Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort.

BACKGROUND: Thyroid cancers are threefold more frequent in women than in men. A role of reproductive or hormonal factors has been suggested but with contradictory results. We investigated potential associations between history of hysterectomy, with or without oophorectomy, and history of benign gynaecological disease (uterine fibroids, endometriosis) and the incidence of differentiated thyroid cancer, in a large French prospective cohort. METHODS: A total of 89 340 women from the E3N cohort were followed up between 1990 and 2012. Gynaecological diseases treated by surgery were self-reported. Thyroid cancers were validated by histological reports. Time-dependent covariates included smoking status, BMI and history of benign thyroid disease. Cox proportional hazard models with age as timescale were used to estimate Hazard Ratios (HR) and 95% confidence intervals (CI). RESULTS: A total of 412 cases of thyroid cancer were diagnosed during follow-up. A history of hysterectomy was associated with an increased risk of differentiated thyroid cancer (adjusted HR=2.05; 95%CI: 1.65-2.55). The association was not altered after further adjustment for reproductive factors. Endometriosis, uterine polyps, ovarian cysts and oophorectomy without hysterectomy were not associated with the risk of thyroid cancer. A history of fibroids was also significantly related to the risk of thyroid cancer over the follow-up period (adjusted HR=1.91; 95%CI: 1.50-2.44) and the increased risk persisted after adjustment for history of hysterectomy. CONCLUSIONS: Women who had either a history of fibroids or hysterectomy had an increased risk of differentiated thyroid cancer. These findings suggest shared biological mechanisms between fibroids and thyroid cancer, which deserve to be further dissected.

Life course evolution of body size and breast cancer survival in the E3N cohort.

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty and early adulthood and body size trajectories from childhood to adulthood. Self-assessed body size at age 8, at puberty, at age 20-25 and at age 35-40 and trajectories of body size of 4,662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models. Four trajectories of body size were identified (T1 "moderate increase," T2 "stable/low increase," T3 "increase at puberty" and T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 vs. T2 = 1.27; 95% CI = 1.01-1.60) and an increased risk of second invasive cancer event (HR T1 vs. T2 = 1.25; 95% CI = 1.06-1.47). Silhouettes at various ages were not associated with survival. Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death.

Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years.

PURPOSE: To assess the association between use of benzodiazepines (including the Z-drugs zopiclone and zolpidem) and cardiovascular mortality in women aged over 50 years. METHODS: We used data from the E3N cohort. Data self-reported in biennial questionnaires was matched with drug reimbursement and vital status/causes of death data. In Cox models, exposure to benzodiazepines was fitted using time-varying variables, the reference category being women with no benzodiazepine delivery since January 2004. RESULTS: Among 85,353 women born 1925-1950 and followed between 2004 and 2011, 506 cardiovascular deaths occurred. Exposure to benzodiazepines was associated with increased cardiovascular mortality when hazard ratios (HRs) were adjusted only for age (HRever use 1.65; 95% CI 1.39, 1.97), but not when further adjusted for antidepressant use (HRever use 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HRever use 0.93; 95% CI 0.75, 1.16). Exposure to hypnotic benzodiazepines remained associated with increased cardiovascular mortality (HRever use 1.23; 95% CI 1.01, 1.51), but with no consistent trend across duration/dose or time since last use, while exposure to anxiolytic benzodiazepines was not (HRever use 0.83; 95% CI 0.67, 1.02). CONCLUSION: In our study, adjustment for antidepressant use strongly attenuated any benzodiazepine-cardiovascular mortality association. Whether the modest association observed with hypnotic benzodiazepines is due to residual confounding deserves further investigation.

Associations between serum lipids and breast cancer incidence and survival in the E3N prospective cohort study.

PURPOSE: Several mechanistic studies support a role of cholesterol or its metabolites in breast cancer etiology, but associations have been inconsistent in epidemiological studies. In observational studies, possible reverse causation must be accounted for using a prospective design. We investigated prospective associations between pre-diagnostic serum lipid concentrations [total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides], and both breast cancer risk and survival in the E3N cohort study. METHODS: Analyses were performed on 583 cases from the E3N prospective cohort diagnosed between 1994 and 2005, and 1,043 controls matched on date, age, recruitment center and menopausal status at blood collection. Odds ratios (OR) and 95% confidence intervals were estimated using conditional logistic regression. Risks of recurrence were estimated among cases using Cox proportional hazards model. Models were adjusted for lifestyle risk factors and mutually adjusted for lipid concentrations. Survival analyses were additionally adjusted for tumor characteristics. RESULTS: Overall, there was no association between any serum lipid and breast cancer risk or survival. In stratified analyses, statistically significant interaction was observed between TC and menopausal status (P interaction = 0.05) and between TC and waist circumference (P interaction = 0.03), although the ORs did not reach statistical significance in any of the strata. There was no statistically significant effect modification by BMI, time between blood donation and diagnosis or ER status. CONCLUSIONS: Our results suggest that serum lipids are not associated with breast cancer risk overall, but that menopausal status and waist circumference should be considered in further studies.

Endometriosis and the risk of skin cancer: a prospective cohort study.

PURPOSE: Endometriosis has been associated with an increased risk of skin melanoma. However, associations with other skin cancer types and how they compare with melanoma are unclear. Our objective was to prospectively investigate the relationships between endometriosis and risk of non-melanoma and melanoma skin cancers. METHODS: E3N is a prospective cohort of 98,995 French women aged 40-65 years in 1990. Data on surgically confirmed endometriosis and skin cancer diagnoses were collected every 2-3 years through self-report, with skin cancer cases confirmed through pathology reports. Hazard Ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox regression models. RESULTS: Between 1990 and 2008, 535 melanoma, 247 squamous-cell carcinoma (SCC), and 1,712 basal-cell carcinoma (BCC) cases were ascertained. Endometriosis was associated with an increased overall risk of skin cancer (HR 1.28, 95% CI 1.05-1.55). When considering skin cancer type, endometriosis was associated with melanoma risk (HR 1.64, 95% CI 1.15-2.35), but not with SCC (HR 1.21, 95% CI 0.62-2.36) or BCC (HR 1.16, 95% CI 0.91-1.48) (non-melanoma skin cancers combined: HR 1.17, 95% CI 0.93-1.46), although no heterogeneity was detected across skin cancer types (Phomogeneity = 0.13). CONCLUSION: These data support an association between a personal history of endometriosis and the risk of skin cancer and suggest that the association is strongest for melanoma.

Nevi, Ambient Ultraviolet Radiation, and Thyroid Cancer Risk: A French Prospective Study.

BACKGROUND: Incidence rates have increased considerably worldwide for both differentiated thyroid cancer and cutaneous melanoma, and two-way associations between these neoplasms have been described. Whether melanoma risk factors are associated with thyroid cancer risk remains unknown. METHODS: Using Cox regression modeling, we prospectively analyzed the relationship between self-reported pigmentary traits, baseline residential ultraviolet (UV) exposure, and thyroid cancer risk in 86,960 women from the E3N cohort, followed-up over 1990-2008 through biennial questionnaires. We assessed associations of pigmentary traits and UV exposure with personal history of benign thyroid diseases using logistic regression modeling. All statistical tests were two sided. RESULTS: In models adjusted for age and thyroid cancer risk factors, number of nevi was positively associated with thyroid cancer risk ("very many" vs. "none": hazards ratio [HR] = 1.7, 95% confidence interval [CI] = 1.0, 2.8; Ptrend = 0.01), independently of residential UV exposure or iodine intake. Risk was inversely associated with latitude and positively associated with mean daily UV level at baseline (HRs for the fourth vs. first quartile of latitude and spring/summer UVB level = 0.7, 95% CI = 0.5, 0.9; Ptrend = 0.03, and HR = 1.9, 95% CI = 1.4, 2.7; Ptrend = 0.02, respectively); associations were restricted to women with dietary iodine below the median intake. Number of nevi and UV level were also associated with personal histories of dysthyroidism and of goiter/nodules, although more weakly so. CONCLUSIONS: Our results suggest that number of nevi and residential UV exposure are associated with the risks of thyroid cancer and benign conditions. They point to novel pathways in thyroid cancer or melanoma etiologies and warrant replication.

Postmenopausal breast cancer risk and interactions between body mass index, menopausal hormone therapy use, and vitamin D supplementation: Evidence from the E3N cohort.

Experimental studies suggest protective effects of vitamin D on breast carcinogenesis, but epidemiological evidence is not conclusive. Body mass index (BMI) has been shown to modulate the effect of supplementation on the vitamin D status, but its potential influence on the relationship with breast cancer risk has been little studied. We investigated a potential interaction between BMI and vitamin D supplementation on breast cancer risk while considering an already reported interaction between vitamin D supplementation and menopausal hormone therapy (MHT) use. Vitamin D supplementation was prospectively investigated in 57,403 postmenopausal women from the French E3N cohort including 2,482 incident breast cancer cases diagnosed between 1995 and 2008. Multivariable hazard ratios (HR) for primary invasive breast cancer and 95% confidence intervals (CI) were estimated using Cox models. Among MHT ever users, vitamin D supplementation was associated with decreased breast cancer risk, similarly across BMI strata (Phomogeneity = 0.83). Among MHT never users, ever vitamin D supplementation was associated with increased postmenopausal breast cancer risk in women with baseline BMI <25 kg/m(2) (HR = 1.51, 95% CI: 1.13, 2.02), but not in women with higher BMI (0.98, 95% CI: 0.62, 1.56), Phomogeneity = 0.12. In conclusion, our findings suggest that vitamin D supplementation may reduce the excess breast cancer risk in MHT users, but draw attention on a potential risk in postmenopausal women not exposed to high exogenous or endogenous hormones, i.e. non-overweight MHT-non users, especially in the present context of increasing vitamin D supplement use and decreasing MHT use.

Prediagnostic body size and breast cancer survival in the E3N cohort study.

Obesity has been associated with poor breast cancer prognosis, however most studies have focused on body mass index (BMI) and few have considered the distribution of adipose tissue. We investigated associations between prediagnostic adiposity and breast cancer survival, considering BMI, waist and hip circumferences (WC and HC), and waist-to-hip ratio (WHR). Analyses included 3,006 women from the French E3N prospective cohort study diagnosed with primary invasive breast cancer between 1995 and 2008. We investigated overall, breast cancer-specific, and disease-free survival, overall and according to stage, menopausal and hormonal status and year of diagnosis, using Cox proportional hazard models adjusted for tumor characteristics and lifestyle risk factors. Women with a prediagnostic HC > 100 cm were at increased risk of death from all causes (hazard ratio (HR)>100 vs < 95 cm = 1.38, 95% Confidence Interval (CI) = 1.02-1.86, Ptrend = 0.02) and from breast cancer (HR>100 vs < 95 cm = 1.50, CI = 1.03-2.17, Ptrend = 0.03), and of second invasive cancer event (HR>100 vs < 95 cm = 1.36, CI = 1.11-1.67, Ptrend = 0.002), compared to those with HC <95 cm. Associations were stronger after adjustment for BMI. BMI, WC and WHR were not associated with survival after breast cancer. Our study underlines the importance of going beyond BMI when studying the association between adiposity and breast cancer survival. Further studies should be conducted to confirm our results on hip circumference.

Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: Estimates from the E3N-EPIC cohort.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Breast cancer risk factors have been widely explored individually; however, little is known about their combined impact. We included 67,634 women from the French E3N prospective cohort, aged 42-72 at baseline. During a 15-year follow-up period, 497 premenopausal and 3,138 postmenopausal invasive breast cancer cases were diagnosed. Population-attributable fractions (PAFs) were used to estimate cases proportions attributable to risk factors under hypothetical scenarios of lowest exposure. We examined overall premenopausal and postmenopausal invasive breast cancers and tumour subtypes (ER status and HER2 expression). Premenopausal breast cancer was not significantly attributable to non-behavioral (61.2%, -15.5 to 91.88%) nor to behavioral (39.9%, -71.0 to 93.9%) factors, contrary to postmenopausal breast cancer (41.9%, 4.5 to 68.7% and 53.5%, 12.8 to 78.7%, respectively). Individually, the highest statistically significant PAFs were obtained in premenopause for birth weight (33.6%, 5.7 to 56.6%) and age at menarche (19.8%, 5.2 to 33.6%) for non-behavioral factors and in postmenopause for history of benign breast diseases (14.9%, 11.6 to 18.0%) and age at menarche (9.7%, 3.9 to 15.5%) for non-behavioral factors and for body shape at menarche (17.1%, 9.7 to 24.3%), use of hormone replacement therapy (14.5%, 9.2 to 19.6%), dietary pattern (10.1%, 2.6 to 17.4%) and alcohol consumption (5.6%, 1.9 to 9.3%) for behavioral factors. These proportions were higher for ER+, HER2- and ER+/HER2- postmenopausal breast cancers. Our data support the hypothesis that in postmenopause, never starting unhealthy behaviors can reduce the number of diagnosed breast cancers.

Energy and macronutrient intake and risk of differentiated thyroid carcinoma in the European Prospective Investigation into Cancer and Nutrition study.

Incidence rates of differentiated thyroid carcinoma (TC) have increased in many countries. Adiposity and dietary risk factors may play a role, but little is known on the influence of energy intake and macronutrient composition. The aim of this study was to investigate the associations between TC and the intake of energy, macronutrients, glycemic index (GI) and glycemic load in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 477,274 middle-age participants (70.2% women) from ten European countries. Dietary data were collected using country-specific validated dietary questionnaires. Total carbohydrates, proteins, fats, saturated, monounsaturated and polyunsaturated fats (PUFA), starch, sugar, and fiber were computed as g/1,000 kcal. Multivariable Cox regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence interval (CI) by intake quartile (Q). After a mean follow-up time of 11 years, differentiated TC was diagnosed in 556 participants (90% women). Overall, we found significant associations only with total energy (HRQ4 vs .Q1 , 1.29; 95% CI, 1.00-1.68) and PUFA intakes (HRQ4 vs .Q1 , 0.74; 95% CI, 0.57-0.95). However, the associations with starch and sugar intake and GI were significantly heterogeneous across body mass index (BMI) groups, i.e., positive associations with starch and GI were found in participants with a BMI ≥ 25 and with sugar intake in those with BMI < 25. Moreover, inverse associations with starch and GI were observed in subjects with BMI < 25. In conclusion, our results suggest that high total energy and low PUFA intakes may increase the risk of differentiated TC. Positive associations with starch intake and GI in participants with BMI ≥ 25 suggest that those persons may have a greater insulin response to high starch intake and GI than lean people.

Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case-control study in nonsmoking postmenopausal women from the EPIC cohort.

Acrylamide, classified in 1994 by IARC as "probably carcinogenic to humans," was discovered in 2002 in some heat-treated, carbohydrate-rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case-control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non-smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type-I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1 : 0.84, 95%CI: 0.49-1.48; HRHbGA;Q5vsQ1 : 0.94, 95%CI: 0.54-1.63) or type-I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. ≥25 kg m(-2) , alcohol drinkers vs. never drinkers, oral contraceptive users vs. non-users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type-I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort.

Reproductive and menstrual factors and risk of differentiated thyroid carcinoma: the EPIC study.

Differentiated thyroid carcinoma (TC) is threefold more common in women than in men and, therefore, a role of female hormones in the etiology of differentiated TC has been suggested. We assessed these hypotheses in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 345,157 women (mean age 51) followed for an average of 11 years, 508 differentiated TC cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No significant associations were observed between differentiated TC risk and number of pregnancies, breast feeding, menopausal status, and age at menarche and at menopause. Significant associations were found with history of infertility problems (HR 1.70; 95% CI 1.12-2.60), a recent pregnancy (HR for ≤ 5 vs. >5 years before recruitment 3.87; 95% CI 1.43-10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95% CI 1.41-3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95% CI 0.25-0.92) and duration of OC use (HR for ≥ 9 vs. ≤ 1 year: 0.66; 95% CI: 0.50-0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR = 1.30, 95% CI 1.02-1.67), but this was not significant after adjustment for type of menopause (HR = 1.22, 95% CI 0.95-1.57). Overall, our findings do not support a strong role of reproductive and menstrual factors, and female hormone use in the etiology of differentiated TC. The few observed associations may be real or accounted for by increased surveillance in women who had infertility problems, recent pregnancies or underwent surgical menopause.

Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study.

BACKGROUND: Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521,330 total participants (approximately 370,000 women) aged 25-70 years at recruitment from 1992 to 2000. METHODS: Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre. RESULTS: After a mean follow-up of 3.6 years (±3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR=0.80, 95% CI=0.62-1.03) and a significant survival benefit in long-term MHT users (⩾5 years use vs never use, HR=0.70, 95% CI=0.50-0.99, P(trend)=0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk. CONCLUSIONS: Further studies are warranted to investigate the possible improvement in EOC survival in MHT users.

A comparison between different prediction models for invasive breast cancer occurrence in the French E3N cohort.

Breast cancer remains a global health concern with a lack of high discriminating prediction models. The k-nearest-neighbor algorithm (kNN) estimates individual risks using an intuitive tool. This study compares the performances of this approach with the Cox and the Gail models for the 5-year breast cancer risk prediction. The study included 64,995 women from the French E3N prospective cohort. The sample was divided into a learning (N = 51,821) series to learn the models using fivefold cross-validation and a validation (N = 13,174) series to evaluate them. The area under the receiver operating characteristic curve (AUC) and the expected over observed number of cases (E/O) ratio were estimated. In the two series, 393 and 78 premenopausal and 537 and 98 postmenopausal breast cancers were diagnosed. The discrimination values of the best combinations of predictors obtained from cross-validation ranged from 0.59 to 0.60. In the validation series, the AUC values in premenopausal and postmenopausal women were 0.583 [0.520; 0.646] and 0.621 [0.563; 0.679] using the kNN and 0.565 [0.500; 0.631] and 0.617 [0.561; 0.673] using the Cox model. The E/O ratios were 1.26 and 1.28 in premenopausal women and 1.44 and 1.40 in postmenopausal women. The applied Gail model provided AUC values of 0.614 [0.554; 0.675] and 0.549 [0.495; 0.604] and E/O ratios of 0.78 and 1.12. This study shows that the prediction performances differed according to menopausal status when using parametric statistical tools. The k-nearest-neighbor approach performed well, and discrimination was improved in postmenopausal women compared with the Gail model.

Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study.

Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (-0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3 : 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3 : 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.

Association between melanocytic nevi and risk of breast diseases: The French E3N prospective cohort.

BACKGROUND: While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk. METHODS AND FINDINGS: We prospectively analyzed data from E3N, a cohort of French women aged 40-65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990-15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with "very many" nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01-1.27 versus "none"; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674-4,649) per 100,000 women with "very many" nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose-response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD. CONCLUSIONS: Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms.

Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992-2008.

We assessed whether different oral progestogens in hormone replacement therapy may differentially affect the risk of endometrial cancer, using data from the Etude Epidémiologique auprès de femmes de l'Education Nationale (E3N), a French cohort study (1992-2008). Hazard ratios and their confidence intervals were derived from Cox models. Among 65,630 postmenopausal women (mean follow-up: 10.8 years), 301 endometrial cancers occurred. Compared with never use, ever use of estrogen + micronized progesterone was associated with an increased risk of endometrial cancer (hazard ratio (HR) = 1.80, 95% confidence interval (CI): 1.38, 2.34) that was significantly more marked with longer duration of use (for ≤5 years, HR = 1.39 (95% CI: 0.99, 1.97); for >5 years, HR = 2.66 (95% CI: 1.87, 3.77)). Although use of estrogen + dydrogesterone was not associated overall with endometrial cancer risk (HR = 1.05, 95% CI: 0.76, 1.45), there was a significantly increased risk with long-term use compared with never use (for >5 years, HR = 1.69, 95% CI: 1.06, 2.70). Users of preparations containing other progesterone derivatives or a norsteroid derivative were not at significantly increased risk (HR = 0.79 (95% CI: 0.60, 1.05) and HR = 1.30 (95% CI: 0.85, 1.99), respectively). In conclusion, micronized progesterone and, to a lesser extent, dydrogesterone at the doses used in France may not be sufficient to prevent estrogen-induced endometrial cancers.

Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort.

Questions remain on how the excess risk of breast cancer associated with menopausal hormone therapy (MHT) evolves after treatment stops. We investigated that issue in the E3N cohort, with 3,678 invasive breast cancers identified between 1992 and 2008 among 78,353 women (881,290 person-years of postmenopausal follow-up). Exposure to MHT was assessed through biennial self-administered questionnaires and classified by type of progestagen component (progesterone or dydrogesterone; other progestagen), duration (short-term ≤5 years; long-term >5 years) and time since last use (current, 3 months-5 years, 5-10 years, 10+ years). Hazard ratios (HR) and confidence intervals (CI) were estimated with Cox models. Among short-term users, only those currently using estrogens associated with a progestagen other than progesterone/dydrogesterone had a significantly elevated breast cancer risk (HR 1.70, 95 % CI 1.50-1.91, compared with never users). Long-term use of this type of MHT was associated with a HR of 2.02 (1.81-2.26) when current and of 1.36 (1.13-1.64), 1.34 (1.04-1.73), and 1.52 (0.87-2.63) when stopped ≤5, 5-10, and 10+ years earlier, respectively. Our results suggest residual increases in breast cancer risk several years after MHT cessation, which are restricted to long-term treatments. Whether increases persist more than 10 years after cessation deserves continuing investigation.

C-reactive protein and postmenopausal breast cancer risk: results from the E3N cohort study.

BACKGROUND: C-reactive protein (CRP), a marker of low-grade inflammation, has been associated with breast cancer risk, but results are scarce and inconsistent. METHODS: A case-control study nested within the E3N prospective cohort included 549 postmenopausal breast cancer cases and 1,040 matched controls, all free of breast cancer at baseline. Serum levels of CRP were measured in samples collected between 1995 and 1999. Unconditional logistic regression models were used to evaluate the association between CRP and breast cancer risk, adjusting for matching factors and known breast cancer risk factors. RESULTS: No association was observed between CRP levels and breast cancer risk overall. However, a significant interaction was observed between CRP levels and body mass index (BMI). A statistically significant increase in breast cancer risk was observed in overweight and obese women (BMI ≥ 25 kg/m(2)) (OR 1.92, 95 % CI 1.20-3.08 for CRP ≥ 2.5 mg/L compared with CRP < 1.5 mg/l, p trend = 0.003, p interaction between CRP and BMI = 0.03). Similar results were observed in women with waist circumference (WC) ≥ 88 cm (p trend = 0.01, p interaction = 0.06) and waist-to-hip ratio (WHR) ≥ 0.80 (p trend = 0.06, p interaction = 0.35). CRP levels were not associated with breast cancer risk in women with normal BMI, WC, or WHR. CONCLUSIONS: We found a positive association between CRP levels and postmenopausal breast cancer risk restricted to women with excess adiposity. The suggested relationship between low-grade inflammation, abdominal adiposity, and postmenopausal breast cancer risk deserves further investigation.

Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study.

Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.08-1.20]) had a stronger risk association than leg length (1.05[1.00-1.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (≤13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and -negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women.