We investigated whether the gut microbiota differed in 48 postmenopausal breast cancer case patients, pretreatment, vs 48 control patients. Microbiota profiles in fecal DNA were determined by ...Illumina sequencing and taxonomy of 16S rRNA genes. Estrogens were quantified in urine. Case-control comparisons employed linear and unconditional logistic regression of microbiota α-diversity (PD_whole tree) and UniFrac analysis of β-diversity, with two-sided statistical tests. Total estrogens correlated with α-diversity in control patients (Spearman Rho = 0.37, P = .009) but not case patients (Spearman Rho = 0.04, P = .77). Compared with control patients, case patients had statistically significantly altered microbiota composition (β-diversity, P = .006) and lower α-diversity (P = .004). Adjusted for estrogens and other covariates, odds ratio of cancer was 0.50 (95% confidence interval = 0.30 to 0.85) per α-diversity tertile. Differences in specific taxa were not statistically significant when adjusted for multiple comparisons. This pilot study shows that postmenopausal women with breast cancer have altered composition and estrogen-independent low diversity of their gut microbiota. Whether these affect breast cancer risk and prognosis is unknown.
Esophageal adenocarcinoma (EA) is characterized by a strong male predominance. Sex steroid hormones have been hypothesized to underlie this sex disparity, but no population-based study to date has ...examined this potential association.
Using mass spectrometry and ELISA, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in plasma from males- 172 EA cases and 185 controls-within the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study, a case-control investigation conducted in Northern Ireland and Ireland. Multivariable adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA.
Higher androgen:estrogen ratio metrics were associated with increased odds of EA (e.g., testosterone:estradiol ratio ORQ4 v. Q1 = 2.58, 95%CI = 1.23-5.43; Ptrend = 0.009). All estrogens and androgens were associated with significant decreased odds of EA. When restricted to individuals with minimal to no decrease in body mass index, the size of association for the androgen:estrogen ratio was not greatly altered.
This first study of sex steroid hormones and EA provides tentative evidence that androgen:estrogen balance may be a factor related to EA. Replication of these findings in prospective studies is needed to enhance confidence in the causality of this effect.
Residential use of pesticides has been associated with increased risk of childhood acute lymphoblastic leukemia (ALL). We evaluated determinants of glyphosate concentrations in house dust and ...estimated ALL risk in the California Childhood Leukemia Study (CCLS).
The CCLS is a population-based case-control study of childhood leukemia in California. Among those < 8-years (no move since diagnosis/reference date), we collected dust (2001–2007) from the room where the child spent the most time while awake and measured > 40 pesticides. Three-to-eight years later, we collected a second sample from non-movers. We used Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry to measure glyphosate (µg/g dust) for 181 ALL cases and 225 controls and for 45 households with a second dust sample. We used multivariable Tobit regression to evaluate determinants of glyphosate concentrations. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated for ALL and quartiles of the concentration (first samples) using unconditional logistic regression. We computed the within- and between-home variance and intraclass correlation coefficient (ICC).
Glyphosate was frequently detected (cases: 98 %; controls: 99 %). Higher concentrations were associated with occupational pesticide exposure, nearby agricultural use, treatment for lawn weeds and bees/wasps, and sampling season. Increasing concentrations were not associated with ALL risk (adjusted ORQ4vsQ1 = 0.8, CI: 0.4–1.4). We observed similar null associations for boys and girls, Hispanics and non-Hispanic whites, and among those who resided in their home since birth (76 cases/117 controls) or age two (130 cases/176 controls). The ICC was 0.32 indicating high within-home temporal variability during the years of our study.
We observed higher concentrations in homes associated with expected predictors of exposure but no association with childhood ALL risk. Due to continuing use, potential exposure to young children is high. It will be important to evaluate risk in future studies with multiple dust measurements or biomarkers of exposure.
Purpose
The comparability between serum, plasma, and urinary measurements of estrogen metabolites via liquid chromatography–tandem mass spectrometry (LC–MS/MS) has not been largely explored, and it ...is unclear if urinary LC–MS/MS measurements are suitable surrogates of circulating levels.
Methods
Serum, plasma (EDTA and heparin), and urinary estrogen/estrogen metabolite levels were measured via LC–MS/MS in paired samples from 64 healthy volunteers (18 men, 20 premenopausal women, 26 postmenopausal women). Geometric means and Spearman correlation coefficients were used to compare individual and combined pathway levels of estrogens/estrogen metabolites across biologic matrices by sex/menopausal status.
Results
Measured concentrations of estrogens/estrogen metabolites across blood matrices were almost identical (percent differences < 4.8%). Parent estrogen concentrations measured in serum and urine were moderately correlated in postmenopausal women (estrone:
r
= 0.69, estradiol:
r
= 0.69). Correlations were similar comparing unconjugated serum estradiol to urinary estrone (
r
= 0.76) and urinary estradiol (
r
= 0.65) in postmenopausal women but were moderate to low in premenopausal women (
r
= 0.60, 0.40, respectively)/men (
r
= 0.33, 0.53, respectively). Comparing metabolite ratios, proportionally higher concentrations of 16-pathway metabolites were measured in urine versus serum across sex/menopausal status groups (e.g., postmenopausal women: 50.3% 16-pathway metabolites/total in urine versus 35.3% in serum).
Conclusions
There is strong agreement between estrogen/estrogen metabolites measurements in serum, heparin plasma, and EDTA plasma. Individual estrogen metabolite concentrations were moderately correlated between urine and serum, but were not well correlated when evaluating pathway- or relative estrogen concentrations. Differences between serum and urine are likely explained by differences in metabolism and/or excretion.
Breast density, as estimated by mammography, is a strong risk factor for breast cancer in pre- and postmenopausal women, but the determinants of breast density have not yet been established. The aim ...of this study was to assess if urinary estrogens or gut microbiota alterations are associated with mammographic density in postmenopausal women.
Among 54 cancer-free, postmenopausal controls in the Breast and Colon Health study, we classified low- versus high-density women with Breast Imaging Reporting and Data System (BI-RADS, 5th edition) mammographic screening data, then assessed associations with urinary estrogens and estrogen metabolites (determined by liquid chromatography/tandem mass spectrometry), and fecal microbiota alpha and beta diversity (using Illumina sequencing of 16S rRNA amplicons).
Multiple logistic regression revealed no significant association between breast density and fecal microbiota metrics (PD_tree P-value = 0.82; un-weighted and weighted UniFrac P = 0.92 and 0.83, respectively, both by MiRKAT). In contrast, total urinary estrogens (and all 15 estrogens/estrogen metabolites) were strongly and inversely associated with breast density (P = 0.01) after adjustment for age and body mass index.
Mammographic density was not associated with the gut microbiota, but it was inversely associated with urinary estrogen levels.
The finding of an inverse association between urinary estrogens and breast density in cancer-free women adds to the growing breast cancer literature on understanding the relationship between endogenous estrogens and mammographic density.
Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may ...impact future invasive breast cancer risk, but this has not been studied among women with BBD.
We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression.
Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99).
Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.
Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer ...risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.
Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.
Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14-14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.
Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.
Postmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes ...surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients.
Formalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS.
CLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone:androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03-0.59). A similar pattern was observed with estradiol:testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04-0.72).
CLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens:androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings.
Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone ...(AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.
In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.
The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.
AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may ...influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies.
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