in pre-menopausal women. BackgroundTo our knowledge, no study investigated the impact of breast adipose tissue infiltration on MACEs in pre-menopausal women. MethodsProspective multicenter cohort study conducted on pre-menopausal women >40 years of age without cardiovascular disease and breast cancer at enrollment. The study started in January 2000 and ended in January 2009, and the end of the follow-up for the evaluation of MACEs was in January 2019. Participants underwent mammography to evaluate breast density and were divided into 4 groups according to their breast density. The primary endpoint was the probability of a MACE at 10 years of follow-up in patients staged for different breast deposition/adipose tissue deposition. ResultsThe propensity score matching divided the baseline population of 16,763 pre-menopausal women, leaving 3,272 women according to the category of breast density from A to D. These women were assigned to 4 groups of the study according to baseline breast density. At 10 years of follow-up, we had 160 MACEs in group 1, 62 MACEs in group 2, 27 MACEs in group 3, and 16 MACEs in group 4. MACEs were predicted by the initial diagnosis of lowest breast density (hazard ratio: 3.483; 95% confidence interval: 1.476 to 8.257). Further randomized clinical trials are needed to translate the results of the present study into clinical practice. The loss of ex vivo breast density models to study the cellular/molecular pathways implied in MACE is another study limitation. ConclusionsAmong pre-menopausal women, a higher evidence of adipose tissue at the level of breast gland (lowest breast density, category A) versus higher breast density shows higher rates of MACEs. Therefore, the screening mammography could be proposed in overweight women to stage breast density and to predict MACEs. (Breast Density in Pre-menopausal Women Is Predictive of Cardiovascular Outcomes at 10 Years of Follow-Up [BRECARD]; NCT03779217)

Abstract P3-08-71: Medication use to reduce mammographic breast density in premenopausal women: A systematic review

Abstract Background: Mammographic breast density (MBD) is a strong modifiable risk factor for breast cancer, especially in premenopausal women. It is estimated that up to 39% of breast cancer cases in premenopausal women could potentially be prevented by reducing dense breasts to non-dense breasts. Therefore, reducing breast density through targeted interventions is an excellent opportunity to substantially reduce breast cancer incidence in premenopausal women. We performed a critical evaluation of the literature to determine the associations of chemoprevention agents use with MBD. This will guide the management of premenopausal women at risk for breast cancer. Methods: Eleven databases were searched on July 2019. We included interventional, cross-sectional, longitudinal or observational studies in Englishreporting the associations of medication with mammographic breast density in premenopausal womenwith no history of breast cancer. Two researchers extracted the data and assessed the quality of the studies. Supplements not otherwise specified were excluded. Results: After de-duplication process, 1,464 citations were screened for eligibility. Seven studies met our inclusion criteria: two observational, four randomized controlled, and one non-randomized controlled trials (RCT). There were two categories of medications: dietary supplements (i.e. vitamin D, calcium, isoflavone) and drugs (non-steroidal anti-inflammatory drugs [NSAIDs], selective estrogen receptor modulators (SERMs) goserelin, and GnRHA deslorelin acetate). In observational studies, calcium use was associated with a significant reduction in MBD, while vitamin D and NSAIDs showed no reduction6. Likewise, Isoflavone and vitamin D in doses of 1000, 2000 or 3,000IU/day were not associated with a reduction in MBD in two different RCT. Groselin, GnRHA, deslorein acetate, statins were not associated with MBD reduction in an RCT’s. SERMs (tamoxifene and raloxifene) were the only drugs associated with reductions in MBD in RCTs. Conclusions: Only a very limited number of medications (SERMs) are associated with reductions in MBD. In view of their low uptake and adherence, identifying other medications that can reduce MBD is crucial, as these could have utility in breast cancer prevention. Citation Format: Ana S. Salazar, Malika Rakhmankulova, Laura E. Simmon, Adetunji Toriola. Medication use to reduce mammographic breast density in premenopausal women: A systematic review [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 P3-08-71.

Adolescent caffeine consumption and mammographic breast density in premenopausal women.

Previous studies suggest that coffee and caffeine intake may be associated with reduced breast cancer risk. To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent caffeine intake with mammographic density in premenopausal women. This study included 751 cancer-free women within the Nurses' Health Study II cohort. Percent breast density (PD), absolute dense (DA) and non-dense areas (NDA) were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square root-transformed. Energy-adjusted adolescent caffeine intake was estimated using the data from a food frequency questionnaire. Information regarding breast cancer risk factors was obtained from questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations of caffeine intake with breast density measures. In multivariable analyses, adolescent caffeine intake was not associated with any of the density phenotypes (caffeine 4th vs. 1st quartile: β = - 1.27, 95% CI - 4.62; 2.09, p-trend = 0.55 for percent density; β = - 0.21, 95% CI - 0.76, 0.34, p-trend = 0.65 for absolute dense area, and β = 0.23, 95% CI - 0.28, 0.74, p-trend = 0.50 for non-dense area). Additional adjustment of the models for body mass index at age 18 resulted in attenuation of the risk estimates. Our findings do not support the hypothesis that adolescent caffeine intake is associated with premenopausal mammographic breast density.

Body mass index, mammographic density, and breast cancer risk by estrogen receptor subtype

BackgroundObesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status.MethodsWe conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight, < 25 kg/m2 versus overweight/obese, ≥ 25 kg/m2). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram.ResultsPercent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant (p = 0.008) interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women [OR per standard deviation increment 2.17 (95% CI 1.50–3.16) vs 1.33 (95% CI 1.11–1.61) respectively, Pheterogeneity = 0.01]. In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage.ConclusionsThe combination of overweight/obesity and elevated breast density in premenopausal women is associated with a higher risk of ER-negative compared with ER-positive cancer. Eighteen percent of premenopausal women in the USA have elevated BMI and breast density and may benefit from lifestyle modifications involving weight loss and exercise.

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.

A Randomized Double-Blind Placebo-Controlled Trial of the Effect of Vitamin D3 Supplementation on Breast Density in Premenopausal Women.

Background: This double-blind, placebo-controlled parallel group trial assessed whether oral supplementation with 1,000, 2,000, or 3,000 IU/day vitamin D3 over one year reduces percent mammographic breast density in premenopausal women.Methods: The trial was conducted between October 2012 and June 2015, among premenopausal female volunteers from Quebec City (Quebec, Canada). Women were randomized with ratio 1:1:1:1 to one of four study arms (1,000, 2,000, or 3,000 IU/day vitamin D3 or placebo). The primary outcome was mean change in percent mammographic breast density. Participants and research team were blinded to study arm assignment.Results: Participants (n = 405) were randomized to receive 1,000 (n = 101), 2,000 (n = 104), or 3,000 IU/day (n = 101) vitamin D3, or a placebo (n = 99). The primary analysis included 391 participants (96, 99, 100, and 96, respectively). After the one-year intervention, mean ± SE change in percent breast density in the arms 1,000 IU/day (-5.5% ± 0.5%) and 2,000 IU/day (-5.9% ± 0.5%) vitamin D3 was similar to that in the placebo arm (-5.7% ± 0.5%) (P values = 1.0). In the 3,000 IU/day vitamin D3 arm, percent breast density also declined but slightly less (-3.8% ± 0.5%) compared with placebo arm (P = 0.03). Adherence to intervention was excellent (92.8%), and reporting of health problems was comparable among study arms (P ≥ 0.95). All participants had normal serum calcium.Conclusions: In premenopausal women, one-year supplementation with 1,000, 2,000, or 3,000 IU/day vitamin D3 resulted in a reduction of percent breast density no greater than that seen with the placebo.Impact: At doses of 1,000-3,000 IU/day, vitamin D supplementation will not reduce breast cancer risk through changes in breast density. Cancer Epidemiol Biomarkers Prev; 26(8); 1233-41. ©2017 AACR.

Sample size and power determination when limited preliminary information is available

BackgroundWe describe a novel strategy for power and sample size determination developed for studies utilizing investigational technologies with limited available preliminary data, specifically of imaging biomarkers. We evaluated diffuse optical spectroscopic imaging (DOSI), an experimental noninvasive imaging technique that may be capable of assessing changes in mammographic density. Because there is significant evidence that tamoxifen treatment is more effective at reducing breast cancer risk when accompanied by a reduction of breast density, we designed a study to assess the changes from baseline in DOSI imaging biomarkers that may reflect fluctuations in breast density in premenopausal women receiving tamoxifen.MethodWhile preliminary data demonstrate that DOSI is sensitive to mammographic density in women about to receive neoadjuvant chemotherapy for breast cancer, there is no information on DOSI in tamoxifen treatment. Since the relationship between magnetic resonance imaging (MRI) and DOSI has been established in previous studies, we developed a statistical simulation approach utilizing information from an investigation of MRI assessment of breast density in 16 women before and after treatment with tamoxifen to estimate the changes in DOSI biomarkers due to tamoxifen.ResultsThree sets of 10,000 pairs of MRI breast density data with correlation coefficients of 0.5, 0.8 and 0.9 were simulated and generated and were used to simulate and generate a corresponding 5,000,000 pairs of DOSI values representing water, ctHHB, and lipid. Minimum sample sizes needed per group for specified clinically-relevant effect sizes were obtained.ConclusionThe simulation techniques we describe can be applied in studies of other experimental technologies to obtain the important preliminary data to inform the power and sample size calculations.

Adolescent fiber intake and mammographic breast density in premenopausal women.

BackgroundTo date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent fiber intake with mammographic density in premenopausal women.MethodsThis study included 743 cancer-free premenopausal women (mean age, 44.9 years) within the Nurses’ Health Study II cohort. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique. Adolescent and adult diet were assessed with a food frequency questionnaire; energy-adjusted nutrient intakes were estimated for each food item. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusted for potential confounders. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber (fruits, vegetables, and nuts).ResultsIn multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of fiber from fruits, vegetables, legumes, or cereal nor specific sources of fiber intake (fruits, vegetables, or nuts) during adolescence were associated with any of the mammographic density phenotypes.ConclusionsOur findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic breast density.