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Background In addition to tumor characteristics and lifestyle factors, cancer relapses are often related to the risk of death but have not been jointly studied. We investigate the prognostic factors of recurrent events and death after a diagnosis of breast cancer and predict individual deaths including a history of recurrences. Methods The E3N (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l’Education Nationale) study is a prospective cohort study that was initiated in 1990 to investigate factors associated with the most common types of cancer. Overall survival and three types of recurrent events were considered: locoregional recurrence, metastasis, and second primary breast cancer. Recurrent events and death were analyzed using a joint frailty model. Results The analysis included 4926 women from the E3N cohort diagnosed with a first primary invasive breast cancer between June 1990 and June 2008; during the follow-up, 1334 cases had a recurrence (median time of follow-up is 7.2 years) and 469 women died. Cases with high grade, large tumor size, axillary nodal involvement, and negative estrogen and progesterone receptors had a higher risk of recurrence or death. Furthermore, smoking increased the risk of relapse. For cases with a medium risk profile in terms of tumor characteristics and lifestyle factors, the probability of dying between 5 and 10 years after diagnosis was 6, 20 and 36% for 0, 1 or 2 recurrences within the first 5 years after diagnosis, respectively. Conclusions Our study showed the importance of considering baseline lifestyle characteristics and history of relapses to dynamically predict the risk of death in breast cancer cases. Medical experience coupled with an estimate of a patient’s survival probability that considers all available information for this patient would enable physicians to make better informed decisions regarding their actions and thus improve clinical output.

Background Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease. Methods Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression. Results Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49–0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19–2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18–1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11–2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05–1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women. Conclusions Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake.

Background Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated ( P < 5.0 × 10 −8 ) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. Results In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10 −31 ), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10 −12 ), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10 −9 ), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10 −7 ) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10 −4 ) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10 −2 ) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10 −3 ), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10 −8 ) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10 −2 ) in the relationship between BMI and endometrial cancer risk. Conclusions Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Background Although obesity is on the rise in Afghanistan, to date no studies have investigated associations with diet and dietary patterns. Therefore, the present study aimed to assess the different dietary patterns consumed among Afghan adults living in Kandahar province and evaluate the correlations between those predominant dietary patterns and anthropometric measures. Methods A cross-sectional study was conducted in Kandahar, Afghanistan, where data on sociodemographic characteristics, anthropometric measurements and diet were collected. A total of 711 men and women aged between 20 and 75 years were included in the final analysis. Dietary data were collected in 2018–2019 using a food frequency questionnaire and dietary patterns were identified by principal component analysis. Dietary pattern scores were then categorised into tertiles, where tertile 1 represented a lower adherence and tertile 3 the highest adherence to the pattern. Bonferroni adjusted P  value of 0.004 was considered statistically significant. Results Three dietary patterns were derived: a Western (WDP, rich in sweet beverages and refined grains), a Fruits and vegetables (FVDP), and a Traditional (TDP, rich in potatoes, fats and oil, and whole grains) dietary pattern. In this population, men had significantly higher adherence to WDP and TDP than women. Participants with higher socioeconomic status had significantly higher adherence to WDP and TDP and lower adherence to the FVDP. In linear regression models adjusted for potential confounders, BMI and waist and hip circumferences were positively correlated with WDP and FVDP and inversely correlated with the TDP, in particular among men and people with high SES, although none of these associations reached the Bonferroni-corrected threshold for statistical significance. Conclusions Three distinct dietary patterns were identified among Afghan adults from Kandahar. Weak positive associations were found between the Western dietary pattern and general and central obesity. Associations of fruits and vegetables and traditional dietary patterns with obesity deserve further evaluation in a larger sample and with more detailed dietary intake assessment methods that also consider preparation methods and food processing.

Breast cancer is the most common cancer in women worldwide. In the Moroccan context, the role of well-known reproductive factors in breast cancer remains poorly documented. The aim of this study was to explore the relationship between menstrual and reproductive factors and breast cancer risk in Moroccan women in the Fez region. A case-control study was conducted at the Hassan II University Hospital of Fez between January 2014 and April 2015. A total of 237 cases of breast cancer and 237 age-matched controls were included. Information on sociodemographic characteristics, menstrual and reproductive history, family history of breast cancer, and lifestyle factors was obtained through a structured questionnaire. Conditional logistic regression models were used to estimate odds ratios and 95% confidence intervals for breast cancer by menstrual and reproductive factors adjusted for potential confounders. Early menarche (OR = 1.60, 95% CI: 1.08-2.38) and nulliparity (OR = 3.77, 95% CI: 1.98-7.30) were significantly related to an increased risk of breast cancer, whereas an early age at first full-term pregnancy was associated with a decreased risk of breast cancer (OR = 0.41, 95% CI: 0.25-0.65). The results of this study confirm the role of established reproductive factors for breast cancer in Moroccan women. It identified some susceptible groups at high risk of breast cancer. Preventive interventions and screening should focus on these groups as a priority. These results should be confirmed in a larger, multicenter study.

Background Although obesity is a well-established risk factor for endometrial cancer, its relationship with genetic susceptibility in determining cancer risk remains unexplored. Current endometrial cancer risk prediction relies primarily on epidemiological factors, with limited consideration of genetic risk. We hypothesized that integrating polygenic risk score (PRS) information with established epidemiological factors could improve risk stratification and reveal whether genetic and lifestyle factors operate independently or jointly. Methods We generated a polygenic risk score for endometrial cancer in 129,829 unrelated female participants of European genetic ancestry (including 956 incident cases with endometrial cancer) in the UK Biobank cohort. We evaluated the prediction model performance using area under the receiver operating characteristic curves (AUCs) and assessed individual and joint associations of body mass index (BMI) and PRS with endometrial cancer using Cox proportional hazards models. Results The integrated model incorporating PRS and epidemiological risk factors achieved statistically significant improvement in predicting endometrial cancer compared with epidemiologic factors alone (AUC = 0.739 versus 0.728; P  = 3.98 × 10 −5 ). Participants in the top 1% PRS distribution had a 3.06-fold increased risk (95% CI 1.97–4.76), with a number needed to screen of 58 individuals. BMI and PRS demonstrated independent effects on endometrial cancer risk, with participants with a BMI ≥ 30 kg/m 2 in the top PRS tertile showing the highest endometrial cancer risk (HR = 4.94; 95% CI 3.65–6.68). Even participants with a BMI < 25 kg/m 2 in the top PRS tertile had a significantly increased risk (HR = 2.01; 95% CI 1.45–2.78). Conclusions Integrating PRS with epidemiological risk factors provides potential for enhanced endometrial cancer risk stratification. PRS effects persist independently of BMI, suggesting genetic risk assessment could complement current screening approaches focused on Lynch Syndrome and identify additional high-risk individuals for targeted prevention strategies.

Background Although anti-inflammatory agents could theoretically have anticancer properties, results from cohort studies on nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer (BC) risk are inconsistent. Methods We investigated the association between NSAID use and BC incidence in the French E3N prospective cohort, which includes 98,995 women born between 1925 and 1950 and insured by a health insurance plan that covers mostly teachers. Self-reported information on lifestyle and medical history has been collected biennially by questionnaires and matched with data from a drug reimbursement database covering the period 2004–2014. Women who self-reported current NSAID use in the 2000 or 2002 questionnaires or with at least two reimbursements in any previous 3-month period were defined as exposed to NSAIDs. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for the association of NSAID use with BC risk. Results In the current analysis, 62,512 postmenopausal women were followed between 2004 and 2014 (9 years on average, starting at a mean age of 63 years; 2864 incident BC). In multivariable models, there was no statistically significant association between NSAID use and BC risk [HR = 1.00 (0.92–1.08), compared with non-exposed women]. The NSAID-BC associations did not differ by NSAID types, BC subtypes, risk factors, and comorbidities, nor by duration and dose of use. However, a statistically significant interaction was observed by proton pump inhibitor (PPI) drug use ( P interaction  = 0.01) whereby a decreased risk of BC with NSAID use was only observed among women who also used PPI before. Conclusion Only women who used NSAIDs after having used PPI had a lower risk of BC. This result is novel and requires replication in other studies.

Introduction The associations between excess adiposity and endometrial cancer (EC) risk may be mediated by altered metabolic profiles. Here, we triangulated evidence from observational and Mendelian randomisation (MR) analyses to investigate the relationship between adiposity traits, circulating metabolites, and their effects on endometrial cancer. Methods Observational analyses were performed in UK Biobank (N cases and controls = 1,005 and 215,339, respectively). Univariable and multivariable MR analyses were performed using female-specific summary statistics for adiposity traits (GIANT consortium; N BMI and WHR = 434,793 and 281,153, respectively), circulating metabolites (UK Biobank; N  = 140,768) and EC (Endometrial Cancer Association Consortium; N cases and controls = 12,906 and 108,979, respectively). Results Higher body mass index (BMI) was associated with increased odds of overall EC, endometrioid EC, and non-endometrioid EC in both observational and MR analyses; however, there was weaker evidence for waist-hip-ratio (WHR). BMI was associated with 165 metabolites, 25 of which were associated with EC risk. Multivariable MR analyses suggest that several lipid metabolites and ratios may mediate the association between BMI and non-endometrioid EC, although analyses using Phenoscanner suggest that alternative pathways such as height and blood cell traits could influence the EC risk. Conclusion Evidence here suggests that higher BMI causes a higher risk of overall and all histological subtypes of EC and variation in numerous circulating metabolites. Several of these metabolites showed relationships consistent with an intermediate role between BMI and non-endometrioid EC, however, further analyses highlighted other potential shared mechanisms that could influence the risk of EC.

Purpose The cellular oxidative stress (balance between pro-oxidant and antioxidant) may be a major risk factor for chronic diseases. Antioxidant capacity of human diet can be globally assessed through the dietary non-enzymatic antioxidant capacity (NEAC). Our aim was to investigate the relationship between the NEAC and all-cause and cause-specific mortality, and to test potential interactions with smoking status, a well-known pro-oxidant factor. Methods Among the French women of the E3N prospective cohort study initiated in 1990, including 4619 deaths among 1,199,011 persons-years of follow-up. A validated dietary history questionnaire assessed usual food intake; NEAC intake was estimated using a food composition table from two different methods: ferric ion reducing antioxidant power (FRAP) and total radical-trapping antioxidant parameter (TRAP). Hazard ratio (HR) estimates and 95 % confidence intervals (CI) were derived from Cox proportional hazards regression models. Results In multivariate analyses, FRAP dietary equivalent intake was inversely associated with mortality from all-causes (HR for the fourth vs. the first quartile: HR 4  = 0.75, 95 % CI 0.67, 0.83, p trend  < 0.0001), cancer, and cardiovascular diseases. Similar results were obtained with TRAP. There was an interaction between NEAC dietary equivalent intake and smoking status for all-cause and cardiovascular disease mortality, but not cancer mortality (respectively, for FRAP, p inter  = 0.002; 0.013; 0.113, results were similar with TRAP), and the association was the strongest among current smokers. Conclusion This prospective cohort study highlights the importance of antioxidant consumption for mortality prevention, especially among current smokers.

BackgroundWomen with higher educational attainment have a higher risk of developing breast cancer (BC). Despite the acknowledged impact of reproductive and lifestyle factors, some excess risks remain unexplained. Many studies support the hypothesis that education has a distinctive effect on physiological processes associated with health, independently of known risk factors.ObjectivesIn this study, we aimed to determine whether the biological embodiment of education could be part of the observed social inequalities in BC risk. We focused on biomarkers from several physiological systems examined individually, and jointly through a biological health score (BHS).DesignProspective cohort study.SettingThis study, based on a subsample of the French E3N cohort, included women with biological data from four nested case–control studies.ParticipantsThe study included 3048 postmenopausal women (17% BC).Main outcome measuresWe first evaluated the association between educational attainment and each biomarker, separately (N=11) and by combining them into a BHS, indicative of an augmented biological health hazard when elevated. Finally, we explored the relationships between the socially patterned biomarkers and BHS, and risk of incident BC.ResultsWomen with higher educational attainment exhibited a lower BHS in comparison to those with lower educational attainment (βhigh education=−0.21 (95% CI −0.42; 0.01), model 2). Specific biomarkers associated with the cardiovascular (systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides (TG), high-density lipoprotein (HDL)), inflammatory (C reactive protein (CRP)) and hormonal systems (sex hormone-binding globulin (SHBG) and oestradiol) were found socially distributed (OR CRP-high=0.70 (95% CI 0.54; 0.91), OR TG-high=0.79 (95% CI 0.61; 1.04), OR DBP-high=0.69 (95% CI 0.53; 0.90), OR SBP-high=0.57 (95% CI 0.44; 0.74), OR HDL-high=0.79 (95% CI 0.60; 1.03), (OR SHBG-high=0.67 (95% CI 0.52; 0.88), OR oestradiol-high=1.34 (95% CI 1.00; 1.79); model 1). Associations persisted after adjustment for cofounders and a large set of potential mediators for two of the investigated cardiovascular markers (OR DBP-high=0.75 (95% CI 0.57; 1.00), OR SBP-high=0.61 (95% CI 0.46; 0.81); model 2). No associations were found between the socially stratified biomarkers and BHS with risk of BC.ConclusionEducational attainment has a direct impact on biological processes suggesting that the biological embodiment of the social environment could be a potential pathway that mediates the association between educational attainment and health. Further studies are needed to specifically investigate the relationships between socially stratified biomarkers and BC risk.