BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

Toenail and serum levels as biomarkers of iron status in pre- and postmenopausal women: correlations and stability over eight-year follow-up.

Iron status is often assessed in epidemiologic studies, and toenails offer a convenient alternative to serum because of ease of collection, transport, and storage, and the potential to reflect a longer exposure window. Very few studies have examined the correlation between serum and toenail levels for trace metals. Our aim was to compare iron measures using serum and toenails on both a cross-sectional and longitudinal basis. Using a subset of the US-wide prospective Sister Study cohort, we compared toenail iron measures to serum concentrations for iron, ferritin and percent transferrin saturation. Among 146 women who donated both blood and toenails at baseline, a subsample (59%, n = 86) provided specimens about 8 years later. Cross-sectional analyses included nonparametric Spearman's rank correlations between toenail and serum biomarker levels. We assessed within-woman maintenance of rank across time for the toenail and serum measures and fit mixed effects models to measure change across time in relation to change in menopause status. Spearman correlations at baseline (follow-up) were 0.08 (0.09) for serum iron, 0.08 (0.07) for transferrin saturation, and - 0.09 (- 0.17) for ferritin. The within-woman Spearman correlation for toenail iron between the two time points was higher (0.47, 95% CI 0.30, 0.64) than for serum iron (0.30, 95% CI 0.09, 0.51) and transferrin saturation (0.34, 95% CI 0.15, 0.54), but lower than that for ferritin (0.58, 95% CI 0.43, 0.73). Serum ferritin increased over time while nail iron decreased over time for women who experienced menopause during the 8-years interval. Based on cross-sectional and repeated assessments, our evidence does not support an association between serum biomarkers and toenail iron levels. Toenail iron concentrations did appear to be moderately stable over time but cannot be taken as a proxy for serum iron biomarkers and they may reflect physiologically distinct fates for iron.

Associations Between Serum Iron Biomarkers and Breast Cancer Tumor Size.

Excess iron has been shown to promote tumor growth in animals whereas iron deficiency has been associated with reduced or slowed tumor growth. The objective of this analysis was to estimate the associations between serum iron biomarkers and tumor size at diagnosis and metastatic status in a sample of breast cancer cases from the Sister Study.The analytic sample included 2,494 incident breast cancer cases with information on tumor size and iron biomarkers, including serum iron (mcg/dL), ferritin (mcg/dL), and percent transferrin saturation, measured in serum collected at baseline. We used Spearman rank correlation and linear regression models to assess the associations between one SD changes in serum iron biomarker levels and natural log of tumor size (cm) adjusting for body mass index and age at study entry.We did not find strong associations between any of the three serum iron biomarkers and tumor size. Adjusted regression slopes (95% confidence interval) were -0.016 (-0.048 to 0.016) for serum iron, -0.032 (-0.064 to <0.001) for ferritin, and -0.010 (-0.043 to 0.023) for transferrin saturation.This study did not provide evidence supporting the hypothesis of a positive association between breast cancer tumor size at diagnosis and prediagnostic serum iron levels. Conflicting evidence between this study and previous research in animal models suggests that iron in the human tumor microenvironment may operate independently of circulating iron or body iron stores.Iron has shown protumorigenic activity in animal models, but our data do not support a positive relationship between breast tumor growth and iron status. SIGNIFICANCE: Using a large sample of women from a U.S. prospective cohort, we assessed associations between several serum iron measures at baseline and breast cancer tumor size and metastatic status. All estimated associations were close to zero with no evidence to support our hypothesis of higher body iron levels associated with larger tumor size. These results suggest the human tumor microenvironment operates independently of circulating serum iron levels.

Development and validation of a prediction model for iron status in a large U.S. cohort of women.

Serum iron levels can be important contributors to health outcomes, but it is not often feasible to rely on blood-based measures for a large epidemiologic study. Predictive models that use questionnaire-based factors such as diet, supplement use, recency of blood donation, and medical conditions could potentially provide a noninvasive alternative for studying health effects associated with iron status. We hypothesized that a model based on questionnaire data could predict blood-based measures of iron status biomarkers. Using iron (mcg/dL), ferritin (mcg/dL), and transferrin saturation (%) based on blood collected at study entry, in a subsample from the U.S.-wide Sister Study (n = 3171), we developed and validated a prediction model for iron with multivariable linear regression models. Model performance based on these cross-sectional data was weak, with R2 less than 0.10 for serum iron and transferrin saturation, but better for ferritin, with an R2 of 0.13 in premenopausal women and 0.19 in postmenopausal women. When menopause was included in the predictive model for the sample, the R2 was 0.31 for ferritin. Internal validation of the estimates indicated some optimism present in the observed prediction model, implying there would be worse performance when applied to new samples from the same population. Serum iron status is hard to assess based only on questionnaire data. Reducing measurement error in both the exposure and outcome may improve the prediction model performance, but environmental heterogeneity, temporal variation, and genetic heterogeneity in absorption and storage may contribute substantially to iron status.

Evidence for familial clustering in breast cancer age of onset.

BACKGROUND: Familial clustering of age at onset would have implications for both personalized screening and aetiology, but has not been studied for breast cancer. METHODS: We prospectively studied a cohort of 23 145 sisters to explore whether their breast cancer risk changed near the age at diagnosis of a previously affected older sister. Using an age-time-dependent variable in a Cox regression model, we estimated hazard ratios for breast cancer when participants were near their sister's diagnosis age, relative to similarly aged women whose sister was diagnosed at a very different age. To rule out a correlation driven by young-onset familial cancer, we separately investigated women who had enrolled at age 50 or older. RESULTS: Of the 23 145 women, 1412 developed breast cancer during follow-up (median 9.5 years). The estimated hazard ratio was 1.80 (95% confidence interval: 1.18, 2.74) at their sister's age at diagnosis, suggesting a substantial increase in risk compared with women of the same age but whose sister was diagnosed at a very different age. Restriction to women who enrolled at or after age 50 produced similar results. CONCLUSIONS: This familial clustering suggests that there may be important genetic and/or early environmental risk factors that influence the timing of breast cancer, even when onset is late in life. Personalized screening might need to account for the age at which a sister was earlier diagnosed with breast cancer.

Association Between Serum Iron Biomarkers and Breast Cancer.

BACKGROUND: Iron is both essential to life and potentially toxic at higher levels. Epidemiologic studies of iron and breast cancer are sparse, with substantial heterogeneity found in a recent meta-analysis. Evidence based on a comprehensive set of iron biomarkers and a large sample size could help clarify relationships between iron body stores and breast cancer risk. METHODS: A case-cohort sample of 6,008 women, including 3,011 incident cases, has been followed for a median of 7.9 years. We estimated breast cancer HRs with Cox models, including age as the primary time scale and including in turn iron, ferritin, percent transferrin saturation, and their first principal component (PC) both as categorical (quartiles) and continuous measures. RESULTS: Adjusted HRs for the highest versus lowest quartiles of iron, ferritin, and transferrin saturation (95% confidence interval) were 1.06 (0.90-1.25), 1.03 (0.87-1.23), and 0.94 (0.80-1.12), respectively, and 1.06 (0.90-1.25) for the first principal component (PC). Associations were similar when follow-up time was restricted to ≤4 or >2 years. Post hoc analyses suggested low iron stores were associated with reduced breast cancer risk, in both pre- and postmenopause and the obese. CONCLUSIONS: A study with one of the largest sample sizes to date and with all three measures of circulating iron, ferritin, and transferrin saturation does not support a strong association between elevated iron stores and breast cancer risk. Further investigation of low iron may be warranted. IMPACT: These results do not support a strong association between iron overload and breast cancer incidence.

Factors associated with binge eating disorder in pregnancy.

OBJECTIVE: To identify factors associated with incidence and course of broadly defined binge eating disorder (BED) in pregnancy. METHOD: As a part of the Norwegian Mother and Child Cohort Study (MoBa), 45,644 women completed a questionnaire at approximately 18 weeks of gestation. RESULTS: Incidence of BED was significantly associated with lifetime sexual abuse, lifetime physical abuse, lifetime major depression, symptoms of anxiety and depression, low life satisfaction, low self-esteem, low partner relationship satisfaction, smoking, alcohol use, lack of social support, and several weight-related factors. Continuation was negatively associated with thoughts of being overweight before pregnancy. Remission was positively associated with thoughts of being overweight before pregnancy and negatively associated with overvaluation of weight. DISCUSSION: Onset of BED in pregnancy was associated with psychological, social and weight-related factors, as well as health behaviors and adverse life events. In women with prepregnancy BED, thoughts of being overweight before pregnancy and overvaluation of weight were associated with course of BED during pregnancy.

Birth outcomes in women with eating disorders in the Norwegian Mother and Child cohort study (MoBa).

OBJECTIVE: We explored the impact of eating disorders on birth outcomes in the Norwegian Mother and Child Cohort Study. METHOD: Of 35,929 pregnant women, 35 reported broad anorexia nervosa (AN), 304 bulimia nervosa (BN), 1,812 binge eating disorder (BED), and 36 EDNOS-purging type (EDNOS-P) in the six months before or during pregnancy. The referent comprised 33,742 women with no eating disorder. RESULTS: Pre-pregnancy body mass index (BMI) was lower in AN and higher in BED than the referent. AN, BN, and BED mothers reported greater gestational weight gain, and smoking was elevated in all eating disorder groups. BED mothers had higher birth weight babies, lower risk of small for gestational age, and higher risk of large for gestational age and cesarean section than the referent. Pre-pregnancy BMI and gestational weight gain attenuated the effects. CONCLUSION: BED influences birth outcomes either directly or via higher maternal weight and gestational weight gain. The absence of differences in AN and EDNOS-P may reflect small numbers and lesser severity in population samples. Adequate gestational weight gain in AN may mitigate against adverse birth outcomes. Detecting eating disorders in pregnancy could identify modifiable factors (e.g., high gestational weight gain, binge eating, and smoking) that influence birth outcomes.

Features associated with diet pill use in individuals with eating disorders.

We investigated the relation between diet pill use and eating disorder subtype, purging and other compensatory behaviors, body mass index (BMI), tobacco and caffeine use, alcohol abuse or dependence, personality characteristics, and Axis I and Axis II disorders in 1,345 participants from the multisite Price Foundation Genetics Studies. Diet pill use was significantly less common in women with restricting type of AN than in women with other eating disorder subtypes. In addition, diet pill use was associated with the use of multiple weight control behaviors, higher BMI, higher novelty seeking, and the presence of anxiety disorders, alcohol abuse or dependence, and borderline personality disorder. Findings suggest that certain clinical and personality variables distinguish individuals with eating disorders who use diet pills from those who do not. In the eating disorder population, vigilant screening for diet pill use should be routine clinical practice.