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Background: Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex hormone levels in postmenopausal women with at least one intact ovary not using hormones. Methods: Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate, prolactin, and sex hormone binding globulin were measured in 1,976 postmenopausal women from the Nurses' Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t tests and ANOVA. Linear regression was used to assess multivariable adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated. Results: Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. A total of 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI < 25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI. Conclusions: This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone. [ABSTRACT FROM AUTHOR]

Background: The relationships between PTEN loss and/or PIK3CA mutation and breast cancer prognosis remain controversial. We aim to examine the associations in large epidemiologic cohorts. Methods: We followed women with invasive breast cancer from the Nurses' Health Studies with available data on tumor PTEN expression (n = 4,111) and PIK3CA mutation (n = 2,930). PTEN expression was evaluated by IHC and digitally scored (0%-100%). Pyrosequencing of six hotspot mutations of PIK3CA was performed. Results: We found loss of PTEN expression (=10%) occurred in 17% of cases, and PIK3CA mutations were detected in 11% of cases. After adjusting for clinical and lifestyle factors, PTEN loss was not associated with worse breast cancer-specific mortality among all samples [HR, 0.85; 95% confidence intervals (CI), 0.71-1.03] or among estrogen receptor (ER)-positive tumors (HR, 0.99; 95% CI, 0.79-1.24). However, among ER-negative tumors, PTEN loss was associated with lower breast cancer-specific mortality (HR, 0.68; 95% CI, 0.48-0.95). PIK3CA mutation was not strongly associated with breast cancer-specific mortality (HR, 0.89; 95% CI, 0.67-1.17). Compared with tumors without PTEN loss and without PIK3CA mutation, those with alterations (n = 540) were not at higher risk (HR, 1.07; 95% CI, 0.86-1.34). However, women with both PTEN loss and PIK3CA mutation (n = 38) were at an increased risk of breast cancer-specific mortality (HR, 1.65; 95% CI, 0.83-3.26). Conclusions: In this large epidemiologic study, the PTEN-mortality association was more pronounced for ER-negative tumors, and the joint PTEN loss and PIK3CA mutation may be associated with worse prognosis. Impact: Further studies with a larger sample of ER-negative tumors are needed to replicate our findings and elucidate underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Identifying risk factors for aggressive forms of breast cancer is important. Tumor factors (e.g., stage) are important predictors of prognosis, but may be intermediates between prediagnosis risk factors and mortality. Typically, separate models are fit for incidence and mortality postdiagnosis. These models have not been previously integrated to identify risk factors for lethal breast cancer in cancer-free women. Methods: We combined models for breast cancer incidence and breast cancer-specific mortality among cases into a multi-state survival model for lethal breast cancer. We derived the model from cancer-free postmenopausal Nurses' Health Study women in 1990 using baseline risk factors. A total of 4,391 invasive breast cancer cases were diagnosed from 1990 to 2014 of which 549 died because of breast cancer over the same period. Results: Some established risk factors (e.g., family history, estrogen plus progestin therapy) were not associated with lethal breast cancer. Controlling for age, the strongest risk factors for lethal breast cancer were weight gain since age 18: > 30 kg versus ± 5 kg, RR = 1.94 [95% confidence interval (CI) = 1.38-2.74], nulliparity versus age at first birth (AAFB) < 25, RR = 1.60 (95% CI = 1.16-2.22), and current smoking = 15 cigarettes/day versus never, RR = 1.42 (95% CI = 1.07-1.89). Conclusions: Some breast cancer incidence risk factors are not associated with lethal breast cancer; other risk factors for lethal breast cancer are not associated with disease incidence. Impact: This multi-state survival model may be useful for identifying prediagnosis factors that lead to more aggressive and ultimately lethal breast cancer. [ABSTRACT FROM AUTHOR]

Background: Estrogens increase breast cancer risk through estrogen receptor (ER)-mediated pathway activation. It is unclear whether a broader assessment of plasma compounds that lead to ER activation would be more strongly related to risk than measurement of individual estrogens. Methods: A prospective nested case-control study was conducted among postmenopausal women in the Nurses' Health Study, that included 371 cases with blood samples collected prior to breast cancer diagnosis and 731 matched controls. Total estrogen pathway activity (EA) was assessed via a luciferase reporter assay using plasma-treated T47D-Kbluc (ATCC) human breast cancer cells. We also assessed the contribution of EA to risk, independent of circulating estrone, estradiol, and estrone sulfate concentrations. Multivariable ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression adjusting for breast cancer risk factors. Results: Women in the highest, versus lowest EA quartile had an 86% increased risk of invasive breast cancer (ORQ4vsQ1, 1.86; 95% CI = 1.16-2.97). After accounting for estradiol only, a weaker association was observed (ORQ4vsQ1, 1.27; 95% CI = 0.75-2.17). No association was observed after accounting for all three estrogens (ORQ4vsQ1, 1.01; 95% CI = 0.56-1.84). Conclusions: A positive association between EA and breast cancer risk was observed. However, the association was substantially attenuated after accounting for levels of other estrogens. Impact: Our study provides a first detailed assessment of a breast cancer cell line-based EA assay and postmenopausal breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ovarian cancer. Methods: We conducted a pooled case-control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype. Results: Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (Ptrend = 0.045; OR, quartile 4 vs. 1 = 1.34; 95% CI = 0.97-1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR = 1.38; 95% CI = 0.74-2.58; Ptrend = 0.32 and OR = 1.41; 95% CI = 0.93-2.13; Ptrend = 0.08, respectively; Pheterogeneity = 0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI = 25 kg/m2, but not BMI < 25 kg/m2 (corresponding OR = 2.68; 95% CI = 1.56-4.59; Ptrend < 0.01 and OR = 0.90; 95% CI = 0.58-1.40; Ptrend = 0.98, respectively; Pheterogeneity < 0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis. Conclusions: We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI = 25 kg/m2. [ABSTRACT FROM AUTHOR]

Background: Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk. Methods: We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case-control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes. Results: Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index (P < 0.05). No measure was correlated with body size at ages 5-10 years, age at menarche, age at first birth, or breastfeeding history (P > 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk. Conclusions: Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer. [ABSTRACT FROM AUTHOR]

Background: Although vitamin D inhibits breast tumor growth in experimental settings, the findings from population-based studies remain inconclusive. Our goals were to investigate the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] concentration and breast cancer recurrence in prospective epidemiologic studies and to explore the molecular underpinnings linking 25(OH)D to slower progression of breast cancer in the Nurses' Health Studies (NHS, N = 659). Methods: Plasma 25(OH)D was measured with a high-affinity protein-binding assay and a radioimmunoassay. We profiled transcriptome-wide gene expression in breast tumors using microarrays. Hazard ratios (HR) of breast cancer recurrence were estimated from covariate-adjusted Cox regressions. We examined differential gene expression in association with 25(OH)D and employed pathway analysis. We derived a gene expression score for 25(OH)D, and assessed associations between the score and cancer recurrence. Results: Although 25(OH)D was not associated with breast cancer recurrence overall [HR = 0.97; 95% confidence interval (CI), 0.88-1.08], the association varied by estrogen-receptor (ER) status (Pinteraction = 0.005). Importantly, among ER-positive stage I to III cancers, every 5 ng/mL increase in 25(OH)D was associated with a 13% lower risk of recurrence (HR = 0.87; 95% CI, 0.76-0.99). A null association was observed for ER-negative cancers (HR = 1.07; 95% CI, 0.91-1.27). Pathway analysis identified multiple gene sets that were significantly (FDR < 5%) downregulated in ER-positive tumors of women with high 25(OH)D (≥30 ng/mL), compared with those with low levels (<30 ng/mL). These gene sets are primarily involved in tumor proliferation, migration, and inflammation. 25(OH)D score derived from these gene sets was marginally associated with reduced risk of recurrence in ER-positive diseases (HR = 0.77; 95% CI, 0.59-1.01) in the NHS studies; however no association was noted in METABRIC, suggesting that further refinement is need to improve the generalizability of the score. Conclusions: Our findings support an intriguing line of research for studies to better understand the mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype. Impact: Vitamin D may present a personal-level secondary-prevention strategy for ER-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA). Methods: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status. Results: Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER- tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P < 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER- disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction. Conclusions: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. Impact: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations. [ABSTRACT FROM AUTHOR]

Background: Prior studies evaluating psychotropic medications in relation to breast cancer risk are inconsistent and have not separately evaluated invasive and in situ disease. Methods: We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of psychotropic medication use (any, typical antipsychotics, atypical antipsychotics, and lithium) with invasive and in situ breast cancer risk among Women's Health Initiative participants (N = 155,737). Results: Prevalence of psychotropic medication use was low (n = 642; 0.4%). During an average 14.8 (SD, 6.5) years of follow-up, 10,067 invasive and 2,285 in situ breast tissues were diagnosed. Any psychotropic medication use was not associated with invasive breast cancer risk compared with nonusers (HR, 0.82; 95% CI, 0.57-1.18). In situ breast cancer risk was higher among "typical" antipsychotic medication users compared with nonusers (HR, 2.05; 95% CI, 0.97-4.30). Conclusions: These findings do not support an association of psychotropic medication use with invasive breast cancer risk. The possible elevation in in situ breast cancer risk associated with "typical" antipsychotics could not be explained by differences in screening mammography utilization and merits further study. [ABSTRACT FROM AUTHOR]

Background: Previous studies associated night-shift work with melatonin disruption, with mixed evidence regarding the modulating effects of chronotype (i.e., diurnal preference). Methods: One hundred and thirty active nurses (84 rotating-shift and 46 day-shift workers) in the Nurses' Health Study II wore a head-mounted light meter and collected spontaneous urine voids over 3 days. 6-Sulfatoxymelatonin (aMT6s), the major urinary metabolite of melatonin, was assessed. Results: Rotating-shift workers on night shifts had more light exposure and lower urinary melatonin levels during the night, and urinary melatonin rhythms with smaller peaks [11.81 ng/mg-creatinine/h, 95% confidence interval (CI), 9.49-14.71 vs. 14.83 ng/mg-creatinine/h, 95% CI, 11.72-18.75] and later peak onset (5.71 hours, 95% CI, 4.76-6.85 vs. 4.10 hours, 95% CI, 3.37-4.99), compared with day-shift workers. Furthermore, evening chronotypes' melatonin rhythms had later peak onset compared with morning types (4.90 hours, 95% CI, 3.94-6.09 vs. 3.64 hours, 95% CI, 2.99-4.43). However, among day-shift workers, morning chronotypes had melatonin rhythms with greater mean levels, larger peaks, and earlier peak onset compared with evening chronotypes; patterns were similar comparing evening versus morning chronotypes among rotating-shift workers on night shifts. The interaction of rotating-shift work and chronotype was significant across all parameters (P < 0.05). Conclusions: As expected, rotating-shift workers on night shifts had greater light exposure and lower urinary melatonin levels during the night compared with day-shift workers. Intriguingly, melatonin rhythms were dependent on both chronotype and rotating-shift work type, and better alignment of rotating-shift work and chronotype appeared to produce less disrupted melatonin rhythms. Impact: The joint effects of shift-work type and chronotype require attention in future studies. [ABSTRACT FROM AUTHOR]

Background: The Gail model and the model developed by Tyrer and Cuzick are two questionnaire-based approaches with demonstrated ability to predict development of breast cancer in a general population. Methods: We compared calibration, discrimination, and net reclassification of these models, using data from questionnaires sent every 2 years to 76,922 participants in the Nurses' Health Study between 1980 and 2006, with 4,384 incident invasive breast cancers identified by 2008 (median follow-up, 24 years; range, 1-28 years). In a random one third sample of women, we also compared the performance of these models with predictions from the Rosner-Colditz model estimated from the remaining participants. Results: Both the Gail and Tyrer-Cuzick models showed evidence of miscalibration (Hosmer-Lemeshow P < 0.001 for each) with notable (P < 0.01) overprediction in higher-risk women (2-year risk above about 1%) and underprediction in lower-risk women (risk below about 0.25%). The Tyrer-Cuzick model had slightly higher C-statistics both overall (P < 0.001) and in age-specific comparisons than the Gail model (overall C, 0.63 for Tyrer-Cuzick vs. 0.61 for the Gail model). Evaluation of net reclassification did not favor either model. In the one third sample, the Rosner-Colditz model had better calibration and discrimination than the other two models. All models had C-statistics <0.60 among women ages ≥70 years. Conclusions: Both the Gail and Tyrer-Cuzick models had some ability to discriminate breast cancer cases and noncases, but have limitations in their model fit. Impact: Refinements may be needed to questionnaire-based approaches to predict breast cancer in older and higher-risk women. [ABSTRACT FROM AUTHOR]

Background: Modified median and subgroup-specific gene centering are two essential preprocessing methods to assign breast cancer molecular subtypes by PAM50. We evaluated the PAM50 subtypes derived from both methods in a subset of Nurses' Health Study (NHS) and NHSII participants; correlated tumor subtypes by PAM50 with IHC surrogates; and characterized the PAM50 subtype distribution, proliferation scores, and risk of relapse with proliferation and tumor size weighted (ROR-PT) scores in the NHS/NHSII. Methods: PAM50 subtypes, proliferation scores, and ROR-PT scores were calculated for 882 invasive breast tumors and 695 histologically normal tumor-adjacent tissues. Cox proportional hazards models evaluated the relationship between PAM50 subtypes or ROR-PT scores/groups with recurrence-free survival (RFS) or distant RFS. Results: PAM50 subtypes were highly comparable between the two methods. The agreement between tumor subtypes by PAM50 and IHC surrogates improved to fair when Luminal subtypes were grouped together. Using the modified median method, our study consisted of 46% Luminal A, 18% Luminal B, 14% HER2-enriched, 15% Basal-like, and 8% Normal-like subtypes; 53% of tumor-adjacent tissues were Normal-like. Women with the Basal-like subtype had a higher rate of relapse within 5 years. HER2-enriched subtypes had poorer outcomes prior to 1999. Conclusions: Either preprocessing method may be utilized to derive PAM50 subtypes for future studies. The majority of NHS/NHSII tumor and tumor-adjacent tissues were classified as Luminal A and Normal-like, respectively. Impact: Preprocessing methods are important for the accurate assignment of PAM50 subtypes. These data provide evidence that either preprocessing method can be used in epidemiologic studies. [ABSTRACT FROM AUTHOR]

Background: Estrogen metabolism in premenopausal women may be related to early life body fatness. Methods: Premenopausal women participating in the Nurses' Health Study II recalled their body fatness at ages 5, 10, and 20 years using a validated 9-level pictogram. Fifteen estrogens and estrogen metabolites (EM) were measured using LC/MS-MS in luteal phase urines from 603 women ages 32-54 years. Geometric means of individual EM, metabolic pathway groups, and pathway ratios were examined by body fatness categories using linear mixed models. Results: Body fatness at each age was inversely associated with adult concentrations of all EM combined, parent estrogens (estrone, estradiol), and the 2-hydroxylation pathway. Women in the top (vs. bottom) category of body fatness at age 10 had 21% lower levels of all EM (Ptrend = 0.003), 24% lower parent estrogens (Ptrend = 0.002), and 36% lower 2-pathway (Ptrend = 0.0003). Body fatness at age 10 was inversely associated with 2-catechols (35% lower, Ptrend = 0.0004) and 2-methylated catechols (30% lower, Ptrend = 0.002). After adjusting for premenopausal body mass index (BMI), these associations remained inverse but were attenuated; only parent estrogens remained statistically significant (21% lower, Ptrend = 0.01). Body fatness at ages 5 and 20 were similarly, but more weakly, associated with estrogen pathways. Conclusions: Estimates of body fatness during early life were inversely associated with premenopausal levels of all EM combined, parent estrogens, and 2-pathway estrogen metabolites. These relationships were not fully explained by adult BMI. [ABSTRACT FROM AUTHOR]

Background: Depression and antidepressant use is highly prevalent among U.S. women and may be related to increased breast cancer risk. However, prior studies are not in agreement regarding an increase in risk. Methods: We conducted a prospective cohort study within the Nurses' Health Study (NHS) and NHSII among females age 25 and older. Over more than 10 years of follow-up in each cohort, 4,014 incident invasive breast cancers were diagnosed. We used Cox proportional hazards regressions with updating of exposures and covariates throughout follow-up to estimate HRs and 95% confidence intervals (CIs) for associations between clinical depression and antidepressant use with invasive breast cancer risk. Analyses were repeated separately for in situ disease, as well as stratified by estrogen receptor (ER) subtype and menopausal status at diagnosis. Results: No statistically significant associations were observed between clinical depression (HR for reporting ≥3 times vs. 0, 1.13; 95% CI, 0.85-1.49) or antidepressant use (HR for reporting ≥3 times vs. 0, 0.92; 95% CI, 0.80-1.05) and invasive breast cancer risk in multivariable analyses. Likewise, we observed no significant associations between clinical depression or antidepressant use and risk of in situ, ER+, ER-, premenopausal, or postmenopausal breast cancer. Conclusions: In the largest prospective study to date, we find no evidence that either depression or antidepressant use increase risk of breast cancer. Impact: The results of this study are reassuring in that neither depression nor antidepressant use appear to be related to subsequent breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Urinary melatonin levels have been associated with a reduced risk of breast cancer in postmenopausal women, but this association might vary according to tumor melatonin 1 receptor (MT1R) expression. Methods: We conducted a nested case-control study among 1,354 postmenopausal women in the Nurses' Health Study, who were cancer free when they provided first-morning spot urine samples in 2000 to 2002; urine samples were assayed for 6-sulfatoxymelatonin (aMT6s, a major metabolite of melatonin). Five-hundred fifty-five of these women developed breast cancer before May 31, 2012, and were matched to 799 control subjects. In a subset of cases, immunohistochemistry was used to determine MT1R status of tumor tissue. We used multivariable-adjusted conditional logistic regression to estimate the relative risk (RR) of breast cancer [with 95% confidence intervals (CI)] across quartiles of creatinine-standardized urinary aMT6s level, including by MT1R subtype. Results: Higher urinary melatonin levels were suggestively associated with a lower overall risk of breast cancer (multivariable-adjusted RR = 0.78; 95% CI = 0.61-0.99, comparing quartile 4 vs. quartile 1; Ptrend = 0.08); this association was similar for invasive vs. in situ tumors (Pheterogeneity = 0.12). There was no evidence that associations differed according to MT1R status of the tumor (e.g., Pheterogeneity for overall breast cancer = 0.88). Conclusions: Higher urinary melatonin levels were associated with reduced breast cancer risk in this cohort of postmenopausal women, and the association was not modified by MT1R subtype. Impact: Urinary melatonin levels appear to predict the risk of breast cancer in postmenopausal women. However, future research should evaluate these associations with longer-term follow-up and among premenopausal women. [ABSTRACT FROM AUTHOR]

Background: Sex hormones are important for breast cancer, but it is unclear whether dietary patterns influence hormone concentrations. Methods: Dietary pattern adherence scores for the alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Alternative Healthy Eating Index (AHEI) were calculated from semiquantitative food frequency questionnaires administered in 1995 and 1999. Premenopausal plasma concentrations of sex hormones were measured in samples collected in 1996 to 1999. We used generalized linear models to calculate geometric mean hormone concentrations across quartiles of dietary pattern scores among 1,990 women in the Nurses' Health Study II. Results: We did not observe significant associations between sex hormone concentrations and the DASH pattern and only one suggestive association between follicular estrone concentrations and the aMED pattern [top vs. bottom quartile -4.4%, 95% confidence interval (CI), -10.6% to 2.1%; Ptrend = 0.06]. However, women in the top versus bottom quartile of AHEI score had lower concentrations of follicular (-9.1%; 95% CI, -16.1% to -1.4%; Ptrend = 0.04) and luteal (-7.5%; 95% CI, -13.6% to -0.9%; Ptrend = 0.01) estrone, luteal-free (-9.3%; 95% CI, -16.8% to -1.1%; Ptrend = 0.01) and total (-6.7 %; 95% CI, -14.3% to 1.5%; Ptrend = 0.04) estradiol, follicular estradiol (-14.2%; 95% CI, -24.6% to -2.4%; Ptrend = 0.05), and androstenedione (-7.8%; 95% CI, -15.4% to 0.4%; Ptrend = 0.03). Conclusion: Diet quality measured by the AHEI is inversely associated with premenopausal estrogen concentrations. Given that we did not observe similar associations with the aMED or DASH patterns, our findings should be interpreted with caution. Impact: Given the role of estrogens in breast cancer etiology, our findings add to the substantial evidence on the benefits of adhering to a healthy diet. [ABSTRACT FROM AUTHOR]

Background: Anti-Müllerian hormone (AMH) is a member of the TGFb family of growth and differentiation factors with a key role in regulating folliculogenesis. In experimental studies, using supraphysiologic concentrations, AMH inhibits breast cancer growth. However, high levels of AMH were associated with increased breast cancer risk in two prior prospective epidemiologic studies. Methods: We conducted a nested case-control study of premenopausal plasma AMH and breast cancer risk within the Nurses' Health Study (NHS) and NHSII. In NHS, 32,826 women donated blood samples in 1989-1990; in NHSII, 29,611 women donated samples in 1996-1999. After blood collection and before February 2004 (NHS) or July 2010 (NHSII), 539 cases were diagnosed among women premenopausal at diagnosis, and were matched 1:1 to controls. ORs and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusting for matching and breast cancer risk factors. Results: Higher plasma levels of AMH were associated with increased breast cancer risk (top vs. bottom quintile multivariate OR, 2.20; 95% CI, 1.34-3.63; P trend = 0.001). The association did not vary by invasive versus in situ disease or by estrogen receptor status. Associations were not significantly different by age at blood or diagnosis. Further adjustment for plasma estradiol or testosterone yielded similar results. Conclusions: Higher circulating AMH levels are associated with increased breast cancer risk among premenopausal women. Impact: The significant positive association between premenopausal plasma AMH levels and subsequent breast cancer risk before menopause suggests AMH may be useful as a marker of breast cancer risk in younger women. [ABSTRACT FROM AUTHOR]

Background: Whether depression and antidepressant (AD) use might influence breast cancer risk is unclear, and these exposures have not been evaluated together in a single, prospective cohort study of breast cancer risk. Methods: Among 71,439 postmenopausal women in the Women's Health Initiative Observational Study (WHI-OS), we estimated multivariable-adjusted HRs for the independent and joint effects of depressive symptoms and AD use on breast cancer risk using Cox proportional hazards regression. Results: When analyzed separately, neither depressive symptoms nor AD use at baseline were associated with a significantly increased risk of total breast cancer (HR = 0.96, 95% CI, 0.85- 1.08; HR = 1.04, 95% CI, 0.92-1.20, respectively) or invasive breast cancer (HR=0.98, 95% CI, 0.86-1.12;HR=1.00, 95% CI, 0.86-1.16, respectively). Current AD use was associated with a borderline-significant increase of in situ breast cancer (HR = 1.30, 95% CI, 0.99-1.75) after adjustment for depressive symptoms; however, this relationship was attenuated after adjustment for mammographic screening (HR = 1.08, 95% CI, 0.76-1.51). No significant variation in total breast cancer risk was observed when the separate and joint effects of depressive symptoms and AD use were explored (P for interaction = 0.14). Conclusion: We found no evidence that either depression or AD use influences breast cancer risk. An elevated risk of in situ disease among AD users could not be ruled out, though is likely due to increased screening in this subgroup. Impact: Given the high prevalence of these exposures, these results may provide reassurance to the millions of womenwho are depressed and/or use ADs each year. [ABSTRACT FROM AUTHOR]

Background: It remains unclear if oral contraceptive (OC) use is associated with the incidence of colorectal cancer. Few studies have examined this association by duration of OC use, time since last OC use, and different cancer subsites. Methods: Among 88,691 participants of the Nurses' Health Study I (NHSI) and 93,080 participants of the Nurses' Health Study II (NHSII), we assessed OC use every 2 years between 1976 and 2010 and categorized it as ever use, duration of use, and time since last use. We included incident colorectal cancer cases through 2010 (NHSI: age at diagnosis = 36-88, N = 1,764; NHSII: age at diagnosis = 33-64, N = 206). Multivariable hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression models. Results: Ever OC use was not associated with colorectal cancer in NHSI [1.01 (0.91, 1.12)] nor NHSII [1.03 (0.69, 1.53)]. In NHSII, when compared with never-users, longer durations (5+ years) of OC use were inversely associated with the risk of colon cancers (Ptrend = 0.02) but the number of endpoints was limited. No other colorectal cancer subsites were associated with OC durations or times since last OC use in either cohort. Conclusions: In two large prospective cohorts, we found little evidence that OC use may be protective for colorectal cancer, except potentially with longer durations of use among younger women. Impact: Our results do not support the previous initial studies that reported an inverse association of recent OC use with colorectal cancer but instead support newer, larger studies demonstrating no such association. [ABSTRACT FROM AUTHOR]

Background: C-reactive protein (CRP) has been evaluated as a risk factor for breast cancer in epidemiologic studies. However, results from prospective studies are inconsistent. Methods: We evaluated the association using prediagnostic blood samples in a case-control study nested within the Nurses' Health Study (NHS) and the full cohort of the Women's Health Study (WHS). A total of 943 cases in the NHS and 1,919 cases in the WHS contributed to the analysis. Conditional logistic regression and Cox proportional hazards model were used in the NHS and WHS, respectively. We pooled our results with prior prospective studies using random effect meta-analysis. Results: In the NHS, higher CRP levels were associated with a suggestively increased risk of breast cancer [quintile 5 vs. 1: relative risk (RR), 1.27; 95% confidence interval (CI), 0.93-1.73; Ptrend = 0.02]; results did not vary significantly by tumor invasiveness or hormone receptor status. However, no association was observed in the WHS for overall risk (quintile 5 vs. 1: RR, 0.89; 95% CI, 0.76-1.06; Ptrend = 0.38) or by tumor invasiveness or hormone receptor status. The meta-analysis (including 5,371 cases from 11 studies) showed a modestly increased risk among women in the highest versus lowest categories of CRP (RR, 1.26; 95% CI, 1.07-1.49). Conclusions: Existing data from prospective studies suggest that CRP, a nonspecific marker of inflammation, is modestly positively associated with breast cancer risk. Impact: Our findings provide support to the concept that inflammation can influence breast cancer development. [ABSTRACT FROM AUTHOR]

Background: Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. Methods: High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. Results: Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). Conclusion: Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Impact: Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. [ABSTRACT FROM AUTHOR]

The article discusses a study which evaluates adult body size and physical activity in relation to breast cancer risk by tumor androgen receptor (AR) status. Topics discussed include assessment of height, weight, and physical activity, determination of AR, estrogen receptor (ER), and progesterone receptor (PR) using immunohistochemistry on tumor tissue and medical/pathology, and association of higher BMI (body mass index) with an increased risk of breast tumors in postmenopausal women.

The article focuses on the research "Vitamin D-Associated Genetic Variation and Risk of Breast Cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)." Topics discussed include relationship between vitamin D status and breast cancer, the associations between single nucleotide polymorphisms in serum 25-hydroxyvitamin D and breast cancer risk, and genetic variation in the vitamin D pathway.

The article discusses a research on association between dietary factors and endometrial cancer risk by using a nutrient-wide association study approach in the European Prospective Investigation (EPIC) and Nurses' Health Study (NHS). It mentions that there limited data on the role of dietary factors in endometrial cancer development. It mentions relation between intake of coffee and endometrial cancer risk. It mentions butter, yogurt and potatoes increase endometrial cancer risk.

The article presents case study on the association of prolactin, lactogenic hormone with breast cancer risk. It mentions the plasma bioactive prolactin levels measured by the Nb2 lymphoma cell bioassay that is sensitive to the somatolactogenic activity of prolactin and growth hormone. It adds that the results reveal similar associations for prolactin levels measured by bioassay and immunoassay with breast cancer risk.

The article looks at a study done in order to determine the relation between alcohol consumption and plasma sex hormone prolactin and on sex hormone-binding globulin in premenopausal women. The study found that alcohol consumption is positively associated with plasma luteal estrogen concentration but not with androgen levels.

The article focuses on the use of dietary insulin load and insulin index scores to represent the insulin demand of overall diets and assessment of their association with endometrial cancer risk in the Nurses' Health Study. It mentions the estimation of incidence rate ratios (RR) and confidence intervals (CI) for risk of endometrial cancer using Cox proportional hazards models. It adds that intake of a diet was not associated with endometrial cancer risk.

The article presents a study that investigated the relationship between acrylamide intake and plasma levels of sex hormones and sex hormone-binding globulin (SHBG). The study reveals no associations between acrylamide and sex hormones or SHBG among premenopausal women overall or among never-smokers and inverse associations for estrone, free estradiol, and estrone sulfate among normal-weight women.

The article discusses a study on the associations between c-peptide, breast cancer risk and breast density measurements in case-control studies. Topics covered include method used for estimating breast cancer associations, the association between hyperinsulinemia and breast cancer risk and the targeting of insulin signaling pathways as a primary prevention of breast cancer in women with hyperinsulinemia.