Educational level and characteristics of invasive breast cancer: findings from a French prospective cohort.

PURPOSE: Breast cancer (BC) characteristics are known to influence patients survival. Social differences have been reported by previous studies for those characteristics but questions persist because of inconsistent conclusions. We aimed to investigate the impact of education on BC stage, grade, and hormone receptor (HR) status, while adjusting for potential confounders including a broad set of health behaviors, anthropometric measures, and reproductive factors. METHODS: In the French E3N cohort, 5236 women developed a primary invasive BC for which there was available information on stage, grade, and HR status. No multivariate analyses was performed for BC stage based on the lack of association in bivariate analyses. Odds ratios and confidence intervals were estimated using multinomial logistic regression models for BC grade or binomial logistic regression models for HR status of BC. RESULTS: Women with a lower education were diagnosed with higher grade BC compared to women with a higher education (1.32 [1.12; 1.57]). This association was slightly attenuated after adjustment for covariates independently and more strongly affected in the fully adjusted model (1.20 [0.99; 1.45]). A significant association was observed between lower education and HR- status of BC (1.20 [1.02; 1.42]) attenuated after adjustment for age at first childbirth (1.12 [0.95; 1.33]). CONCLUSION: In this cohort, education was associated with BC grade and HR status but not stage at diagnosis. The link between education and BC grade was not entirely explained by the different adjustments. A specific mechanism could be at play and deserves further investigations.

Reproductive characteristics, use of exogenous hormones and Parkinson disease in women from the E3N study.

Despite experimental studies suggesting a disease-modifying role of oestrogens, results from epidemiological studies on the relation of reproductive characteristics and hormonal exposures with Parkinson disease in women are conflicting. We used the data from the E3N cohort study including 98 068 women aged 40-65 years in 1990 followed until 2018. Parkinson disease was ascertained using a validation process based on drug claim databases and medical records. Reproductive characteristics and hormonal exposures were self-reported (11 questionnaires). Associations of exposures with Parkinson disease incidence were investigated using time-varying Cox proportional hazards regression with a 5-year exposure lag and age as the timescale adjusted for confounders. We identified 1165 incident Parkinson disease cases during a mean follow-up of 22.0 years (incidence rate = 54.7 per 100 000 person-years). Parkinson disease incidence was higher in women with early (<12 years, HR = 1.21, 95% CI = 1.04-1.40) or late age at menarche (≥14 years, HR = 1.18, 95% CI = 1.03-1.35) than in women with menarche at 12-13 years. Nulliparity was not associated with Parkinson disease, but Parkinson disease incidence increased with the number of children in parous women (P-trend = 0.009). Women with artificial (surgical, iatrogenic) menopause were at greater risk than women with natural menopause (HR = 1.28, 95% CI = 1.09-1.47), especially when artificial menopause occurred at an early age (≤45.0 years). Postmenopausal hormone therapy tended to mitigate greater risk associated with artificial or early menopause (≤45.0 years). While fertility treatments were not associated with Parkinson disease overall, ever users of clomiphene were at greater Parkinson disease risk than never users (HR = 1.81, 95% CI = 1.14-2.88). Other exposures (breastfeeding, oral contraceptives) were not associated with Parkinson disease. Our findings suggest that early and late age at menarche, higher parity, and artificial menopause, in particular at an early age, are associated with increased Parkinson disease incidence in women. In addition, there was some evidence that use of exogenous hormones may increase (fertility treatments) or decrease (postmenopausal hormone therapy) Parkinson disease incidence. These findings support the hypothesis that hormonal exposures play a role in the susceptibility to neurodegenerative diseases. If confirmed, they could help to identify subgroups at high risk for Parkinson disease.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Antiplatelet drugs and breast cancer risk in a large nationwide Danish case-control study.

Low-dose aspirin has been hypothesized to prevent cancer risk by inhibiting platelet aggregation. However, the anti-cancer effect of low-dose aspirin has recently been questioned and its effect on breast cancer development remains unclear. The impact of other antiplatelet drugs on breast cancer risk has rarely been evaluated. Thus, this study aimed to investigate the associations between breast cancer risk and antiplatelet drug use in a nationwide nested case-control study. From the Danish healthcare registries, we identified as cases all women with invasive breast cancer diagnosis between 2001 and 2018 (n = 68 852). The date of diagnosis corresponded to the index date. We matched cases to 10 population controls on age and calendar time, using risk set sampling. Controls were assigned the same index date as their matched case. We used the prescription registry to identify exposure to low-dose aspirin, clopidogrel and dipyridamole. We defined ever use of antiplatelet drugs as at least two prescriptions filled up to 1 year before the index date. We applied conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for breast cancer associated with the use of antiplatelet drugs, overall, by breast cancer subtype and by cumulative dose. Twelve percent of women had ever been exposed to low-dose aspirin, 2% to clopidogrel and 2% to dipyridamole. In multivariable models, breast cancer risk was not associated with ever use of low-dose aspirin (OR = 1.00 [0.97-1.03]), clopidogrel (OR = 0.93 [0.87-1.00]), and dipyridamole (OR = 1.02 [0.94-1.10]), compared with never use, and there was no evidence of a dose-response relation. However, we found an inverse association between dipyridamole use and breast cancer risk among women aged <55 years old, with suggestion of a dose-response relationship (OR per 1000 Defined Daily Doses = 0.72 [0.54-0.95]). Associations did not differ by breast cancer histological type, estrogen receptor status or clinical stage at diagnosis. Overall, the findings from this study do not support the use of antiplatelet drugs for breast cancer prevention.

Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study.

BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). CONCLUSIONS: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.

Statin Use and Incidence of Parkinson's Disease in Women from the French E3N Cohort Study.

BACKGROUND: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose-response relations based on time-varying exposures. OBJECTIVES: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. METHOD: We used data from the E3N cohort study of French women (follow-up, 2004-2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case-control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time-varying multivariable Cox proportional hazards regression models to examine the statins-PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. RESULTS: The case-control study (693 cases, 13,784 controls) showed differences in case-control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54-79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67-1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51-0.98), with a dose-response relation for the mean daily dose (P-linear trend = 0.02). There was no association for hydrophilic statins. CONCLUSION: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose-response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A prospective study of the association between living in a rural environment during childhood and risk of psoriasis.

Psoriasis is one of the most common immune-mediated inflammatory diseases (IMIDs). Living in a rural environment during childhood is associated with a decreased risk of certain IMIDs, like asthma, in adulthood. However, its role in other IMIDs, such as psoriasis is still unclear. To evaluate the relationships between different factors related to the environment during childhood and the risk of psoriasis in adulthood we conducted a study in E3N, a French prospective cohort composed of 98 995 women. During the 1990-2018 follow-up of 72 154 study participants, we identified 1 967 incident cases of psoriasis from self-reports in self-administered structured questionnaires. During the 2004-2018 follow-up of 67 917 study participants, 188 moderate-to-severe cases of psoriasis were identified through self-reports and from data from a drug reimbursement database. We fitted Cox proportional hazards regression models with age as the time scale from which we estimated hazard ratios adjusted for putative confounders (aHRs). We found inverse associations with risk of psoriasis for rural birthplace [aHR: 0.89 (95%CI: 0.79-0.96)] and for having farming parents [aHR: 0.84 (95%CI: 0.72-0.97)]. For moderate-to-severe psoriasis we found a nominally similar inverse association with rural birthplace but not with having farming parents. Our results suggest that an exposure to a rural environment during childhood may be associated with a reduced risk of psoriasis. These findings may help to improve our understanding of the pathogenesis of psoriasis.

Circulating inflammatory biomarkers, adipokines and breast cancer risk-a case-control study nested within the EPIC cohort.

BACKGROUND: Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status. METHODS: Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration. RESULTS: Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77-1.03), OR= 0.88 (0.76-1.01) and OR= 0.87 (0.75-1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05-1.29), OR= 1.11 (1.01-1.23), OR= 1.10 (0.99-1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68-1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66-0.97), CRP: OR = 0.85 (0.72-1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96-1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89-1.16), CRP: OR = 1.04 (0.92-1.16)]. CONCLUSIONS: Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation.

Identifying Protective Drugs for Parkinson's Disease in Health-Care Databases Using Machine Learning.

BACKGROUND: Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest. OBJECTIVE: We aimed at detecting potentially protective associations between marketed drugs and PD through a large-scale automated screening strategy. METHODS: We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case-control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2-year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status. RESULTS: Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC-C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD). CONCLUSIONS: We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML-based signal detection algorithms for identifying drugs inversely associated with PD risk in health-care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Use of systemic glucocorticoids and risk of breast cancer in a prospective cohort of postmenopausal women.

BACKGROUND: Glucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk. METHODS: We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade. RESULTS: Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85-1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HRinsitu = 1.34 (1.01-1.78); HRinvasive = 0.86 (0.76-0.97); Phomogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HRER+ = 0.82 (0.72-0.94); HRER- = 1.21 (0.88-1.66); Phomogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HRstage1 = 0.87 (0.75-1.01); HRstage2 = 0.67 (0.52-0.86); HRstage3/4 = 1.49 (1.02-2.20); Phomogeneity = 0.01]. CONCLUSION: This study suggests that the association between systemic glucocorticoid use and breast cancer risk may differ by tumour subtype and stage.