Biomarkers of mammographic density in premenopausal women.
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ABSTRACT: Background
While mammographic density is one of the strongest risk factors for breast cancer, little is known about its determinants, especially in young women. We applied targeted metabolomics to identify circulating metabolites specifically associated with mammographic density in premenopausal women. Then, we aimed to identify potential correlates of these biomarkers to guide future research on potential modifiable determinants of mammographic density.Methods
A total of 132 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids, hexose) were measured by tandem liquid chromatography/mass spectrometry in plasma samples from 573 premenopausal participants in the Mexican Teachers' Cohort. Associations between metabolites and percent mammographic density were assessed using linear regression models, adjusting for breast cancer risk factors and accounting for multiple tests. Mean concentrations of metabolites associated with percent mammographic density were estimated across levels of several lifestyle and metabolic factors.Results
Sphingomyelin (SM) C16:1 and phosphatidylcholine (PC) ae C30:2 were inversely associated with percent mammographic density after correction for multiple tests. Linear trends with percent mammographic density were observed for SM C16:1 only in women with body mass index (BMI) below the median (27.4) and for PC ae C30:2 in women with a BMI over the median. SM C16:1 and PC ae C30:2 concentrations were positively associated with cholesterol (total and HDL) and inversely associated with number of metabolic syndrome components.Conclusions
We identified new biomarkers associated with mammographic density in young women. The association of these biomarkers with mammographic density and metabolic parameters may provide new perspectives to support future preventive actions for breast cancer.
SUBMITTER: His M
PROVIDER: S-EPMC8305592 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Prior research suggests that several endogenous hormones in premenopausal women are associated with breast cancer risk; however, few studies have evaluated associations of endogenous hormones with mammographic density (MD) in premenopausal women. We conducted a cross-sectional study of plasma hormone levels in relation to MD among 634 cancer-free premenopausal women in the Nurses' Health Study II. We measured percent MD from screening mammograms using a computer-assisted method. We assayed estradiol, estrone, and estrone sulfate in blood samples timed in early follicular and mid-luteal phases of the menstrual cycle as well as testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, sex hormone-binding globulin (SHBG), and anti-Müllerian hormone in luteal or untimed samples. We used multivariable linear regression to quantify the association of %MD with quartiles of each hormone, adjusting for age, body mass index, and breast cancer risk factors. Women in the highest quartile of follicular estradiol levels had significantly greater %MD compared to those in the lowest quartile [difference, 6.7 percentage points; 95% confidence interval (CI) 2.2, 11.3; p-trend?<?0.001]. Similar associations were observed for follicular free estradiol but not luteal-phase estradiol. Also, women in the top (vs. bottom) quartile of free testosterone had significantly lower %MD (difference, -?4.7; 95% CI -?8.7, -?0.8; p-trend?=?0.04). Higher SHBG was significantly associated with higher percent MD (difference, 4.8; 95% CI 1.1, 8.6; p-trend?=?0.002). Percent MD was not strongly associated with other measured hormones. Results were similar in analyses that excluded women with anovulatory cycles. Our findings suggest that follicular estradiol and SHBG may play an important role in premenopausal percent MD.
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Project description:PurposeMammographic density is a strong risk factor for breast cancer. Although diet is associated with breast cancer risk, there are limited studies linking adult diet, including milk intake, with mammographic density. Here, we investigate the association of milk intake with mammographic density in premenopausal women.MethodsWe analyzed data from 375 cancer-free premenopausal women who had routine screening mammography at Washington University School of Medicine, St. Louis, Missouri in 2016. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. We collected information on recent milk intake (past 12 months), and categorized skim milk and low/reduced-fat milk intake into 4 groups: < 1/week, 1/week, 2-6 times/week, ≥ 1/day, while whole and soy milk intake were categorized into 2 groups: < 1/week, ≥ 1/week. We used multivariable linear regression model to evaluate the associations of milk intake and log-transformed volumetric percent density, dense volume, and non-dense volume.ResultsIn multivariable analyses, volumetric percent density was 20% (p-value = 0.003) lower in the 1/week group, 14% (p-value = 0.047) lower in the 2-6/week group, and 12% (p-value = 0.144) lower in the ≥ 1/day group (p-trend = 0.011) compared with women who consumed low/reduced-fat milk < 1/week. Attenuated and non-significant associations were observed for low/reduced-fat milk intake and dense volume. There were no associations of whole, skim, and soy milk intake with volumetric percent density and dense volume.ConclusionsRecent low/reduced-fat milk intake was inversely associated with volumetric percent density in premenopausal women. Studies on childhood and adolescent milk intake and adult mammographic density in premenopausal women are needed.
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Project description:PURPOSE:Consumption of alcoholic beverages during adolescence and early adulthood has been consistently associated with higher breast cancer risk. The influence of alcohol consumption early in life on mammographic breast density, a marker of breast cancer risk, is inconclusive. This study examined associations of alcohol consumption across the life course with premenopausal mammographic density. METHODS:The study population included 1211 premenopausal women in the Nurses' Health Study II without cancer, who recalled their alcohol consumption at age 15 through enrollment in 1989 (baseline), and had mammograms available. Recent alcohol consumption was updated over follow-up. Percent and absolute measures of mammographic density were quantified on digitized film mammograms. Generalized linear regression was used to assess associations. RESULTS:There were no notable differences in any of the three density measures for alcohol consumption at any age (15-17, 18-22, 23-30, and 31-mammogram). Neither alcohol consumption before first pregnancy nor after first pregnancy was significantly associated with any of the three density measures. CONCLUSIONS:Moderate alcohol consumption during different age intervals during adolescence and early adulthood was not associated with mammographic density in premenopausal women.
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Project description:ImportanceFamily 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.ObjectivesTo investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements.Design, setting, and participantsThis 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.ExposuresFamily history of breast cancer (FHBC).Main outcomes and measuresThe 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.ResultsOf 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.Conclusions and relevanceIn 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.
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Project description:Mammographic density is a strong and independent risk factor for breast cancer and is considered an intermediate marker of risk. The major predictors of premenopausal mammographic density, however, have yet to be fully elucidated. To test the hypothesis that urinary estrogen metabolism profiles are associated with mammographic density, we conducted a cross-sectional study among 352 premenopausal women in the Nurses' Health Study II (NHSII). We measured average percent mammographic density using a computer-assisted method. In addition, we assayed 15 estrogens and estrogen metabolites (jointly termed EM) in luteal-phase urine samples. We used multivariable linear regression to quantify the association of average percent density with quartiles of each individual EM as well as the sum of all EM (total EM), EM groups defined by metabolic pathway, and pathway ratios. In multivariable models controlling for body mass index and other predictors of breast density, women in the top quartile of total EM had an average percent density 3.4 percentage points higher than women in the bottom quartile (95 % confidence interval: -1.1, 8.0; p trend = 0.08). A non-significant positive association was noted for the 2-hydroxylation pathway catechols (breast density was 4.0 percentage points higher in top vs. bottom quartile; p trend = 0.06). In general, we observed no associations with parent estrogens or the 4- or 16-hydroxylation pathways or pathway ratios. These results suggest that urinary luteal estrogen profiles are not strongly associated with premenopausal mammographic density. If these profiles are associated with breast cancer risk, they may not act through influences on breast density.
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Project description: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. 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. 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. 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.
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Project description:The receptor activator of nuclear factor-?B (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (P trend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (P trend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (P trend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.
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Project description:Background A decrease in breast density due to tamoxifen preventive therapy might indicate greater benefit from the drug. It is not known whether mammographic density continues to decline after 1 year of therapy, or whether measures of breast density change are sufficiently stable for personalised recommendations. Methods Mammographic density was measured annually over up to 5 years in premenopausal women with no previous diagnosis of breast cancer but at increased risk of breast cancer attending a family-history clinic in Manchester, UK (baseline 2010-2013). Tamoxifen (20 mg/day) for prevention was prescribed for up to 5 years in one group; the other group did not receive tamoxifen and were matched by age. Fully automatic methods were used on mammograms over the 5-year follow-up: three area-based measures (NN-VAS, Stratus, Densitas) and one volumetric (Volpara). Additionally, percentage breast density at baseline and first follow-up mammograms was measured visually. The size of density declines at the first follow-up mammogram and thereafter was estimated using a linear mixed model adjusted for age and body mass index. The stability of density change at 1 year was assessed by evaluating mean squared error loss from predictions based on individual or mean density change at 1 year. Results Analysis used mammograms from 126 healthy premenopausal women before and as they received tamoxifen for prevention (median age 42 years) and 172 matched controls (median age 41 years), with median 3 years follow-up. There was a strong correlation between percentage density measures used on the same mammogram in both the tamoxifen and no tamoxifen groups (all correlation coeficients > 0.8). Tamoxifen reduced mean breast density in year 1 by approximately 17–25% of the inter-quartile range of four automated percentage density measures at baseline, and from year 2, it decreased further by approximately 2–7% per year. Predicting change at 2 years using individual change at 1 year was approximately 60–300% worse than using mean change at 1year. Conclusions All measures showed a consistent and large average tamoxifen-induced change in density over the first year, and a continued decline thereafter. However, these measures of density change at 1 year were not stable on an individual basis.
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