High systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic ...estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation.
Fifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM), and their sum (total estrogens) were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, β-glucuronidase and β-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each loge estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created zero, low (below median of detected sequences), high and compared to loge estrogens, β-glucuronidase and β-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with α=0.05.
In men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM) were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R≥0.50, P≤0.003). These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57-0.70, P=0.03-0.002). Estrone, but not other EM, in urine correlated significantly with functional activity of fecal β-glucuronidase (R=0.36, P=0.04). In contrast, fecal β-glucuronidase correlated inversely with fecal total estrogens, both conjugated and deconjugated (R≤-0.47, P≤0.01). Premenopausal female estrogen levels, which were collected across menstrual cycles and thus highly variable, were completely unrelated to fecal microbiome and enzyme parameters (P≥0.6).
Intestinal microbial richness and functions, including but not limited to β-glucuronidase, influence levels of non-ovarian estrogens via enterohepatic circulation. Thus, the gut microbial community likely affects the risk for estrogen-related conditions in older adults. Understanding how Clostridia taxa relate to systemic estrogens may identify targets for interventions.
Background Adding genotypes from seven single-nucleotide polymorphisms (SNPs), which had previously been associated with breast cancer, to the National Cancer Institute's Breast Cancer Risk ...Assessment Tool (BCRAT) increases the area under the receiver operating characteristic curve from 0.607 to 0.632. Methods Criteria that are based on four clinical or public health applications were used to compare BCRAT with BCRATplus7, which includes the seven genotypes. Criteria included number of expected life-threatening events for the decision to take tamoxifen, expected decision losses (in units of the loss from giving a mammogram to a woman without detectable breast cancer) for the decision to have a mammogram, rates of risk reclassification, and number of lives saved by risk-based allocation of screening mammography. For all calculations, the following assumptions were made: Hardy–Weinberg equilibrium, linkage equilibrium across SNPs, additive effects of alleles at each locus, no interactions on the logistic scale among SNPs or with factors in BCRAT, and independence of SNPs from factors in BCRAT. Results Improvements in expected numbers of life-threatening events were only 0.07% and 0.81% for deciding whether to take tamoxifen to prevent breast cancer for women aged 50–59 and 40–49 years, respectively. For deciding whether to recommend screening mammograms to women aged 50–54 years, the reduction in expected losses was 0.86% if the ideal breast cancer prevalence threshold for recommending mammography was that of women aged 50–54 years. Cross-classification of risks indicated that some women classified by BCRAT would have different classifications with BCRATplus7, which might be useful if BCRATplus7 was well calibrated. Improvements from BCRATplus7 were small for risk-based allocation of mammograms under costs constraints. Conclusions The gains from BCRATplus7 are small in the applications examined. Models with SNPs, such as BCRATplus7, have not been validated for calibration in independent cohort data. Additional studies are needed to validate a model with SNPs and justify its use.
The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized ...the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients.
We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors.
Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.
Women with unilateral breast cancer are increasingly opting for the removal of not only the involved breast, but also for the removal of the opposite uninvolved breast (contralateral prophylactic ...mastectomy CPM), although the risk of contralateral breast cancer (CBC) has decreased in recent years. Models to predict the absolute risk of CBC can help a woman decide whether to undergo CPM. Our objective is to illustrate that a better decision can be made if the patient and doctor also have estimates of the absolute risks of regional and distant recurrences and mortality from non-breast cancer causes.
We based our analyses on two published models for CBC and published information on the hazards of regional and distant recurrences and non-breast cancer mortality. Assuming that CPM eliminates CBC but has no effect on other events, we calculated how much CPM reduces a woman's CBC risk and total risk from all these events for 10 hypothetical women with various subtypes of breast cancer and risk factors.
The risk of CBC and total risk vary greatly, depending on the breast cancer subtype. In some cases, a decision for or against CPM can be based on CBC risk alone, but in others, additional consideration of total risk may cause a woman to decline CPM.
There is a potential to develop more informative tools for deciding on CPM. Realizing this potential will require more and better data to validate existing models of absolute CBC risk and to characterize the hazards of regional and distant recurrences and deaths from non-breast cancer causes for women with various subtypes of breast cancers and risk factors.
Human immunodeficiency virus and Covid‐19 (or SARS‐CoV‐2) differ in their incubation distributions and in their susceptibility to immunologic defense. These features affect our ability to predict the ...course of these epidemics and to control them.
ABSTRACT We estimate relative hazards and absolute risks (or cumulative incidence or crude risk) under cause-specific proportional hazards models for competing risks from double nested case-control ...(DNCC) data. In the DNCC design, controls are time-matched not only to cases from the cause of primary interest, but also to cases from competing risks (the phase-two sample). Complete covariate data are available in the phase-two sample, but other cohort members only have information on survival outcomes and some covariates. Design-weighted estimators use inverse sampling probabilities computed from Samuelsen-type calculations for DNCC. To take advantage of additional information available on all cohort members, we augment the estimating equations with a term that is unbiased for zero but improves the efficiency of estimates from the cause-specific proportional hazards model. We establish the asymptotic properties of the proposed estimators, including the estimator of absolute risk, and derive consistent variance estimators. We show that augmented design-weighted estimators are more efficient than design-weighted estimators. Through simulations, we show that the proposed asymptotic methods yield nominal operating characteristics in practical sample sizes. We illustrate the methods using prostate cancer mortality data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study of the National Cancer Institute.
...Prof-SC is a high-risk cohort. ...BCRAT recommends the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model for such women. To evaluate BCRAT, one ...should restrict attention to those without BRCA1 or BRCA2 mutations, in whom BCRAT performed surprisingly well.1 The expected-to-observed ratio was 0·97 (95% CI 0·89–1·06), indicating excellent overall calibration. ...the concordance statistic for BRCAT (0·64) differed little from the values attained by the BOADICEA (0·65) and International Breast Cancer Intervention Study (0·66) models, which require more extensive information.
U.S. breast cancer incidence has been changing, as have distributions of risk factors, including body mass index (BMI), age at menarche, age at first live birth, and number of live births.
Using data ...for U.S. women from large nationally representative surveys, we estimated risk factor distributions from 1980 to 2008. To estimate ecologic associations with breast cancer incidence, we fitted Poisson models to age- and calendar year-specific incidence data from the NCI's Surveillance, Epidemiology and End Results registries from 1980 to 2011. We then assessed the proportion of incidence attributable to specific risk factors by comparing incidence from models that only included age and calendar period as predictors with models that additionally included age- and cohort-specific categorized mean risk factors. Analyses were stratified by age and race.
Ecologic associations usually agreed with previous findings from analytic epidemiology. From 1980 to 2011, compared with the risk factor reference level, increased BMI was associated with 7.6% decreased incidence in women ages 40 to 44 and 2.6% increased incidence for women ages 55 to 59. Fewer births were associated with 22.2% and 3.99% increased incidence in women ages 40 to 44 and 55 to 59 years, respectively. Changes in age at menarche and age at first live birth in parous women did not significantly impact population incidence from 1980 to 2011.
Changes in BMI and number of births since 1980 significantly impacted U.S. breast cancer incidence.
Quantifying long-term impact of risk factor trends on incidence is important to understand the future breast cancer burden and inform prevention efforts.
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Abstract
Background
The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who ...received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women.
Methods
HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448).
Results
Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9–11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers.
Conclusion
More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.
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