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The incidence of thyroid cancer in women is increasing at an alarming rate, with greatest risk in the reproductive years. Establishing relationships of hormonally related reproductive factors with thyroid cancer has been difficult. We aimed to elucidate potential risk factors for thyroid cancer in a large cohort of women. Among 116,228 women in the Nurses' Health Study II followed from 1989 to 2013, 620 cases of thyroid cancer were identified. We examined reproductive and hormone-related factors, including age at menarche, age at menopause, parity, oral contraceptive use, and postmenopausal hormone therapy use. Pregnancy, reproductive years, and months of breastfeeding were used as surrogate markers for exposure to endogenous reproductive hormones. We used multivariable Cox models to calculate relative risks and 95% confidence intervals for the associations between these factors and risk of thyroid cancer. Number of reproductive years of 41 years or more was associated with more than double the risk of thyroid cancer compared with 30 years or fewer (relative risk, 2.20; 95% confidence interval, 1.19–4.06). The other variables analyzed (parity number, months of breastfeeding, age at menarche, menopausal status, and postmenopausal hormone therapy) were not associated with the risk of thyroid cancer. Women who entered menopause at age 45 years or older had a higher risk of thyroid cancer compared with women who entered menopause at a younger age. This result did not reach statistical significance; however, there was a linear trend between later age at menopause and increased risk of thyroid cancer (p trend =.009). This study used a unique large, longitudinal dataset to assess thyroid cancer risk factors and potential confounders over an extended time frame. Our key finding suggests increased risk of thyroid cancer may be associated with a variety of indicators of longer reproductive years. The Nurses' Health Study II has provided new insights into the hormonal risks associated with thyroid cancer. [ABSTRACT FROM AUTHOR]

Objective: To prospectively evaluate the association between dietary fat intake and risk of uterine fibroids; and to evaluate the association between erythrocyte membrane fatty acid (FA) levels and fibroid risk.Design: Prospective cohort study. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence interval (CI). In a subset of participants 34 individual FAs were measured and logistic regression analysis was used to estimate odds ratios (ORs) and 95% CI for the association between FA tertiles and fibroids.Setting: Not applicable.Patient(s): Premenopausal US women (81,590) in the Nurses' Health Study II, aged 25-42 years at enrollment in 1989 for whom diet was assessed by a food frequency questionnaire. A total of 553 participants with erythrocyte FA measurements.Intervention(s): Not applicable.Main Outcome Measure(s): Cases of fibroids were defined on the basis of self-reported ultrasound or hysterectomy confirmation.Result(s): A total of 8,142 cases of ultrasound-confirmed or hysterectomy-confirmed were diagnosed during an 18-year period (1991-2009). No associations were observed between intake of any dietary fats and fibroids in the multivariable models. However, when erythrocyte FAs were examined, an inverse association was observed between total n-3 polyunsaturated FAs and likelihood of fibroids (OR for third versus first tertile, 0.41; 95% CI 0.19-0.89). In addition, total trans FAs were associated with more odds of fibroids (OR for third tertile, 3.33; 95% CI 1.50-7.38).Conclusion(s): Our findings provide preliminary suggestions that n-3 polyunsaturated FAs and trans FAs may play a role in fibroid etiology; however, these results should be confirmed in future studies. [ABSTRACT FROM AUTHOR]

Given these divergent biologic properties, glucocorticoids could theoretically reduce breast cancer risk via anti-inflammatory effects or could increase breast cancer risk and progression by inducing insulin resistance and promoting immunosuppression [[2]]. As authors of this study note, estrogen inhibition induced by glucocorticoids may explain the lower risk of ER-positive tumors observed in this study. Keywords: Glucocorticoids; Breast cancer; Estrogen receptor EN Glucocorticoids Breast cancer Estrogen receptor 1 3 3 08/04/21 20210802 NES 210802 This comment refers to the article available at https://doi.org/10.1186/s12916-021-02004-6. [Extracted from the article]

Background To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models. Methods We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics. Results When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC. Conclusions Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model. [ABSTRACT FROM AUTHOR]

Objectives. To review the contribution of the Nurses' Heath Study (NHS) and the NHS II in identifying risk and protective factors for breast cancer incidence and survival. Methods. We conducted a narrative review of NHS and NHS II articles on breast cancer incidence and survival published from 1976 to 2016, with a focus on exogenous and endogenous hormones; lifestyle factors, including diet, physical activity, and aspirin use; intermediate markers of risk; and genetic factors. Results. With the investigation of individual risk factors, as well as their incorporation into risk prediction models, the NHS has contributed to the identification of ways in which women may reduce breast cancer risk, including limiting alcohol consumption, reducing the duration of postmenopausal estrogen-plus-progestin use, avoiding weight gain, and increasing vegetable consumption. In addition, the NHS has helped elucidate the roles of several biomarkers and contributed to the identification of risk alleles. Conclusions. The NHS has contributed to our understanding of lifestyle, hormonal, and genetic risk factors for breast cancer, highlighting the importance of exposures across the life course, and has helped identify lifestyle changes that may reduce risk and improve survival after a diagnosis of breast cancer. [ABSTRACT FROM AUTHOR]

Understanding how the timing of exposure to endogenous hormones influences cancer development is critical to elucidating disease etiology. Prolactin increases proliferation and cell motility, processes important in later stage tumor development, suggesting that levels proximate (versus distant) to diagnosis may better predict risk. Thus, we calculated relative risks (RR) and 95% confidence intervals (CI) for prolactin levels on samples collected <10 (proximate) versus ≥10 (distant) years before diagnosis in the Nurses' Health Study (NHS) and NHSII with breast cancer risk, including in a subset of NHS women providing two samples 10 years apart. We measured prolactin via immunoassay in cases diagnosed from 1990 to 2010 (NHS) and 1999 to 2009 (NHSII) and matched controls. Overall, 2,468 cases and 4,021 controls had prolactin measured <10 years and 953 cases and 1,339 controls >10 years before diagnosis/reference date. There was an increased risk for higher proximate prolactin levels [RR, >15.7 vs. ≤8.1 ng/mL (i.e., top vs. bottom quartiles)=1.20; 95% CI, 1.03-1.40; Ptrend = 0.005], but not for distant levels (RR = 0.97; Ptrend = 0.94); results were similar among women with two blood samples (Pinteraction, proximate vs. distant = 0.07). The positive association was stronger for ER+ disease (RR = 1.28; Ptrend = 0.003) and postmenopausal women (RR = 1.37; Ptrend = 0.0002). Among postmenopausal women, the association was P strongest for ER+ disease (RR = 1.52) and lymph node-positive cases (RR = 1.63). Our data suggest that prolactin levels measured <10 years before diagnosis are most strongly associated with postmenopausal breast cancer risk, especially for ER+ tumors and metastatic disease. This corresponds with biologic data that prolactin is etiologically important in tumor promotion. [ABSTRACT FROM AUTHOR]

Background Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. Methods We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All Pvalues are two-sided. Results Statistically significant inverse associations with breast cancer were observed for (β-carotene (top vs bottom quintile RR = 0.87, 95% CI = 0.71 to 1.05, Ptrend=.04), [β-carotene (RR = 0.83, 95% CI = 0.70 to 0.98, Ptrend=.02), lutein+zeaxanthin (RR = 0.84, 95% CI = 0.70 to 1.01, Ptrend=.05), lycopene (RR = 0.78, 95% Cl = 0.62 to 0.99, Ptrend=.02), and total carotenoids (RR = 0.81, 95% CI = 0.68 to 0.96, Ptrend=.01). [β-Cryptoxanthin was not statistically significantly associated with risk.Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER-:) than for ER tumors (eg, [β-carotene: ER-: top vs bottom quintile RR = 0.52, 95% CI = 0.36 to 0.77, Ptrend=.001; ER+: RR = 0.83, 95% CI = 0.66 to 1.04, Ptrend=.06; Pheterogeneity=.01 ), Conclusions This comprehensive prospective analysis suggests women with higher circulating levels of α-carotene, [β-carotene, lutein+zeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer. [ABSTRACT FROM AUTHOR]

Few studies have assessed the association between endogenous steroid hormone levels and a subsequent diagnosis of endometriosis. We prospectively evaluated premenopausal plasma sex hormone levels and the risk of laparoscopically confirmed endometriosis in a nested case-control study within Nurses' Health Study II. Between blood collection (1996–1999) and 2009, we ascertained 446 women with incident endometriosis and matched them to 878 controls through risk-set sampling. We conducted multivariable conditional logistic regression accounting for matching and confounders to estimate relative risks (RRs) and 95% confidence intervals (CIs). Women with greater early follicular-phase total or free estradiol levels had a nonlinear increased risk of endometriosis (early follicular total estradiol: second quartile vs. first, RR = 2.23 (95% CI: 1.44, 3.47); third quartile, RR = 1.83 (95% CI: 1.16, 2.88); fourth quartile, RR = 1.68 (95% CI: 1.05, 2.68); early follicular free estradiol: second quartile vs. first, RR = 1.63 (95% CI: 1.05, 2.54); third quartile, RR = 2.02 (95% CI: 1.31, 3.12); fourth quartile, RR = 1.04 (95% CI: 0.66, 1.65)). Free testosterone assessed in quartile categories was not associated with endometriosis, although a threshold effect was observed, with a positive association among women in the top 2% of free testosterone levels. Levels of mid–luteal-phase total and free estradiol, follicular and luteal estrone, total testosterone, progesterone, and sex hormone binding globulin were not associated with endometriosis risk. These results support the role of sex steroids in endometriosis etiology, although the relationships suggest complex threshold effects. [ABSTRACT FROM AUTHOR]

Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N=247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30-0.88; estradiol = 0.51; 95% CI, 0.30-0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08-2.81; Ptrend = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99-2.62; Ptrend = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non-parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35-0.96; Ptrend = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non-parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk. [ABSTRACT FROM AUTHOR]

The article presents a study associating physical activity with breast cancer risk among postmenopausal women. Variation across levels of other risk factors is examined. Findings suggest that moderate physical activity including brisk walking, may reduce postmenopausal breast cancer risk. Body mass index (BMI), weight change since 18 years of age and use of postmenopausal hormones (PMH) were taken into account.

The article presents a study which examines the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS) as a risk factor for breast cancer in premenopausal women in Nurses' Health Study II. The study enrolled 112, 292 women, aged 25 to 42 years old, who are breast cancer free. The Cox proportional hazards models were used to compute for the multivariate relative risks. Results indicate that there were no significant relationship between the use of aspirin, NSAIDS, and acetaminophen and the risk for breast cancer. Findings inferred that the use of aspirin, NSAIDS, and acetaminophen is not associated with the risk of breast cancer in premenopausal women.

Abstract: Multiple lines of evidence support a central role of hormones in the etiology of breast cancer. In epidemiologic studies, considerable effort has focused on delineating the role of endogenous hormones in risk of breast cancer among postmenopausal women. Recently, substantial additional data has accrued from prospective studies where endogenous hormones are measured in study subjects prior to disease diagnosis. In this review, the epidemiologic evidence linking sex steroids—estrogens, testosterone, and progesterone, specifically—with subsequent risk of breast cancer in both premenopausal and postmenopausal women is summarized. Overall, a strong positive association between breast cancer risk and circulating levels of both estrogens and testosterone has now been well confirmed among postmenopausal women; women with hormone levels in the top 20% of the distribution (versus bottom 20%) have a two- to three-fold higher risk of breast cancer. Evidence among premenopausal women is more limited, though increased risk associated with higher levels of testosterone is consistent. However, both positive and null associations have been observed with estrogens and progesterone and clearly more evaluation is needed. [Copyright &y& Elsevier]

Background: Higher levels of endogenous sex steroid hormones are associated with increased risks of breast cancer in postmenopausal women. Data for premenopausal women are sparse, in part because of the complexity of measuring hormone levels that vary cyclically. We prospectively evaluated associations between plasma sex hormone levels and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II. Methods: From 1996 to 1999, blood samples were collected from 18 521 premonoupausal women during the early follicular and mid-luteal phases of their menstrual cycles. A total of 197 cases of breast cancer were diagnosed among these women after blood collection and before June 1, 2003: these cases subjects were matched to 394 control subjects. Logistic regression models, controlling for breast cancer risk factors, were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Women in the highest (versus the lowest) quartiles of follicular total and free estradiol levels had statistically significantly increased risks of breast cancer (RR = 2.1 [95% CI - 1.1 to 4.1], Ptrend = .08, and RR = 2.4 [95% CI = 1.3 to 4.5]. Ptrend = .01, respectively); the associations were stronger for invasive breast cancer and for estrogen and progesterone receptor-positive (ER+/PR+) tumors. Luteal estradiol levels were not associated with breast cancer risk. Higher levels of total and free testosterone and androstenedione in both menstrual cycle phases were associated with modes, non-statistically significant increases in overall risk of breast cancer and with stronger, statistically significant increases in risks of invasive and ER+/PR+ cancers (e.g., RR of invasive cancers for the top [versus bottom] quartile of luteal total testosterone levels = 2.0 [95% CI = 1.4 to 6.0], Ptrend = .02). Levels of estrone, estrone sulfate, progesterone, and sex hormone-binding globulin were not associated with breast cancer risk. The absolute number of cases observed over 3 years were 30 among women in the lowest 25% of follicular total estradiol levels and 50 among women in the highest 25%. Conclusions: Levels of circulating estrogens and androgens may be important in the etiology of premenopausal breast cancer. [ABSTRACT FROM AUTHOR]

The article reports on a study which looked at whether adult weight change affected the risk of postmenopausal breast cancer. Researchers found that women who gained weight later in life, especially after menopause, had an increased risk of breast cancer. Weight loss after menopause was found to be associated with a decreased risk.

Background Experimental evidence suggests that statins protect against breast carcinogenesis by interrupting cell cycle progression and promoting apoptosis. Evidence in humans is limited and inconsistent. The relation between serum cholesterol levels and breast cancer risk is itself unclear; because cholesterol is the precursor to sex steroid hormones, higher levels could plausibly increase risk. Methods The associations of statins, general lipid-lowering drugs, and reported cholesterol levels with breast cancer risk were assessed in the Nurses’ Health Study, with 6 to 12 years of follow-up. A total of 79 994 women aged 42 to 69 years and free of cancer were followed prospectively for up to 12 years. Current statin use, including duration, was assessed retrospectively in 2000 in 75 828 women. Self-reported serum cholesterol level was assessed prospectively between 1990 and 2000 in 71 921 women. Results Overall, we documented 3177 incident cases of invasive breast cancer. Compared with nonusers, current lipid-lowering drug users experienced similar breast cancer risk (multivariate relative risk [RR], 0.99; 95% confidence interval [CI], 0.86-1.13). Current use of statins also was not significantly associated with breast cancer risk (RR, 0.91; 95% CI, 0.76-1.08). Associations by duration of current use were similarly null. Self-reported serum cholesterol levels were not associated with breast cancer risk in postmenopausal women with levels of 240 mg/dL or higher (≥6.22 mmol/L) compared with less than 180 mg/dL (<4.66 mmol/L) (RR, 1.04; 95% CI, 0.91-1.17). Conclusion Overall, these data suggest that serum cholesterol levels and the use of lipid-lowering drugs in general and of statins in particular are not substantially associated with breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Levels of endogenous hormones have been associated with the risk of breast cancer among postmenopansal women. Little research, however, has investigated the association between hormone levels and tumor receptor status or invasive versus in situ tumor status. Nor has the relation between breast cancer risk and postmenopausal progesterone levels been investigated. We prospectively investigated these relations in a case-control study nested within the Nurses' Health Study. Methods: Blood samples were prospectively collected during 1989 and 1990. Among eligible postmenopausal women, 322 cases of breast cancer (264 invasive, 41 in situ, 153 estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [ER+PR+], and 39 ER-negative and PR-negative [ER-/PR-] disease) were reported through June 30, 1998. For each case subject, two control subjects (n = 643) were matched on age and blood collection (by month and time of day). Endogenous hormone levels were measured in blood plasma. We used conditional and unconditional logistic regression analyses to assess associations and to control for established breast cancer risk factors. Results: We observed a statistically significant direct association between breast cancer risk and the level of both estrogens and androgens, but we did not find any (by year) statistically significant associations between this risk and the level of progesterone or sex hormone binding globulin. When we restricted the analysis to case subjects with ER+/PR+ tumors and compared the highest with the lowest fourths of plasma hormone concentration, we observed an increased risk of breast cancer associated with estradiol (relative risk [RR] = 3.3, 95% confidence interval [CI] = 2.0 to 5.4), testosterone (RR = 2.0, 95% CI = 1.2 to 3.4), androstenedione (RR = 2.5, 95% CI = 1.4 to 4.3), and dehydroepiandrosterone sulfate (RR = 2.3, 95% CI = 1.3 to 4.1). In addition, all hormones tended to be associated most strongly with in situ disease. Conclusion: Circulating levels of sex steroid hormones may be most strongly associated with risk of ER+/PR+ breast tumors. [ABSTRACT FROM AUTHOR]

Background Although several dietary patterns have been associated with incident colorectal cancer (CRC), it is unclear which diet is optimal. Methods Participants included 48 409 men and 169 772 women from three USA-based prospective cohort studies. We compared the associations of 18 dietary patterns with CRC risk, including two reference scores. The reference scores were derived based on the dietary recommendations for cancer prevention and CRC-specific dietary risk factors mentioned in the 2018 World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) Third Expert Report. Multivariable Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and 95% CIs. Results Most dietary patterns showed moderate correlations with the WCRF dietary score (absolute values of Spearman correlation coefficients: 0.45–0.63), except the Plant-based diet index, low-carbohydrate diets, the Empirical dietary index for hyperinsulinemia (EDIH) and Empirical dietary inflammation pattern (EDIP). HR for the 10th–90th percentile difference in the score was 0.86 (95% CI: 0.78–0.94) for the Dietary Approaches to Stop Hypertension score (DASH), 1.15 (1.06–1.26) for Western dietary pattern, 1.20 (1.10–1.31) for EDIH and 1.23 (1.13–1.34) for EDIP. These associations between patterns and CRC risk persisted after adjusting for the two reference scores. Conclusions Although further research is needed to improve the WCRF/AICR dietary recommendations, our comprehensive assessment of dietary patterns revealed that the DASH, Western dietary pattern, EDIH and EDIP may be the most relevant diets for preventing CRC. [ABSTRACT FROM AUTHOR]

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses' Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q < 0.25, including 3 associations with q < 0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer. We investigated the germline genetic determinants of immune features in the breast tumor microenvironment. Our results reveal genetic links between tumor immune profiles, especially those related to interferon signaling, and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying alcohol‐induced breast carcinogenesis are not fully understood but may involve hormonal changes. Methods: Cross‐sectional associations were investigated between self‐reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta‐analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two‐sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6–7.6) and free testosterone (7.8%; 4.1–11.5), and an inverse association with SHBG (–8.1%; –11.3% to –4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk. Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions. Sex hormones are therefore likely to be part of the mechanism through which alcohol increases breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Sexual minority (SM) individuals (e.g., those with same‐sex attractions/partners or who identify as lesbian/gay/bisexual) experience a host of physical and mental health disparities. However, little is known about sexual orientation‐related disparities in gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP; gestational hypertension [gHTN] and preeclampsia). Objective: To estimate disparities in GDM, gHTN and preeclampsia by sexual orientation. Methods: We used data from the Nurses' Health Study II—a cohort of nurses across the US enrolled in 1989 at 25–42 years of age—restricted to those with pregnancies ≥20 weeks gestation and non‐missing sexual orientation data (63,518 participants; 146,079 pregnancies). Our primary outcomes were GDM, gHTN and preeclampsia, which participants reported for each of their pregnancies. Participants also reported their sexual orientation identity and same‐sex attractions/partners. We compared the risk of each outcome in pregnancies among heterosexual participants with no same‐sex experience (reference) to those among SM participants overall and within subgroups: (1) heterosexual with same‐sex experience, (2) mostly heterosexual, (3) bisexual and (4) lesbian/gay participants. We used modified Poisson models to estimate risk ratios (RR) and 95% confidence intervals (CI), fit via weighted generalised estimating equations, to account for multiple pregnancies per person over time and informative cluster sizes. Results: The overall prevalence of each outcome was ≤5%. Mostly heterosexual participants had a 31% higher risk of gHTN (RR 1.31, 95% CI 1.03, 1.66), and heterosexual participants with same‐sex experience had a 31% higher risk of GDM (RR 1.31, 95% CI 1.13, 1.50), compared to heterosexual participants with no same‐sex experience. The magnitudes of the risk ratios were high among bisexual participants for gHTN and preeclampsia and among lesbian/gay participants for gHTN. Conclusions: Some SM groups may be disparately burdened by GDM and HDP. Elucidating modifiable mechanisms (e.g., structural barriers, discrimination) for reducing adverse pregnancy outcomes among SM populations is critical. [ABSTRACT FROM AUTHOR]

Background: Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow‐up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. Methods: We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow‐up Study, leveraging repeated measurements throughout up to 40 years of follow‐up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all‐causes (HR, 95% CI was 3.16, 2.64–3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27–10.1), respiratory disease (3.43, 1.38–8.51), neurodegenerative disease (5.13, 2.09–12.6), and kidney disease (8.55, 1.98–36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. Conclusion: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all‐cause and cause‐specific mortality and greater loss in life expectancy. [ABSTRACT FROM AUTHOR]

Background Inflammation and metabolic dysregulation are associated with increased risk of colorectal cancer (CRC); the underlying mechanisms are not fully understood. We characterized metabolomic signatures of inflammation and metabolic dysregulation and evaluated the association of the signatures and individual metabolites with CRC risk. Methods Among 684 incident CRC cases and 684 age-matched controls in the Nurses' Health Study (n = 818 women) and Health Professionals Follow-up Study (n = 550 men), we applied reduced rank and elastic net regression to 277 metabolites for markers of inflammation (C-reactive protein, interleukin 6, tumor necrosis factor receptor superfamily member 1B, and growth differentiation factor 15) or metabolic dysregulation (body mass index, waist circumference, C-peptide, and adiponectin) to derive metabolomic signatures. We evaluated the association of the signatures and individual metabolites with CRC using multivariable conditional logistic regression. All statistical tests were 2-sided. Results We derived a signature of 100 metabolites that explained 24% of variation in markers of inflammation and a signature of 73 metabolites that explained 27% of variation in markers of metabolic dysregulation. Among men, both signatures were associated with CRC (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.07 to 1.68 per 1-standard deviation increase, inflammation; OR = 1.25, 95% CI = 1.00 to 1.55 metabolic dysregulation); neither signature was associated with CRC in women. A total of 11 metabolites were individually associated with CRC and biomarkers of inflammation or metabolic dysregulation among either men or women. Conclusion We derived metabolomic signatures and identified individual metabolites associated with inflammation, metabolic dysregulation, and CRC, highlighting several metabolites as promising candidates involved in the inflammatory and metabolic dysregulation pathways for CRC incidence. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Cancer risk factors are more common among sexual minority populations (e.g., lesbian, bisexual) than their heterosexual peers, yet little is known about cancer incidence across sexual orientation groups.The 1989–2017 data from the Nurses’ Health Study II, a longitudinal cohort of female nurses across the United States, were analyzed (N = 101,543). Sexual orientation‐related cancer disparities were quantified by comparing any cancer incidence among four sexual minority groups based on self‐disclosure—(1) heterosexual with past same‐sex attractions/partners/identity; (2) mostly heterosexual; (3) bisexual; and (4) lesbian women—to completely heterosexual women using age‐adjusted incidence rate ratios (aIRR) calculated by the Mantel‐Haenszel method. Additionally, subanalyses at 21 cancer disease sites (e.g., breast, colon/rectum) were conducted.For all‐cancer analyses, there were no statistically significant differences in cancer incidence at the 5% type I error cutoff among sexual minority groups when compared to completely heterosexual women; the aIRR was 1.17 (95% CI,0.99–1.38) among lesbian women and 0.80 (0.58–1.10) among bisexual women. For the site‐specific analyses, incidences at multiple sites were significantly higher among lesbian women compared to completely heterosexual women: thyroid cancer (aIRR, 1.87 [1.03–3.41]), basal cell carcinoma (aIRR, 1.85 [1.09–3.14]), and non‐Hodgkin lymphoma (aIRR, 2.13 [1.10–4.12]).Lesbian women may be disproportionately burdened by cancer relative to their heterosexual peers. Sexual minority populations must be explicitly included in cancer prevention efforts. Comprehensive and standardized sexual orientation data must be systematically collected so nuanced sexual orientation‐related cancer disparities can be accurately assessed for both common and rare cancers. [ABSTRACT FROM AUTHOR]

Reproductive events, such as ovulation, trigger an inflammatory cascade. Few studies have examined their long-term influence on inflammatory profiles. We included 3,393 premenopausal and 3,915 postmenopausal women with intact ovaries/uterus from the Nurses' Health studies (Nurses' Health Study (1989–1990) and Nurses' Health Study II (1996–1999)) in an analysis of the association between lifetime ovulatory years (LOY) and levels of inflammatory biomarkers. We estimated LOY as age at menopause (age at blood collection for premenopausal women) minus age at menarche, subtracting years of oral contraceptive (OC) use and 1 year per pregnancy. After adjustment for other inflammation-related factors (e.g. body mass index, exercise, diet), every 5-year increase in LOY was associated with lower C-reactive protein (CRP) levels in both premenopausal (difference = −11.5%, 95% confidence interval: −15.0, −8.0; P  < 0.0001) and postmenopausal (difference = −7.2%, 95% confidence interval: −10.0, −4.3; P  < 0.0001) women. Older age at menopause (P  = 0.007), earlier menarche (P  = 0.007), and shorter duration of OC use (P  = 0.002) were associated with lower CRP levels in postmenopausal women, whereas duration of OC use was positively associated with CRP levels in premenopausal women (P  < 0.0001). LOY was modestly inversely associated with interleukin 6 in postmenopausal women (P  = 0.03). Notably, the associations of CRP with LOY were similar in magnitude to associations with exercise and a healthy diet, though weaker than the association with body mass index. Although many reproductive events induce acute inflammation, increased LOY was associated with lower chronic systemic inflammation even after menopause. [ABSTRACT FROM AUTHOR]

Key Points: Question: Among people with weight loss within the past 2 years, is the rate of cancer diagnosis significantly increased during the subsequent 12 months compared with those without recent weight loss? Findings: Among 157 474 health professionals followed up for a mean of 28 years, recent weight loss of greater than 10.0% of body weight was associated with an increased rate of cancer during the next 12 months vs those without recent weight loss (1362 cancer cases/100 000 person-years vs 869 cancer cases/100 000 person-years, respectively; between-group difference, 493 cases/100 000 person-years). Meaning: Recent weight loss was associated with a significantly higher rate of cancer during the next 12 months compared with those without recent weight loss. Importance: Weight loss is common in primary care. Among individuals with recent weight loss, the rates of cancer during the subsequent 12 months are unclear compared with those without recent weight loss. Objective: To determine the rates of subsequent cancer diagnoses over 12 months among health professionals with weight loss during the prior 2 years compared with those without recent weight loss. Design, Setting, and Participants: Prospective cohort analysis of females aged 40 years or older from the Nurses' Health Study who were followed up from June 1978 until June 30, 2016, and males aged 40 years or older from the Health Professionals Follow-Up Study who were followed up from January 1988 until January 31, 2016. Exposure: Recent weight change was calculated from the participant weights that were reported biennially. The intentionality of weight loss was categorized as high if both physical activity and diet quality increased, medium if only 1 increased, and low if neither increased. Main Outcome and Measures: Rates of cancer diagnosis during the 12 months after weight loss. Results: Among 157 474 participants (median age, 62 years [IQR, 54-70 years]; 111 912 were female [71.1%]; there were 2631 participants [1.7%] who self-identified as Asian, Native American, or Native Hawaiian; 2678 Black participants [1.7%]; and 149 903 White participants [95.2%]) and during 1.64 million person-years of follow-up, 15 809 incident cancer cases were identified (incident rate, 964 cases/100 000 person-years). During the 12 months after reported weight change, there were 1362 cancer cases/100 000 person-years among all participants with recent weight loss of greater than 10.0% of body weight compared with 869 cancer cases/100 000 person-years among those without recent weight loss (between-group difference, 493 cases/100 000 person-years [95% CI, 391-594 cases/100 000 person-years]; P <.001). Among participants categorized with low intentionality for weight loss, there were 2687 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 1220 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 1467 cases/100 000 person-years [95% CI, 799-2135 cases/100 000 person-years]; P <.001). Cancer of the upper gastrointestinal tract (cancer of the esophagus, stomach, liver, biliary tract, or pancreas) was particularly common among participants with recent weight loss; there were 173 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 36 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 137 cases/100 000 person-years [95% CI, 101-172 cases/100 000 person-years]; P <.001). Conclusions and Relevance: Health professionals with weight loss within the prior 2 years had a significantly higher risk of cancer during the subsequent 12 months compared with those without recent weight loss. Cancer of the upper gastrointestinal tract was particularly common among participants with recent weight loss compared with those without recent weight loss. This study compares the rates of subsequent cancer diagnoses over 12 months among health professionals in the Nurses' Health Study and the Health Professionals Follow-Up Study with weight loss during the prior 2 years compared with those without recent weight loss. [ABSTRACT FROM AUTHOR]

Mitochondria are key cytoplasmic organelles in eukaryotic cells that generate adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation. Mitochondrial DNA (mtDNA) copy number (mtDNAcn) is considered a biomarker for both mitochondrial quantity and function as well as cellular oxidative stress level. Previous epidemiologic findings revealed that weight gain, higher body mass index (BMI), smoking, and high insulinemic potential of lifestyle were associated with lower leukocyte mtDNAcn. Carnitines are a group of compounds that play a critical role in energy production. We quantified the associations of plasma L-carnitine levels with leukocyte mtDNAcn. We then examined the association between mtDNAcn and L-carnitine (HMDB0000062) in 538 U.S. men without cancers, diabetes, or cardiovascular disease at blood collection from the Health Professionals Follow-Up Study (HPFS). We found a significant inverse association between L-carnitine and mtDNAcn (ρ = −0.1, P = 0.02). This implies that the carnitine metabolic pathway may be associated with mitochondrial function and oxidative stress. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the potential connection between working night shifts, sleep patterns, and the risk of thyroid cancer among nurses. The researchers followed over 114,000 women for 26 years and identified 588 cases of thyroid cancer. The study found that there was no link between working night shifts and thyroid cancer risk. However, it did suggest a possible association between frequently having difficulty falling or staying asleep and a higher risk of thyroid cancer. Among nurses who worked night shifts for over 10 years and experienced sleep difficulties most of the time, there was a modestly increased risk of thyroid cancer. In summary, the research suggests that sleep problems among those who work night shifts may be linked to an increased risk of thyroid cancer. However, more research is needed to confirm these findings and better understand the relationship between night shift work, sleep patterns, and thyroid cancer. Night shift work has been associated with breast, prostate, and colorectal cancer, but evidence on other types of cancer is limited. We prospectively evaluated the association of rotating night shift work, sleep duration, and sleep difficulty with thyroid cancer risk in the Nurses' Health Study 2 (NHS2). We assessed rotating night shift work duration (years) at baseline and throughout follow-up (1989–2015) and sleep characteristics in 2001. Cox proportional hazard models, adjusted for potential confounders, were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for (a) shift work duration, (b) sleep duration, and (c) difficulty falling or staying asleep. We stratified the analyses of night shift work by sleep duration and sleep difficulty. Over 26 years of follow-up, 588 incident cases were identified among 114,534 women in the NHS2 cohort. We observed no association between night shift work and the risk of thyroid cancer. Difficulty falling or staying asleep was suggestively associated with a higher incidence of thyroid cancer when reported sometimes (HR 1.26, 95% CI 0.95, 1.66) and all or most of the time (HR 1.35, 95% CI 1.00, 1.81). Night shift workers (10+ years) with sleep difficulty all or most of the time (HR 1.47; 0.58–3.73) or with >7 h of sleep duration (HR 2.17; 95% CI, 1.21–3.92) had a higher risk of thyroid cancer. We found modest evidence for an increased risk of thyroid cancer in relation to sleep difficulty, which was more pronounced among night shift workers. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We evaluated fiber intake during adolescence and early adulthood in relation to breast cancer (BC) risk in the Nurses' Health Study II. METHODS: Among 90 534 premenopausal women who completed a dietary questionnaire in 1991, we documented 2833 invasive BC cases during 20 years of follow-up. In 1998,44 263 of these women also completed a questionnaire about their diet during high school; among these women, we documented 1118 cases of BC by end of follow-up. Multivariable-adjusted Cox proportional hazards regression was used to model relative risks (RRs) and 95% confidence intervals (CIs) for BC across categories of dietary fiber. RESULTS: Among all women, early adulthood total dietary fiber intake was associated with significantly lower BC risk (RR for highest versus lowest quintile 0.81; 95% CI 0.72-0.91; Ptrend = -002). Higher intakes of soluble fiber (RR for highest versus lowest quintile 0.86; 95% CI 0.77-0.97; Ptrend = .02) and insoluble fiber (RR for highest versus lowest quintile 0.80; 95% CI 0.71-0.90; Ptrend < .001) were each associated with lower BC risk. Total dietary fiber intake in adolescence was also associated with lower BC risk (RR for highest versus lowest quintile 0.84; 95% CI 0.70-1.01; Ptrend = .04). For the average of fiber intake during adolescence and early adult life, the RR comparing highest with lowest quintiles was 0.75 (95% CI 0.62-0.91, Ptrend = .004). CONCLUSIONS: Our findings support the hypothesis that higher fiber intakes reduce BC risk and suggest that intake during adolescence and early adulthood may be particularly important. [ABSTRACT FROM AUTHOR]

A response by A. Heather Eliassen, Robert L. Barbieri and Susan E. Hankinson to a letter to the editor about their article "Endogenous Steroid Hormone Concentrations and Risk of Breast Cancer Among Premenopausal Women" in the 2006 issue is presented.

Objective: To prospectively investigate population‐based metabolomics for incident gout and reproduce the findings for recurrent flares, accounting for serum urate. Methods: We conducted a prediagnostic metabolome‐wide analysis among 105,615 UK Biobank participants with nuclear magnetic resonance metabolomic profiling data (168 total metabolites) from baseline blood samples collected 2006–2010 in those without history of gout. We calculated hazard ratios (HRs) for incident gout, adjusted for gout risk factors, excluding and including serum urate levels, overall and according to fasting duration before sample collection. Potential causal effects were tested with 2‐sample Mendelian randomization. Poisson regression was used to calculate rate ratios (RRs) for the association with recurrent flares among incident gout cases. Results: Correcting for multiple testing, 88 metabolites were associated with risk of incident gout (N = 1,303 cases) before serum urate adjustment, including glutamine and glycine (inversely), and lipids, branched‐chain amino acids, and most prominently, glycoprotein acetyls (GlycA; P = 9.17 × 10−32). Only GlycA remained associated with incident gout following urate adjustment (HR 1.52 [95% confidence interval (95% CI) 1.22–1.88] between extreme quintiles); the HR increased progressively with fasting duration before sample collection, reaching 4.01 (95% CI 1.36–11.82) for ≥8 hours of fasting. Corresponding HRs per SD change in GlycA levels were 1.10 (95% CI 1.04–1.17) overall and 1.54 (95% CI 1.21–1.96) for ≥8 hours of fasting. GlycA levels were also associated with recurrent gout flares among incident gout cases (RR 1.90 [95% CI 1.27–2.85] between extreme quintiles) with larger associations with fasting. Mendelian randomization corroborated a potential causal role for GlycA on gout risk. Conclusion: This prospective, population‐based study implicates GlycA, a stable long‐term biomarker reflecting neutrophil overactivity, in incident and recurrent gout flares (central manifestation from neutrophilic synovitis) beyond serum urate. [ABSTRACT FROM AUTHOR]

Background: Olive oil consumption may reduce breast cancer risk, but it is unclear whether olive oil is beneficial for breast cancer prevention in populations outside of Mediterranean regions, namely in the U.S., where the average consumption of olive oil is low compared with Mediterranean populations. We examined whether olive oil intake was associated with breast cancer risk in two prospective cohorts of U.S. women. Methods: We used multivariable-adjusted time-varying Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence interval (CI) for breast cancer among 71,330 (Nurses' Health Study, 1990–2016) and 93,295 women (Nurses' Health Study II, 1991–2017) who were free of cancer at baseline. Diet was assessed by a validated semi-quantitative food frequency questionnaire every 4 years. Results: During 3,744,068 person-years of follow-up, 9,638 women developed invasive breast cancer. The multivariable-adjusted HR (95% CI) for breast cancer among women who had the highest consumption of olive oil (>1/2 tablespoon/d or >7 g/d) compared with those who never or rarely consumed olive oil, was 1.01 (0.93, 1.09). Higher olive oil consumption was not associated with any subtype of breast cancer. Conclusion: We did not observe an association between higher olive oil intake and breast cancer risk in two large prospective cohorts of U.S. women, whose average olive oil consumption was low. Prospective studies are needed to confirm these findings and to further investigate whether different varieties of olive oil (e.g., virgin and extra virgin olive oil) may play a role in breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non‐European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans‐ethnic PRS for body mass index (BMI) through this relatively new international effort. Methods: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta‐analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. Results: We show that in the absence of a well powered trans‐ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans‐ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans‐ethnic linkage disequilibrium reference panels. The ported trans‐ethnic scores outperform population specific‐PRS across all non‐European ancestry populations investigated including East Asians and three‐way admixed Brazilian cohort. Conclusions: Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans‐ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three‐way admixed Brazilians. [ABSTRACT FROM AUTHOR]

To evaluate the association between alcohol consumption and breast cancer risk in younger women, overall and by family history of breast cancer and folate intake, we prospectively followed 93,835 US women aged 27-44 years in Nurses' Health Study II who had alcohol consumption data in 1991. Alcohol consumption and folate intake were measured by food frequency questionnaire every 4 years. We documented 2,866 incident cases of invasive breast cancer between 1991 and 2011. Alcohol consumption was not associated with breast cancer risk overall (for intake of ≥10g/day vs. nondrinking, multivariate hazard ratio = 1.07, 95% confidence interval: 0.94, 1.22). When the association was stratified by family history and folate intake, a positive association between alcohol consumption and breast cancer was found among women with a family history and folate intake less than 400 µg/day (multivariate hazard ratio = 1.82, 95% confidence interval: 1.06,3.12; P-trend = 0.08). Alcohol consumption was not associated with breast cancer in other categories of family history and folate intake (P-interaction = 0.55). In conclusion, in this population of younger women, higher alcohol consumption was associated with increased risk of breast cancer among those with both a family history of breast cancer and lower folate intake. [ABSTRACT FROM AUTHOR]

Background Although unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance and hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. Methods We followed 48 330 women from the Nurses' Health Study (1984-2016) and 85 426 women from the Nurses' Health Study II (1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type I endometrial cancer risk. Results We documented 1462 type I endometrial cancer cases over 2 823 221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vsQ1 = 1.46, 95% CI = 1.24 to 1.73; P trend <.001; EDIH HRQ5vsQ1 = 1.58, 95% CI = 1.34 to 1.87; P trend <.001). Additional adjustment for body mass index attenuated the associations (EDIP HR = 1.03, 95% CI = 0.87 to 1.22; EDIH HR = 1.01, 95% CI = 0.85 to 1.21), and mediation analyses showed that body mass index may explain 60.4% (95% CI = 37.4% to 79.6%; P <.001) and 71.8% (95% CI = 41.0% to 90.4%; P <.001) of the association of endometrial cancer with EDIP and EDIH, respectively. Conclusions In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in order to reply to the comment on the article "Serum lipids, lipid-lowering drugs, and the risk of breast cancer," by A. H. Eliassen and colleagues in a 2005 issue.

Only few longitudinal studies with high risk of bias have examined relationship between pets and adolescents' mental health. Our prospective cohort study followed depression-free US adolescents aged 12–18, enrolled in the Growing Up Today Study from pet ownership assessment in 1999 to possible occurrence of high depressive symptoms defined based on the McKnight Risk Factor Survey between 2001 and 2003. Propensity-score-adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using generalized estimating equation models. Among 9631 adolescents [42.4 % male, mean age 14.9 years (SD 1.6)], we found no association between pet ownership and risk of high depressive symptoms (OR any_pet = 1.14; 95%CI, 0.95–1.38). Stratified analyses revealed no evidence of effect modification by sex, but effect modification by maternal history of depression (depressed mothers OR any_pet = 0.83; 95 % CI: 0.58–1.19, non-depressed mothers OR any_pet = 1.27; 95 % CI: 1.02–1.58; P intx = 0.03), which differed further by children's sex. Effects were more pronounced among children with a history of childhood abuse (OR any_pet = 0.41 (0.14–1.15); P intx ≤0.03). No major differences by type of pet owned were observed in any of these analyses. Our sample is predominantly white and all are offspring of nurses with a similar academic background which could affect generalizability. Overall, we found no association between pet ownership and depression during adolescence, however subgroup analyses indicated some individuals may benefit from a pet. Future longitudinal studies with more detailed exposure assessments, including pet attachment are needed to further explore the potential of human-animal interaction on mental health. • Previous studies on pet ownership and depression risk are at high risk of bias. • Our data show that only some subgroups might benefit from pet ownership. • Studies with detailed exposure assessments, including pet attachment are needed. [ABSTRACT FROM AUTHOR]

Objective: We evaluated prospectively the association between incident early- (diagnosed before 40 years of age) and later-onset type 2 diabetes and early- (diagnosed before 50 years of age) and later-onset cancer risk.Research Design and Methods: We prospectively followed 228,073 eligible participants in the Nurses' Health Studies for up to 38 years. Hazard ratios (HRs) and 95% CI were estimated using Cox models.Results: We documented 18,290 type 2 diabetes, 6,520 early-onset cancer, and 36,907 later-onset cancer cases during follow-up. In fully adjusted analyses, early-onset type 2 diabetes was associated with increased risk of early-onset total cancer (HR [95% CI] 1.47 [1.06-2.04]), diabetes-related cancer (2.11 [1.38-3.23]), and obesity-related cancer (1.75 [1.08-2.82]), and the risk elevations were restricted to those with a BMI at 18 years of age of ≥21 kg/m2 (total cancer: 1.75 [1.20-2.56]; diabetes-related cancer: 2.43 [1.50-3.94]; and obesity-related cancer: 1.84 [1.05-3.22]). Early-onset type 2 diabetes was associated with higher risk of later-onset diabetes-related and obesity-related cancer specifically among individuals with higher BMI at 18 years of age. Later-onset type 2 diabetes was associated with a higher risk of later-onset total cancer (1.15 [1.11-1.20]), diabetes-related cancer (1.17 [1.12-1.22]), and obesity-related cancer (1.18 [1.13-1.24]). In analyses based on refined timing, the HRs attenuated substantially with aging.Conclusions: Incident early-onset type 2 diabetes was associated with increased risk of early-onset total cancer and diabetes- and obesity-related cancer, especially in those with higher BMI at 18 years of age. The impact of early-onset type 2 diabetes on cancer risk may be inherently stronger than that of later-onset type 2 diabetes.Article Highlights: The relationship between incident early- and later-onset type 2 diabetes and risk of early- and later-onset cancer is unclear. We investigated this topic based on 228,073 U.S. women and up to 38 years of follow-up. Our findings suggested that incident early-onset type 2 diabetes was associated with increased risk of early-onset total cancer, and diabetes- and obesity-related cancer, especially in those with higher BMI at age 18 years. Cancer prevention efforts tailored for patients with early-onset type 2 diabetes may need to focus on those with higher adolescent or emerging adulthood BMI. The impact of early-onset type 2 diabetes on cancer risk may be inherently stronger than that of later-onset type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. Methods Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2–like, HER2-enriched–like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. Results Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2–like, and HER2-enriched–like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (P heterogeneity <.001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (P heterogeneity <.001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. Conclusions This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction. [ABSTRACT FROM AUTHOR]

Background: The inverse association between physical activity and coronary heart disease (CHD) risk has primarily been shown in studies of middle-aged and older adults. Evidence for the benefits of frequency, type, and volume of leisure-time physical activity in young women is limited.Methods: We conducted a prospective analysis among 97 230 women aged 27 to 44 years at baseline in 1991. Leisure-time physical activity was assessed biennially by questionnaire. Cox proportional hazards models were used to examine the associations between physical activity frequency, type, and volume, and CHD risk.Results: During 20 years of follow-up, we documented 544 incident CHD cases. In multivariable-adjusted models, the hazard ratio (95% confidence interval) of CHD comparing ≥30 with <1 metabolic equivalent of task-hours/wk of physical activity was 0.75 (0.57-0.99) (P, trend=0.01). Brisk walking alone was also associated with significantly lower CHD risk. Physical activity frequency was not associated with CHD risk when models also included overall activity volume. Finally, the association was not modified by body mass index (kg/m(2)) (P, interaction=0.70). Active women (≥30 metabolic equivalent of task-hours/wk) with body mass index<25 kg/m(2) had 0.52 (95% confidence interval, 0.35-0.78) times the rate of CHD in comparison with women who were obese (body mass index≥30 kg/m(2)) and inactive (physical activity <1 metabolic equivalent of task-hours/wk).Conclusions: These prospective data suggest that total volume of leisure-time physical activity is associated with lower risk of incident CHD among young women. In addition, this association was not modified by weight, emphasizing that it is important for normal weight, overweight, and obese women to be physically active. [ABSTRACT FROM AUTHOR]

Background: The Breast Cancer Risk Assessment Tool (BCRAT, "Gail model") is commonly used for breast cancer prediction; however, it has not been validated for women age 75 years and older.Methods: We used Nurses' Health Study (NHS) data beginning in 2004 and Women's Health Initiative (WHI) data beginning in 2005 to compare BCRAT's performance among women age 75 years and older with that in women age 55 to 74 years in predicting five-year breast cancer incidence. BCRAT risk factors include: age, race/ethnicity, age at menarche, age at first birth, family history, history of benign breast biopsy, and atypia. We examined BCRAT's calibration by age by comparing expected/observed (E/O) ratios of breast cancer incidence. We examined discrimination by computing c-statistics for the model by age. All statistical tests were two-sided.Results: Seventy-three thousand seventy-two NHS and 97 081 WHI women participated. NHS participants were more likely to be non-Hispanic white (96.2% vs 84.7% in WHI, P < .001) and were less likely to develop breast cancer (1.8% vs 2.0%, P = .02). E/O ratios by age in NHS were 1.16 (95% confidence interval [CI] = 1.09 to 1.23, age 57-74 years) and 1.31 (95% CI = 1.18 to 1.45, age ≥ 75 years, P = .02), and in WHI 1.03 (95% CI = 0.97 to 1.09, age 55-74 years) and 1.10 (95% CI = 1.00 to 1.21, age ≥ 75 years, P = .21). E/O ratio 95% confidence intervals crossed one among women age 75 years and older when samples were limited to women who underwent mammography and were without significant illness. C-statistics ranged between 0.56 and 0.58 in both cohorts regardless of age.Conclusions: BCRAT accurately predicted breast cancer for women age 75 years and older who underwent mammography and were without significant illness but had modest discrimination. Models that consider individual competing risks of non-breast cancer death may improve breast cancer risk prediction for older women. [ABSTRACT FROM AUTHOR]

Background: Evidence is limited on inflammation-related dietary patterns and mortality in ovarian cancer survivors.Methods: We examined the associations between pre- and post-diagnosis dietary patterns, including change in diet from before to after diagnosis, and mortality among 1003 ovarian cancer survivors in two prospective cohort studies. Dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and Alternative Healthy Eating Index (AHEI) were calculated based on food frequency questionnaires. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer-specific and all-cause mortality.Results: Pre-diagnosis EDIP score and AHEI were not associated with mortality. Among non-high grade serous cases, a higher post-diagnosis EDIP score was associated with increased risk of all-cause mortality (HR5th vs 1st quintile = 1.95, 95% CI = 1.04-3.67, p-trend = 0.06). Compared to survivors consuming a low EDIP score diet before and after diagnosis, high post-diagnosis EDIP was associated with increased risk of ovarian cancer specific mortality (pre-to-post diagnosis low/high, HR = 1.38, 95% CI = 0.99-1.92; high/high HR = 1.58, 95% CI = 1.09-2.30) and all-cause mortality (low/high HR = 1.44, 95% CI = 1.06-1.95; high/high HR = 1.55, 95% CI = 1.10-2.19).Conclusion: Consuming a more inflammatory dietary pattern post-diagnosis was associated with increased mortality in ovarian cancer survivors, suggesting limiting the inflammatory potential of diet post-diagnosis could lead to enhanced survivorship. [ABSTRACT FROM AUTHOR]

Background: Adiposity is consistently positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk, though the reasons for this difference remain unclear.Methods: In this nested case-control study of 1649 breast cancer cases and 1649 matched controls from the Nurses' Health Study (NHS) and the NHSII, we selected lipid and polar metabolites correlated with BMI, waist circumference, weight change since age 18, or derived fat mass, and developed a metabolomic score for each measure using LASSO regression. Logistic regression was used to investigate the association between this score and breast cancer risk, adjusted for risk factors and stratified by menopausal status at blood draw and diagnosis.Results: Metabolite scores developed among only premenopausal or postmenopausal women were highly correlated with scores developed in all women (r = 0.93-0.96). Higher metabolomic adiposity scores were generally inversely related to breast cancer risk among premenopausal women. Among postmenopausal women, significant positive trends with risk were observed (e.g., metabolomic waist circumference score OR Q4 vs. Q1 = 1.47, 95% CI = 1.03-2.08, P-trend = 0.01).Conclusions: Though the same metabolites represented adiposity in pre- and postmenopausal women, breast cancer risk associations differed suggesting that metabolic dysregulation may have a differential association with pre- vs. postmenopausal breast cancer. [ABSTRACT FROM AUTHOR]

Experimental and epidemiologic data support a protective role for melatonin in breast cancer etiology, yet studies in premenopausal women are scarce. In a case-control study nested within the Nurses’ Health Study II cohort, we measured the concentration of melatonin’s major urinary metabolite, 6-sulfatoxymelatonin (aMT6s), in urine samples collected between 1996 and 1999 among 600 breast cancer cases and 786 matched controls. Cases were predominantly premenopausal women who were diagnosed with incident breast cancer after urine collection and before June 1, 2007. Using multivariable conditional logistic regression, we computed odds ratios and 95% confidence intervals. Melatonin levels were not significantly associated with total breast cancer risk (for the fourth (top) quartile (Q4) of aMT6s vs. the first (bottom) quartile (Q1), odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.64, 1.28; Ptrend = 0.38) or risk of invasive or in situ breast cancer. Findings did not vary by body mass index, smoking status, menopausal status, or time between urine collection and diagnosis (all Pinteraction values ≥ 0.12). For example, the odds ratio for total breast cancer among women with ≤5 years between urine collection and diagnosis was 0.74 (Q4 vs. Q1; 95% CI: 0.45, 1.20; Ptrend = 0.09), and it was 1.20 (Q4 vs. Q1; 95% CI: 0.72, 1.98; Ptrend = 0.70) for women with >5 years. Our data do not support an overall association between urinary melatonin levels and breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Overall mortality rates from coronary heart disease (CHD) in the United States have declined in recent decades, but the rate has plateaued among younger women. The potential for further reductions in mortality rates among young women through changes in lifestyle is unknown.Objectives: The aim of this study was to estimate the proportion of CHD cases and clinical cardiovascular disease (CVD) risk factors among young women that might be attributable to poor adherence to a healthy lifestyle.Methods: A prospective analysis was conducted among 88,940 women ages 27 to 44 years at baseline in the Nurses' Health Study II who were followed from 1991 to 2011. Lifestyle factors were updated repeatedly by questionnaire. A healthy lifestyle was defined as not smoking, a normal body mass index, physical activity ≥ 2.5 h/week, television viewing ≤ 7 h/week, diet in the top 40% of the Alternative Healthy Eating Index-2010, and 0.1 to 14.9 g/day of alcohol. To estimate the proportion of CHD and clinical CVD risk factors (diabetes, hypertension, and hypercholesterolemia) that could be attributed to poor adherence to a healthy lifestyle, we calculated the population-attributable risk percent.Results: During 20 years of follow-up, we documented 456 incident CHD cases. In multivariable-adjusted models, nonsmoking, a healthy body mass index, exercise, and a healthy diet were independently and significantly associated with lower CHD risk. Compared with women with no healthy lifestyle factors, the hazard ratio for CHD for women with 6 lifestyle factors was 0.08 (95% confidence interval: 0.03 to 0.22). Approximately 73% (95% confidence interval: 39% to 89%) of CHD cases were attributable to poor adherence to a healthy lifestyle. Similarly, 46% (95% confidence interval: 43% to 49%) of clinical CVD risk factor cases were attributable to a poor lifestyle.Conclusions: Primordial prevention through maintenance of a healthy lifestyle among young women may substantially lower the burden of CVD. [ABSTRACT FROM AUTHOR]

Background Overall mortality rates from coronary heart disease (CHD) in the United States have declined in recent decades, but the rate has plateaued among younger women. The potential for further reductions in mortality rates among young women through changes in lifestyle is unknown. Objectives The aim of this study was to estimate the proportion of CHD cases and clinical cardiovascular disease (CVD) risk factors among young women that might be attributable to poor adherence to a healthy lifestyle. Methods A prospective analysis was conducted among 88,940 women ages 27 to 44 years at baseline in the Nurses’ Health Study II who were followed from 1991 to 2011. Lifestyle factors were updated repeatedly by questionnaire. A healthy lifestyle was defined as not smoking, a normal body mass index, physical activity ≥ 2.5 h/week, television viewing ≤ 7 h/week, diet in the top 40% of the Alternative Healthy Eating Index–2010, and 0.1 to 14.9 g/day of alcohol. To estimate the proportion of CHD and clinical CVD risk factors (diabetes, hypertension, and hypercholesterolemia) that could be attributed to poor adherence to a healthy lifestyle, we calculated the population-attributable risk percent. Results During 20 years of follow-up, we documented 456 incident CHD cases. In multivariable-adjusted models, nonsmoking, a healthy body mass index, exercise, and a healthy diet were independently and significantly associated with lower CHD risk. Compared with women with no healthy lifestyle factors, the hazard ratio for CHD for women with 6 lifestyle factors was 0.08 (95% confidence interval: 0.03 to 0.22). Approximately 73% (95% confidence interval: 39% to 89%) of CHD cases were attributable to poor adherence to a healthy lifestyle. Similarly, 46% (95% confidence interval: 43% to 49%) of clinical CVD risk factor cases were attributable to a poor lifestyle. Conclusions Primordial prevention through maintenance of a healthy lifestyle among young women may substantially lower the burden of CVD. [ABSTRACT FROM AUTHOR]

Study Question: Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women?Summary Answer: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7.What Is Known Already: AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown.Study Design, Size, Duration: We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts.Participants/materials, Setting, Methods: In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10-8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses.Main Results and the Role Of Chance: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored.Large Scale Data: The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/).Limitations, Reasons For Caution: Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels.Wider Implications Of the Findings: Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing.Study Funding/competing Interest(s): Nurses' Health Study and Nurses' Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.'s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Ministère de l'Économie, de la Science et de l'Innovation du Québec' through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests. [ABSTRACT FROM AUTHOR]

Among 683 participants in the Women's Lifestyle Validation Study (2010–2012), we evaluated the performance of a self-administered physical activity questionnaire (PAQ) and Web-based 24-hour recalls (Activities Completed Over Time in 24 Hours (ACT24)) using multiple comparison methods. Two PAQs, 4 ACT24s, two 7-day accelerometer measurements, 1 doubly labeled water (DLW) physical activity level (PAL) measure (repeated; n  = 90), and 4 resting pulse rate measurements were collected over 15 months. The deattenuated correlation between the PAQ and DLW PAL was 0.41 (95% confidence interval (CI): 0.33, 0.49) for total physical activity (PA) and 0.40 (95% CI: 0.31, 0.48) for moderate-to-vigorous PA (MVPA). These correlations were similar when using accelerometry as the comparison method. Single and averaged ACT24 measurements had lower correlations with DLW and accelerometry as comparison methods. The PAQ showed inverse correlations with DLW body fat percentage and resting pulse rate. Using the method of triads, the estimated correlation of the PAQ with true total PA was 0.54 (95% CI: 0.47, 0.62) and that with true MVPA was 0.60 (95% CI: 0.52, 0.69). For averaged ACT24, the estimated correlations were 0.50 (95% CI: 0.43, 0.59) for total PA and 0.47 (95% CI: 0.39, 0.58) for MVPA, and for averaged accelerometry, these estimated correlations were 0.72 (95% CI: 0.64, 0.81) and 0.62 (95% CI: 0.53, 0.71), respectively. The PAQ provided reasonable validity for total PA and MVPA. [ABSTRACT FROM AUTHOR]

Background: Some previous studies suggested that high supplemental vitamin C intake may be associated with an increased risk of breast cancer, although evidence is inconsistent.Objectives: Our objective was to study the association between vitamin C intake and breast cancer risks using regularly updated assessments of intake over a long follow-up.Methods: We prospectively followed 88,041 women aged 33 to 60 years from the Nurses' Health Study (1980-2014) and 93,372 women aged 26 to 45 years from the Nurses' Health Study II (1991-2013). A total of 11,258 incident invasive breast cancers among 181,413 women were diagnosed. Data on vitamin C intake were collected every 2-4 years via a validated FFQ and specific questions on dietary supplement use. Multivariate HRs and 95% CIs for incident invasive breast cancer were estimated with Cox models.Results: During follow-up, 82% of participants ever used supplements containing vitamin C, including multivitamins. Cumulative total vitamin C intake (HR for quintiles 5 compared with 1 = 0.97; 95% CI: 0.91-1.03; Ptrend = 0.81), dietary vitamin C intake (HR for quintiles 5 compared with 1 = 0.98; 95% CI: 0.92-1.04; Ptrend = 0.57), and supplemental vitamin C intake (HR for quintiles 5 compared with 1 in users = 1.02; 95% CI: 0.94-1.09; Ptrend = 0.77) were not associated with breast cancer risks. Results were unchanged when different exposure latencies were considered. The results did not differ by menopausal status, postmenopausal hormone therapy use, or BMI. No differences were observed by estrogen receptor status of the tumor.Conclusions: Our results do not support any important association between total, dietary, or supplemental vitamin C intake and breast cancer risks. [ABSTRACT FROM AUTHOR]

The authors responded to invited commentaries on their article "Estimated Number of Lifetime Ovulatory Years and Its Determinants in Relationto Levels of Circulating Inflammatory Biomarkers" that is published within the issue. Topics covered include the need for more studies to better understand the role of estrogen and progestin formulations to inflammation and hormone-related carcinogenesis and their response to concern regarding the potential measurement error in estimations of LOY.

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting.Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors.Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women.Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM. [ABSTRACT FROM AUTHOR]