Habitual Phytoestrogen Intake Is Associated with Breast Composition in Girls at 2 Years after Menarche Onset.

BACKGROUND: High phytoestrogen intake during adolescence is associated with a reduced risk of breast cancer. Breast density (BD) is a strong predictor of breast cancer and can be considered an early marker. We aim to assess the association between the mean habitual intake of isoflavones, lignans, and total phytoestrogens intake during puberty until 2 years after menarche onset and absolute fibroglandular volume (AFGV) and percentage of fibroglandular volume (%FGV) in Hispanic girls at the end of puberty. METHODS: Longitudinal study set up in the Growth and Obesity Chilean Cohort Study (GOCS). We included 329 girls with dietary data (multiple 24-hours recalls) from puberty until 2 years after menarche onset (81% had 2-4 recalls). Two international datasets were used to estimate isoflavones, lignans, and total phytoestrogens in the diet. Breast composition was measured by dual energy X-ray absorptiometry at 2 years after menarche. Multiple linear regression models were used to assess the association between isoflavones, lignans, and total phytoestrogens intake and AFGV and %FGV. RESULTS: The average total phytoestrogen intake was 1 mg/day and %FGV was 50.7% (SD = 15.2) and AFGV 218.8 cm3 (SD = 79.3). An inverse association was found between consumption of isoflavones and AFGV, as well as, with total phytoestrogens [Q4 vs. Q1 adjusted model ß = -49.2 cm3; 95% CI (-85.5 to -13.0)]. CONCLUSIONS: Girls with a higher intake of total phytoestrogens and isoflavones during puberty until 2 years after menarche onset had significantly lower AFGV. IMPACT: Although the intake of phytoestrogens is low in Western populations, higher consumption of them during a critical period of life like puberty could be beneficial to reduce breast cancer during adulthood.

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 (ß = 1.06; 95% CI = 0.93-1.21; p-trend = 0.61) and caffeinated tea: ≥1 time/day (ß = 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 (ß = 1.22; 95% CI = 1.06-1.39) but not in African American women (ß = 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 (ß = 1.52; 95% CI = 1.11-2.07) but not in NHW women (ß = 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.

Efficient focusing of microwave hyperthermia for small deep-seated breast tumors treatment using particle swarm optimization.

Focused microwave hyperthermia is a technique with advantage of high accuracy and low side effects for breast tumor treatments. In this study, an efficient focusing technique for noninvasive microwave hyperthermia treatment for breast tumors is presented. Particle Swarm Optimization (PSO) is used to find the optimum excitations (phases and amplitudes) of a three dimension (3D) Micro-Strip Patch (MSP) antenna array operating at 2.45 GHz. The antenna excitations are optimized to maximize the power loss density and the Specific Absorption Rate (SAR) at the tumor location, to reach the required hyperthermia temperature (above 42 °C) at the tumor location without causing hot spots in healthy tissues. The technique is tested on a challenging scenario of a 3D realistic breast model having a tumor less than 1 cm3 volume and embedded in different locations deep in the glandular tissue of a very dense breast. The results confirmed the capability of the focusing technique.

The Influence of Vitamin D on Mammographic Density: Results from CALGB 70806 (Alliance) a Randomized Clinical Trial.

Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. -1.6 ng/mL; P < 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was -0.75 (-0.26, 1.76; P = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). PREVENTION RELEVANCE: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects.

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

Background: Higher 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. Methods: We 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. Results: We 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. Conclusions: A 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.

Association of breast cancer with MRI background parenchymal enhancement: the IMAGINE case-control study.

BACKGROUND: Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. METHODS: The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years' experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. RESULTS: The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1/BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05-2.11; p = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92-2.27; p = 0.1). CONCLUSIONS: BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.

YY1 is a cis-regulator in the organoid models of high mammographic density.

MOTIVATION: Our previous study has shown that ERBB2 is overexpressed in the organoid model of MCF10A when the stiffness of the microenvironment is increased to that of high mammographic density (MD). We now aim to identify key transcription factors (TFs) and functional enhancers that regulate processes associated with increased stiffness of the microenvironment in the organoid models of premalignant human mammary cell lines. RESULTS: 3D colony organizations and the cis-regulatory networks of two human mammary epithelial cell lines (184A1 and MCF10A) are investigated as a function of the increased stiffness of the microenvironment within the range of MD. The 3D colonies are imaged using confocal microscopy, and the morphometries of colony organizations and heterogeneity are quantified as a function of the stiffness of the microenvironment using BioSig3D. In a surrogate assay, colony organizations are profiled by transcriptomics. Transcriptome data are enriched by correlative analysis with the computed morphometric indices. Next, a subset of enriched data are processed against publicly available ChIP-Seq data using Model-based Analysis of Regulation of Gene Expression to predict regulatory transcription factors. This integrative analysis of morphometric and transcriptomic data predicted YY1 as one of the cis-regulators in both cell lines as a result of the increased stiffness of the microenvironment. Subsequent experiments validated that YY1 is expressed at protein and mRNA levels for MCF10A and 184A1, respectively. Also, there is a causal relationship between activation of YY1 and ERBB2 when YY1 is overexpressed at the protein level in MCF10A. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Omega-3 Fatty Acids Responsive Proteins and Reduction in Breast Density in Obese Postmenopausal Women.

We reported that breast density (BD) was inversely correlated with the plasma level of DHA in postmenopausal obese, but not in nonobese, women given Lovaza (n-3FA). To identify protein biomarkers for the possible differential effect of n-3FA on BD between obese and nonobese women, an iTRAQ method was performed to analyze plasma from obese and lean women at each time point (baseline, 12 and 24-months, n = 10 per group); 173 proteins with >95% confidence (Unuses Score >1.3 and local false discovery rate estimation <5%) were identified. Comparative analysis between various groups identified several differentially expressed proteins (hemopexin precursor, vitamin D binding protein isoform 1 precursor [VDBP], fibronectin isoform 10 precursor [FN], and α-2 macroglobulin precursor [A2M]). Western blot analysis was performed to verify the differential expression of proteins in the iTRAQ study, and those found to be altered in a tumor protective fashion by an n-3FA rich diet in our previous preclinical study; gelsolin, VDBP, and FN were altered by n-3FA in a manner consistent with reduction in inflammation in obese women. To test the impact of our findings on breast cancer risk reduction by n-3FA, a posthoc analysis revealed that n-3FA administration reduced BD selectively in obese postmenopausal women.

Effect of oral phytoestrogens on endometrial thickness and breast density of perimenopausal and postmenopausal women: A systematic review and meta-analysis.

BACKGROUND: Phytoestrogens constitute an alternative, non-pharmacologic approach for the management of menopausal symptoms. However, few studies have focused on their safety, specifically in relation to endometrial thickness and breast density. AIM: To systematically search for and quantitatively synthesize the evidence regarding the effect of phytoestrogens on endometrial thickness and breast density in perimenopausal and postmenopausal women. METHODS: Randomized controlled trials (RCTs) examining the effect of phytoestrogens compared with placebo or menopausal hormone therapy (MHT) on endometrial thickness and/or breast density in perimenopausal or postmenopausal women were searched for in the MEDLINE, CENTRAL and Scopus databases as well as "gray literature" sources until October 31, 2018. Main outcomes were the change from baseline in endometrial thickness and breast density. Statistical analysis was performed with RevMan 5.3, using R language and Open Meta-Analyst software. RESULTS: The meta-analysis for endometrial thickness included 30 RCTs (with a total of 3497 women), and that for breast density four RCTs (with a total of 674 women). Phytoestrogens did not affect endometrial thickness compared with placebo [weighted mean difference (WMD) -0.04 mm, 95% confidence interval (CI) -0.18 to 0.11, I2 66%] or MHT (WMD -1.40 mm, 95% CI -2.98 to 0.18, I2 84%). In addition, phytoestrogens did not affect breast density compared with placebo [standardized mean difference (SMD) -0.76, 95% CI -1.54 to 0.2, I2 95%). CONCLUSION: Phytoestrogens have no effect on endometrial thickness or breast density, when administered at various doses and for various durations, in perimenopausal and postmenopausal women. However, the high heterogeneity of the studies makes it necessary to conduct RCTs with less risk of systematic error.

Effects of isoflavones on breast tissue and the thyroid hormone system in humans: a comprehensive safety evaluation.

Isoflavones are secondary plant constituents of certain foods and feeds such as soy, linseeds, and red clover. Furthermore, isoflavone-containing preparations are marketed as food supplements and so-called dietary food for special medical purposes to alleviate health complaints of peri- and postmenopausal women. Based on the bioactivity of isoflavones, especially their hormonal properties, there is an ongoing discussion regarding their potential adverse effects on human health. This review evaluates and summarises the evidence from interventional and observational studies addressing potential unintended effects of isoflavones on the female breast in healthy women as well as in breast cancer patients and on the thyroid hormone system. In addition, evidence from animal and in vitro studies considered relevant in this context was taken into account along with their strengths and limitations. Key factors influencing the biological effects of isoflavones, e.g., bioavailability, plasma and tissue concentrations, metabolism, temporality (pre- vs. postmenopausal women), and duration of isoflavone exposure, were also addressed. Final conclusions on the safety of isoflavones are guided by the aim of precautionary consumer protection.

The Effect of Vitamin D Supplementation on Breast Density Changes: A Clinical Trial Study.

The aim of this study was to determine the effect of supplementation with 50,000 IU/monthly vitamin D for 1 yr on breast density in Iranian women. METHODS: This double-blind, placebo-controlled, single center clinical trial was conducted among 400 women aged 40 yr and older. Participants were allocated to 2 groups. Group 1 received vitamin D (Cholecalciferol) 50,000 IU in tablet form, monthly, for 1 yr. Group 2 received vitamin E 400 IU in tablet form, monthly, for the same period of time. Participants had follow-up clinic visits every 6 mo and received an annual mammogram. RESULTS: Final data were evaluated based on 216 and 194 women in the vitamin D and control groups. The mean decrease in mammographic density was -5.01%(95% CI, -9.9% to -0.01%) and -2.34 %(95% CI, -6.84% to -2.15%) in the vitamin D and control groups, respectively. There was no significant association between vitamin D consumption and breast density after 1 yr (OR = 0.7, 95% CI, 0.46 to 1.06; P = 0.1).Similar results were observed when multivariate model of logistic regression analysis was performed. CONCLUSIONS: This study showed that monthly consumption of 50,000 IU of vitamin D supplementation for 1 yr did not affect breast density.

Associations of coffee consumption and caffeine intake with mammographic breast density.

PURPOSE: Previous studies suggest that coffee and caffeine intake may be associated with reduced breast cancer risk. We investigated the association of coffee and caffeine intake with mammographic breast density by woman's menopausal status and, in postmenopausal women, by hormone therapy (HT). METHODS: This study included 4130 cancer-free women within the Nurses' Health Study and Nurses' Health Study II cohorts. Percent breast density (PD) was measured from digitized film mammograms using a computer-assisted thresholding technique and square root-transformed for the analysis. Average cumulative coffee/caffeine consumption was calculated using data from all food frequency questionnaires preceding the mammogram date. Information regarding breast cancer risk factors was obtained from questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations of regular, decaffeinated, and total coffee, and energy-adjusted caffeine intake with percent density. RESULTS: In multivariable analyses, decaffeinated coffee was positively associated with PD in premenopausal women (2+ cups/day: ß = 0.23, p trend = 0.03). In postmenopausal women, decaffeinated and total coffee were inversely associated with PD (decaffeinated 2+ cups/day: ß = - 0.24, p trend = 0.04; total 4+ cups/day: ß = - 0.16, p trend = 0.02). Interaction of decaffeinated coffee with menopausal status was significant (p-interaction < 0.001). Among current HT users, regular coffee and caffeine were inversely associated with PD (regular coffee 4+ cups/day: ß = - 0.29, p trend = 0.01; caffeine 4th vs. 1st quartile: ß = - 0.32, p trend = 0.01). Among past users, decaffeinated coffee was inversely associated with PD (2+ cups/day ß = - 0.70, p trend = 0.02). CONCLUSIONS: Associations of decaffeinated coffee with percent density differ by woman's menopausal status. Associations of regular coffee and caffeine with percent density may differ by HT status.

A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer.

Epidemiologic and animal studies suggest a protective role of green tea against breast cancer. However, the underlying mechanism is not understood. We conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density (MD), as a potential mechanism, involving 1,075 healthy postmenopausal women. Women assigned to the treatment arm consumed daily 4 decaffeinated GTE capsules containing 1,315 mg total catechins, including 843 mg epigallocatechin-3-gallate (EGCG) for 12 months. A computer-assisted method (Madena) was used to assess MD in digital mammograms at baseline and month 12 time points in 932 completers (462 in GTE and 470 in placebo). GTE supplementation for 12 months did not significantly change percent MD (PMD) or absolute MD in all women. In younger women (50-55 years), GTE supplementation significantly reduced PMD by 4.40% as compared with the placebo with a 1.02% PMD increase from pre- to postintervention (P = 0.05), but had no effect in older women (Pinteraction = 0.07). GTE supplementation did not induce MD change in other subgroups of women stratified by catechol-O-methyltransferase genotype or level of body mass index. In conclusion, 1-year supplementation with a high dose of EGCG did not have a significant effect on MD measures in all women, but reduced PMD in younger women, an age-dependent effect similar to those of tamoxifen. Further investigation of the potential chemopreventive effect of green tea intake on breast cancer risk in younger women is warranted. Cancer Prev Res; 10(12); 710-8. ©2017 AACR.

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.

A web-based personalized risk communication and decision-making tool for women with dense breasts: Design and methods of a randomized controlled trial within an integrated health care system.

BACKGROUND: Mammographic breast density is one of the strongest risk factors for breast cancer after age and family history. Mandatory breast density disclosure policies are increasing nationally without clear guidance on how to communicate density status to women. Coupling density disclosure with personalized risk counseling and decision support through a web-based tool may be an effective way to allow women to make informed, values-consistent risk management decisions without increasing distress. METHODS/DESIGN: This paper describes the design and methods of Engaged, a prospective, randomized controlled trial examining the effect of online personalized risk counseling and decision support on risk management decisions in women with dense breasts and increased breast cancer risk. The trial is embedded in a large integrated health care system in the Pacific Northwest. A total of 1250 female health plan members aged 40-69 with a recent negative screening mammogram who are at increased risk for interval cancer based on their 5-year breast cancer risk and BI-RADS® breast density will be randomly assigned to access either a personalized web-based counseling and decision support tool or standard educational content. Primary outcomes will be assessed using electronic health record data (i.e., chemoprevention and breast MRI utilization) and telephone surveys (i.e., distress) at baseline, six weeks, and twelve months. DISCUSSION: Engaged will provide evidence about whether a web-based personalized risk counseling and decision support tool is an effective method for communicating with women about breast density and risk management. An effective intervention could be disseminated with minimal clinical burden to align with density disclosure mandates. Clinical Trials Registration Number:NCT03029286.

Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women.

BACKGROUND/OBJECTIVES: Conversion of saturated fatty acids to monounsaturated fatty acids by the enzyme stearoyl-Co-A-desaturase (SCD-1) is emerging as a major factor in promoting carcinogenesis including breast cancer. The aim of our study was to explore the regulation of SCD-1 by Raloxifene and omega-3 fatty acids in women at increased risk of breast cancer based on high breast density. SUBJECTS/METHODS: As a reflection of SCD-1 activity, we measured the ratios of palmitoleic acid (C16:1n7) to palmitic acid (C16:0) (SCD-16) and oleic acid (C18:1n9) to steric acid (C18:0) (SCD-18) in plasma samples of postmenopausal women enrolled in our clinical trial (NCT00723398) designed to test the effects of the antiestrogen, Raloxifene and/or the omega-3 preparation Lovaza, on breast density, a validated biomarker of breast cancer risk. RESULTS: We report that Lovaza but not Raloxifene-reduced SCD-16 and SCD-18 for the 2-year duration of the trial. Importantly, decreasing levels of SCD-16 and SCD-18 were associated with a progressive reduction in breast density but only in obese women (body mass index ⩾30). CONCLUSIONS: Body mass index-related factors play an important role in the reduction of breast density and hence breast cancer risk by omega-3 fatty acids. SCD-1 may be a useful biomarker in future clinical trials testing the benefit of nutritional interventions in reducing obesity-associated breast cancer risk.

The Effect of California's Breast Density Notification Legislation on Breast Cancer Screening.

PURPOSE: Half of US states mandate women be notified if they have dense breasts on their mammogram, yet guidelines and data on supplemental screening modalities are limited. Breast density (BD) refers to the extent that breast tissue appears radiographically dense on mammograms. High BD reduces the sensitivity of screening mammography and increases breast cancer risk. The aim of this study was to determine the potential impact of California's 2013 BD notification legislation on breast cancer screening patterns. METHODS: We conducted a cohort study of women aged 40 to 74 years who were members of a large Northern California integrated health plan (approximately 3.9 million members) in 2011-2015. We calculated pre- and post-legislation rates of screening mammography and magnetic resonance imaging (MRI). We also examined whether women with dense breasts (defined as BI-RADS density c or d) had higher MRI rates than women with nondense breasts (defined as BI-RADS density a or b). RESULTS: After adjustment for race/ethnicity, age, body mass index, medical facility, neighborhood median income, and cancer history, there was a relative 6.6% decrease (relative risk [RR] 0.934, confidence interval [CI] 0.92-0.95) in the rate of screening mammography, largely driven by a decrease among women <50 years. While infrequent, there was a relative 16% increase (RR 1.16, CI 1.07-1.25) in the rate of screening MRI, with the greatest increase among the youngest women. In the postlegislation period, women with extremely dense breasts (BI-RADS d) had 2.77 times (CI 1.93-3.95) the odds of a MRI within 9 months of a screening mammogram compared with women with nondense breasts (BI-RADS b). CONCLUSIONS: In this setting, MRI rates increased in the postlegislation period. In addition, women with higher BD were more likely to have supplementary MRI. The decrease in mammography rates seen primarily among younger women may have been due to changes in national screening guidelines.

Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet: A Systematic Review.

Background Lower breast density (BD) is associated with lower risk of breast cancer and may serve as a biomarker for the efficacy of chemopreventive strategies. This review explores parameters that are thought to be associated with lower BD. We conducted a systematic review of articles published to date using the PRISMA strategy. Articles that assessed change in BD with estrogen-receptor modulators (tamoxifene [TAM], raloxifene [RLX], and tibolone) and aromatase inhibitors (AIs), as well as cross-sectional and longitudinal studies (LSs) that assessed association between BD and physical activity (PA) or diet were reviewed. Results Ten studies assessed change in BD with TAM; all reported TAM-mediated BD decreases. Change in BD with RLX was assessed by 11 studies; 3 reported a reduction in BD. Effect of tibolone was assessed by 5 RCTs; only 1 reported change in BD. AI-mediated BD reduction was reported by 3 out of 10 studies. The association between PA and BD was assessed by 21 studies; 4 reported an inverse association. The relationship between diet and BD was assessed in 34 studies. All studies on calcium and vitamin D as well as vegetable intake reported an inverse association with BD in premenopausal women. Two RCTs demonstrated BD reduction with a low-fat, high-carbohydrate intervention. Conclusion TAM induces BD reduction; however, the effect of RLX, tibolone, and AIs on BD is unclear. Although data on association between diet and BD in adulthood are contradictory, intake of vegetables, vitamin D, and calcium appear to be associated with lower BD in premenopausal women.

Influence of Obesity on Breast Density Reduction by Omega-3 Fatty Acids: Evidence from a Randomized Clinical Trial.

Preclinical data indicate that omega-3 fatty acids (n-3FA) potentiate the chemopreventive effect of the antiestrogen (AE) tamoxifen against mammary carcinogenesis. The role of n-3FA in breast cancer prevention in humans is controversial. Preclinical and epidemiologic data suggest that n-3FA may be preferentially protective in obese subjects. To directly test the protective effect of n-3FA against breast cancer, we conducted a 2-year, open-label randomized clinical trial in 266 healthy postmenopausal women (50% normal weight, 30% overweight, 20% obese) with high breast density (BD; ≥25%) detected on their routine screening mammograms. Eligible women were randomized to one of the following five groups (i) no treatment, control; (ii) raloxifene 60 mg; (iii) raloxifene 30 mg; (iv) n-3FA lovaza 4 g; and (v) lovaza 4 g plus raloxifene 30 mg. The 2-year change in BD, a validated biomarker of breast cancer risk, was the primary endpoint of the study. In subset analysis, we tested the prespecified hypothesis that body mass index (BMI) influences the relationship between plasma n-3FA on BD. While none of the interventions affected BD in the intention-to-treat analysis, increase in plasma DHA was associated with a decrease in absolute breast density but only in participants with BMI >29. Our results suggest that obese women may preferentially experience breast cancer risk reduction from n-3FA administration.

An association of boswellia, betaine and myo-inositol (Eumastós) in the treatment of mammographic breast density: a randomized, double-blind study.

OBJECTIVE: Mammographic breast density is a recognized risk factor for breast cancer. The causes that lead to the proliferation of the glandular breast tissue and, therefore, to an increase of breast density are still unclear. However, a treatment strategy to reduce the mammary density may bring about very relevant clinical outcomes in breast cancer prevention. Myo-inositol is a six-fold alcohol of cyclohexane, has already been proved to modulate different pathways: inflammatory, metabolic, oxidative and endocrine processes, in a wide array of human diseases, including cancer and the genesis of mammary gland and breast diseases, like fibrosis, as well as metabolic and endocrine cues. Similarly, boswellic acid and betaine (three-methyl glycine) both inhibit inflammation and exert protective effects on breast physiology. Based on this scientific background, we hypothesized that a combination including, boswellic acid, betaine and myo-inositol would be able to reduce breast density working on different pathways. PATIENTS AND METHODS: In this study, seventy-six premenopausal women were randomly assigned to the placebo and the experimental drug arms (Eumastós) for six months. RESULTS: After 6 months of treatment, statistically significant difference between the two groups was recorded on the breast density reduction (60% vs. 9%), using mammographic as well as ultrasound examination. CONCLUSIONS: Preliminary data collected here with support the starting assumptions, that the association comprising boswellic acid, betaine and myo-inositol significantly reduces mammary density, providing the first evidence for a new and safe approach for the management of mammographic density treatment.