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.

Dietary Inflammatory Index and risk of breast cancer: evidence from a prospective cohort of 67,879 women followed for 20 years in France.

BACKGROUND: Inflammation is implicated in breast cancer development, and diet is one of the modifiable risk factors involved in the regulation of chronic inflammation. Previous studies on the association between breast cancer risk and Dietary Inflammatory Indexes (DII) derived from food frequency questionnaires and data on inflammatory potential of dietary components have reported inconsistent results. OBJECTIVE: To investigate the association between the DII and the risk of breast cancer using data from a large population-based cohort study. DESIGN: A total of 67,879 women from the E3N cohort were followed from 1993 to 2014. A total of 5686 breast cancer cases were diagnosed during the follow-up. The food frequency questionnaire administered at baseline in 1993 was used to calculate an adapted DII. Cox proportional hazard models using age as the time scale were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Spline regression was used to determine any dose-response relationship. We also evaluated effect modification by menopausal status, body mass index, smoking status and alcohol consumption. RESULTS: The median DII score of the study population was slightly pro-inflammatory (DII = + 0.39); ranged from - 4.68 in the lowest quintile to + 4.29 in the highest quintile. The HR increased linearly with the DII (HR per 1SD = 1.04 [95% CI: 1.01, 1.07]), and reached 1.13 [95% CI: 1.04, 1.23] in the 5th quintile group as compared to the first. A positive linear dose-response relationship was also observed when modeling DII with spline functions. Slightly higher HRs were observed in non-smokers (HR for 1-SD increase 1.06 [95% CI: 1.02, 1.10]; p trend = 0.001) and in low-alcohol consumers (≤ 1 glass/day) (HR for 1-SD increase 1.05 [95% CI: 1.01, 1.08]; p trend = 0.002). CONCLUSION: Our results suggest a positive association between DII and breast cancer risk. Consequently, the promotion of anti-inflammatory diet may contribute to breast cancer prevention.

Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study.

OBJECTIVE: To assess the relationships between female hormonal exposures and risk of RA in a prospective cohort of French women. METHODS: E3N (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is an on-going French prospective cohort that included 98 995 women aged 40-65 years in 1990. Every 2-3 years, women completed mailed questionnaires on their lifestyles, reproductive factors and health conditions. Cox proportional hazards regression models were used to determine factors associated with risk of incident RA, with age as the time scale, adjusted for known risk factors of RA, and considering endogenous and exogenous hormonal factors. Hazard ratios (HRs) and 95% CIs were estimated. Effect modification by smoking history was investigated. RESULTS: A total of 698 incident cases of RA were ascertained among 78 452 women. In multivariable-adjusted Cox regression models, risk of RA was increased with early age at first pregnancy (<22 vs ≥27 years; HR = 1.34; 95% CI 1.0, 1.7) and menopause (≤45 vs ≥53 years; HR = 1.40; 95% CI 1.0, 1.9). For early menopause, the association was of similar magnitude in ever and never smokers, although the association was statistically significant only in ever smokers (HR = 1.54; 95% CI 1.0, 2.3). We found a decreased risk in nulliparous women never exposed to smoking (HR = 0.44; 95% CI 0.2, 0.8). Risk of RA was inversely associated with exposure to progestogen only in perimenopause (>24 vs 0 months; multi-adjusted HR = 0.77; 95% CI 0.6, 0.9). CONCLUSIONS: These results suggest an effect of both endogenous and exogenous hormonal exposures on RA risk and phenotype that deserves further investigation.

Modifiable risk factors for advanced vs. early breast cancer in the French E3N cohort.

Advanced breast cancer (BC) is associated with heavier treatments and poorer prognosis than early BC. Despite mammographic screening, advanced BC incidence remains stable. Little is known about risk factors differentially associated with advanced BC. We analyzed factors predicting for postmenopausal advanced vs. early BC in the E3N cohort. E3N has been prospectively following 98,995 French women aged 50-65 years at baseline since 1990. Hazard ratios (HRs) and 95% confidence intervals (CIs) for advanced and early invasive BC were estimated with multivariate Cox competing risk hazard models. With a median follow-up of 15.7 years, 4,941 postmenopausal BC were diagnosed, including 1,878 (38%) advanced BC. Compared to early BC, advanced BC was differentially associated with excess weight (HR 1.39 [95% CI = 1.26-1.53] vs. 1.08 [95% CI = 1.00-1.17], phomogeneity < 0.0001) and living in a rural area (HR 1.14 [95% CI = 1.00-1.31] vs. 0.93 [95% CI = 0.82-1.04], phomogeneity 0.02). Excess weight was the only differential risk factor for advanced BC for hormone-dependent BC and for women compliant with screening recommendations. Previous mammography was associated with reduced advanced BC risk (HR 0.86 [95% CI = 0.73-1.00]) and increased early BC risk (HR 1.36 [95% CI = 1.18-1.56], phomogeneity < 0.0001), but only for hormone-dependent BC. Excess weight appears to be mostly associated with advanced BC, especially hormone-dependent BC. These results add to the evidence for maintaining weight within the recommended limits.

Association between endometriosis and risk of type 2 diabetes: Results from the prospective E3N cohort.

OBJECTIVE: Several studies suggest an association between endometriosis and the risk of cardio-metabolic diseases. This study aimed to prospectively evaluate the association between history of endometriosis and incident type 2 diabetes. STUDY DESIGN: E3N is a prospective cohort of 98,995 French women aged 40-65 years at inclusion. Multivariable Cox regression models were used to estimate hazard ratios and 95 % confidence intervals for the association between endometriosis and incident type 2 diabetes. We evaluated effect modification by age, body mass index, infertility treatment, adherence to the Mediterranean diet, and menopausal status. RESULTS: Age at inclusion was 51 ± 6 years and there were 2672 incident cases of type 2 diabetes. A total of 4606 women reported surgically-confirmed endometriosis among 83,582 women with no history of diabetes at inclusion. Endometriosis was not associated with type 2 diabetes risk in a model adjusted for age, BMI, physical activity, smoking, education, age at menarche and oral contraceptive use (hazard ratio [HR] = 1.09; 95 % confidence interval [CI] = 0.92-1.29), neither after further adjustment for family history of diabetes, hypertension and menopausal status (HR = 0.97;95%CI = 0.80-1.16). The relationship did not differ by age at inclusion, BMI, infertility treatment, diet or menopausal status (p > 0.05). CONCLUSIONS: Surgically-confirmed endometriosis was not associated with the risk of type 2 diabetes in this large cohort, confirming that endometriosis is not a risk marker for type 2 diabetes.

Childhood and adulthood passive and active smoking, and the ABO group as risk factors for pancreatic cancer in women.

OBJECTIVES: Active smoking and the A blood group are associated with pancreatic adenocarcinoma (PC) risk. However, potential interactions between those risk factors and the role of passive smoking have been little investigated. We aimed to explore specific and joint associations of passive and active smoking, and effect modification by the ABO blood group in French women. METHODS: The study included 96,594 women from the E3N prospective cohort, mean age: 49 years (SD 6.7). Information on active and passive smoking was reported at inclusion and throughout follow-up. Cases were classified according to the International Classification of Diseases 10. Associations with passive and active smoking and effect modification by the ABO blood group were investigated with multivariable Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During a 24-year median follow-up, 346 incident PC cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08-2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08-2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91-1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42-5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10-2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant. CONCLUSIONS: Both current smoking and passive smoking in childhood were associated with PC risk, with a maximal risk of current smokers exposed to passive smoking during childhood. Possible interactions between blood groups and active or passive smoking must be investigated in a larger series.

Passive smoking in childhood and adulthood and risk of rheumatoid arthritis in women: results from the French E3N cohort study.

OBJECTIVE: The association between passive smoking exposure in childhood or in adulthood, and the risk of rheumatoid arthritis (RA) has been incompletely investigated. We aimed to assess the relationship between exposure to passive smoking and the risk of incident RA in a French prospective cohort of healthy women. METHODS: The E3N Study (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is a French prospective cohort of women included in 1990. Exposures to passive smoking were assessed using self-reported questionnaires. RA cases were self-reported and subsequently validated. Cox proportional hazards regression models adjusted for age and for potential confounders were used to estimate HRs and 95% CIs for incident RA. RESULTS: Among 79 806 women, 698 incident cases of RA were identified; 10 810 (13.5%) women were exposed to passive smoking in childhood, and 42 807 (53.6%) in adulthood. Median age at inclusion was 47.8 years. Passive smoking in childhood and in adulthood was associated with RA risk in all models (HRs (95% CIs) 1.24 (1.01 to 1.51) and 1.19 (1.02 to 1.40), respectively). The absolute risk of RA among never smokers with exposure to passive smoking in childhood and/or adulthood (47.6/100 000 person-years) was close to the risk of ever smokers with no passive smoking exposure (47.2/100 000 person-years), while it was highest in ever smokers also exposed to passive smoking (53.7/100 000 person-years). CONCLUSION: Exposure to passive smoking in childhood and/or adulthood increases the risk of RA by the same order than active smoking. Such exposure should be suppressed, especially in individuals at risk of RA.

Lifetime female hormonal exposure and risk of rheumatoid arthritis in postmenopausal women: Results from the French E3N cohort.

OBJECTIVE: To assess the relationships between lifetime female hormonal exposures and the risk of incident RA in postmenopausal women. METHODS: E3N is an ongoing French prospective cohort of 98,995 women since 1990 aged 40-65 years at enrolment. Data on reproductive/hormonal factors and treatments were regularly recorded. Exposures were defined as follows: - reproductive span (in years)=duration from menarche to menopause; - total ovulatory years=reproductive span-(number of full-term pregnancies×0.75+number of miscarriages×0.25+total duration of breast feeding+total duration of oral contraception); - lifetime duration of hormonal exposure (in years)=reproductive span+total duration of menopausal hormonal therapy; - composite estrogen score (CES, range=0-6): 1 point for each item: early menarche, high parity, history of hysterectomy, use of oral contraception, use of menopausal hormonal therapy and late menopause. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident RA were estimated using Cox proportional hazards regression models with age as the time scale. RESULTS: Among the 78,391 postmenopausal cohort women, 637 validated incident RA cases occurred. Lifetime durations of hormonal exposures were not associated with incident RA in postmenopausal women. High (CES=4-6) versus low (CES=0-1) estrogen exposure was inversely associated with the risk of RA: HR 0.37; 95% CI 0.2-0.8. CONCLUSION: In the E3N cohort, high lifetime estrogen exposure, that summarizes cumulative endogenous and exogenous exposures, was associated with a decreased risk of RA in postmenopausal women.

Mediterranean Diet and Risk of Rheumatoid Arthritis: Findings From the French E3N-EPIC Cohort Study.

OBJECTIVE: The Mediterranean diet has been reported to be associated with a significant reduction in risk of noncommunicable diseases. We undertook this study to assess the relationship between adherence to the Mediterranean diet and the risk of rheumatoid arthritis (RA), especially in high-risk individuals. METHODS: The E3N study (Etude Epidémiologique Auprès des Femmes de la Mutuelle Générale de l'Education Nationale) is a French prospective cohort study that has included 98,995 women since 1990. Dietary data were collected via a validated food frequency questionnaire in 1993. Adherence to the Mediterranean diet was assessed using a 9-unit dietary score evaluating consumption of vegetables, legumes, cereal products, fish, meat, dairy products, olive oil, and alcohol. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident RA were estimated using Cox proportional hazards regression models adjusted for age and the main potential confounders, including smoking. RESULTS: Among 62,629 women, we identified 480 incident cases of RA. In the entire study population, the Mediterranean diet adherence score was not associated with RA risk (HR 0.86 [95% CI 0.67-1.09] for high score versus low score; P for trend = 0.09); however, among ever-smokers, a higher score was associated with a decreased risk of RA (HR 0.91 [95% CI 0.84-0.99] for 1-point increase in score; P = 0.03). In ever-smokers, the absolute risks of RA in those with high scores and those with low scores were 38.3 and 51.5 per 100,000 person-years, respectively, compared to 35.8 per 100,000 person-years in never-smokers with high Mediterranean diet scores. CONCLUSION: Our results suggest that adherence to the Mediterranean diet could reduce the high risk of RA among ever-smoking women. Our results must be confirmed in future research.

Pigmentary traits, sun exposure, and risk of non-Hodgkin's lymphoma/chronic lymphocytic leukemia: A study within the French E3N prospective cohort.

To investigate whether risk factors for keratinocyte carcinomas (KCs), namely pigmentary traits and sun exposure, are associated with risk of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL). E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Cancer data were collected at baseline and updated every 2-3 years. Hazard Ratios (HRs) and 95% confidence intervals (CIs) for associations between pigmentary traits and sun exposure, and risk of CLL/NHL were estimated using Cox models. With a median follow-up of 24 years, 622 incident cases of CLL/NHL were ascertained among the 92,097 included women. The presence of nevi was associated with CLL/NHL risk: HR for "many or very many nevi" relative to "no nevi": 1.56 [1.15; 2.11]. Such association with number of nevi appears to be mostly limited to risk of CLL: HR for "many or very many nevi": 3.00 [1.38; 6.52]; versus 1.32 [0.94; 1.84] for NHL. Women whose skin was highly sensitive to sunburn also had a higher risk of CLL: HR = 1.96 [1.21; 3.18], while no increase in risk of NHL was observed. Skin or hair color, number of freckles, and average daily ultraviolet (UV) dose during spring and summer in location of residence at birth or at inclusion (kJ/m2 ) were not associated with CLL/NHL risk. Some pigmentary traits (presence of nevi and skin sensitivity), but not sun exposure, were associated with CLL/NHL. These observations suggest that CLL may share some constitutional risk factors with keratinocyte cancers.

Hysterectomy, non-malignant gynecological diseases, and the risk of incident hypertension: The E3N prospective cohort.

OBJECTIVES: While it has been reported that women with uterine fibroids or endometriosis are commonly overweight and hypertensive, the association between non-malignant gynecological diseases and the risk of hypertension has been little studied prospectively. The aim of this study was to investigate in a large French cohort of women whether a history of hysterectomy, uterine fibroids, or endometriosis was prospectively related to an increased risk of incident hypertension. STUDY DESIGN: We analyzed 50,286 women from the E3N cohort who were free of hypertension at baseline, with a median follow-up of 16.4 years. MAIN OUTCOME MEASURES: Gynecological diseases were based on self-report. Cox proportional hazards models with age as the timescale were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Covariates included smoking status, body mass index (BMI), physical activity, and hormonal factors. RESULTS: A total of 12,073 women (24%) developed hypertension during follow-up. Women with a history of hysterectomy had an increased risk of incident hypertension, which persisted after adjustment for potential confounding factors (adjusted HR=1.18, 95% CI 1.12-1.24). Risk was similar in women with hysterectomy with or without oophorectomy. Risk of hypertension was higher in women with a history of endometriosis (HRendometriosis 1.19, 95%CI 1.11-1.22) or uterine fibroids (HRfibroids 1.18, 95%CI 1.13-1.22), irrespective of hysterectomy. Associations were similar after further adjustment for BMI. CONCLUSIONS: Hysterectomy and non-malignant gynecological diseases were associated with an increased risk of hypertension in this large prospective study. Women with these conditions may benefit from blood pressure monitoring. ClinicalTrials.gov identifier: NCT03285230.

Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study.

BACKGROUND: Soy-based dietary supplements have been promoted as natural alternatives to menopausal hormone therapy, but their potential effect on breast cancer development is controversial. OBJECTIVES: We examined the relation between the consumption of soy supplements and the risk of breast cancer, overall and by tumor hormone receptor status, among women aged >50 y. METHODS: In total, 76,442 women from the Etude Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort, born between 1925 and 1950, were followed from 2000 to 2011 (11.2 y on average, starting at a mean age of 59.5 y; 3608 incident breast cancers), with soy supplement use assessed every 2-3 y. HRs of breast cancer were estimated with the use of multivariable Cox models. RESULTS: Compared with never using soy supplements, the HRs associated with current use of soy supplements were 0.92 (95% CI: 0.76, 1.11) for all, 0.78 (95% CI: 0.60, 0.99) for estrogen receptor (ER)-positive, and 2.01 (95% CI: 1.41, 2.86) for ER-negative breast cancers. There was no association between past use of soy supplements and breast cancer. HRs for current use were 1.36 (95% CI: 0.95, 1.93) and 0.82 (95% CI: 0.65, 1.02) among women with and without a family history of breast cancer, respectively (P-interaction = 0.03) and 1.06 (95% CI: 0.87, 1.30) ≥5 y after menopause compared with 0.50 (95% CI: 0.31, 0.81) in premenopause or ≤5 y postmenopause (P-interaction = 0.04). CONCLUSIONS: In this cohort of women aged >50 y, we report opposing associations of soy supplements with ER-positive and ER-negative breast cancer risk. Our results also caution against the use of these supplements in women with a family history of breast cancer. Whether the risk profile of soy supplements could be more favorable among premenopausal or recently postmenopausal women deserves further investigation.

Use of Bisphosphonates and Risk of Breast Cancer in a French Cohort of Postmenopausal Women.

Purpose To assess whether bisphosphonate (BP) use is associated with decreased breast cancer incidence in a cohort of postmenopausal women. Methods The study population included 64,438 postmenopausal women participating in the French E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) prospective cohort, with data self-reported in biennial questionnaires matched with data from a drug reimbursement database. Exposure to BPs and the use of other osteoporosis treatments during follow-up were determined using reimbursement data. Other covariates (breast cancer risk factors, clinical risk factors for osteoporotic fractures, and bone mineral density surveillance) originated from the questionnaires. Hazard ratios (HRs) of breast cancer were estimated using Cox proportional hazards models, considering exposure as a time-varying variable. Results Over an average of 7.2 years of follow-up (2004 to 2011), 2,407 first primary breast cancer cases were identified. The HR of breast cancer associated with exposure to BPs was 0.98 (95% CI, 0.85 to 1.12). We found no effect modification by age, body mass index, time since menopause, use of hormone replacement therapy, use of calcium supplements, or use of vitamin D supplements. There was no heterogeneity across BP molecules and no trend according to cumulative dose, duration of use, or time since last use. We observed a decrease in breast cancer risk restricted to the year after treatment initiation (HR, 0.56; 95% CI, 0.36 to 0.87), which was likely explained by healthy screenee bias. Finally, we did not find any variation in HRs across breast carcinomas defined by their estrogen receptor or invasive or in situ status. Conclusion In our observational cohort of postmenopausal women observed from 2004 to 2011, BP use, likely prescribed for the management of osteoporosis, was not associated with decreased breast cancer incidence.