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Few studies have investigated the consequences of caregiving on the objectively measured physiological health outcomes in China. This study used population-based longitudinal data to examine the association between parental caregiving and blood pressure among Chinese women. This is a retrospective analysis of 2586 women using five waves of data from the Ever-Married Women Survey component of the China Health and Nutrition Survey (2000, 2004, 2006, 2009, and 2011). We applied growth curve models to examine trajectories of systolic blood pressure (SBP) and diastolic blood pressure (DBP) associated with parental caregiving among women in China. In multivariable analyses of blood pressure trajectories adjusting for potential confounders, parental caregivers had higher systolic (β-coefficient (β) = 1.16; p ≤ 0.01) and diastolic blood pressure (β = 0.75; p ≤ 0.01) compared with non-caregivers across multiple waves. Caregivers and non-caregivers had similar levels of systolic blood pressure at baseline, but caregivers exhibited relatively higher growth rate over time. Diastolic blood pressure was much higher among caregivers at the baseline measure, and across time relative to non-caregivers. Moreover, low-intensity but not high-intensity caregivers showed higher growth rate compared with non-caregivers for both SBP and DBP. Our results demonstrate the negative cardiovascular consequences of parental caregiving among Chinese women. Findings from the study can be used to develop future stress management interventions to decrease hypertension risk within women who provide care to their parents.

PURPOSE: Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the association. We used global metabolomics profiling to identify serum metabolites and metabolic pathways that could potentially mediate the alcohol-breast cancer association. METHODS: A cross-sectional analysis of reported alcohol consumption and serum metabolite concentrations was conducted among 211 healthy women 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-Up Study (DISC06). Alcohol-metabolite associations were evaluated using multivariable linear mixed effects regression. RESULTS: Alcohol was significantly (FDR p

Background: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. Methods: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992–1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. Results: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85–4.11); Ptrend = 0.17] or ovarian cancer risk [1.16 (0.58–2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09–0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18–0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39–6.93); 0.01]. Conclusions: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. Impact: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

Phthalates, plasticizers ubiquitous in household and personal care products, have been associated with metabolic disturbances. Despite the noted racial differences in phthalate exposure and the prevalence of metabolic syndrome (MetS), it remains unclear whether associations between phthalate metabolites and MetS vary by race and sex. A cross-sectional analysis was conducted among 10,017 adults from the National Health and Nutritional Examination Survey (2005–2014). Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were estimated for the association between 11 urinary phthalate metabolites and MetS using weighted sex and race stratified multivariable logistic regression. Higher MCOP levels were significantly associated with increased odds of MetS among women but not men, and only remained significant among White women (POR Q4 vs. Q1 = 1.68, 95% CI: 1.24, 2.29, p-trend = 0.001). Similarly, the inverse association observed with MEHP among women, persisted among White women only (POR Q4 vs. Q1 = 0.53, 95% CI: 0.35, 0.80, p-trend = 0.003). However, ΣDEHP metabolites were associated with increased odds of MetS only among men, and this finding was limited to White men (POR Q4 vs. Q1 = 1.54, 95% CI: 1.01, 2.35, p-trend = 0.06). Among Black men, an inverse association was observed with higher MEP levels (POR Q4 vs. Q1 = 0.43, 95% CI: 0.24, 0.77, p-trend = 0.01). The findings suggest differential associations between phthalate metabolites and MetS by sex and race/ethnicity.

Background: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women. Methods: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992–1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)]. Results: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40–1.25; progesterone HR, 1.25; 95% CI, 0.71–2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75–1.44; Ptrend, 0.06). Conclusions: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women. Impact: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.

This abstract was withdrawn by the authors. Citation Format: Trabert B, Bauer DC, Brinton LA, Buist DS, Cauley JA, Dallal CM, Gierach GL, Falk RT, Hue TF, Lacey, Jr. JV, LaCroix AZ, Tice JA, Xu X. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-04.

Background: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found. Methods: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30–65 yielding 14,158 type-specific infections. Findings: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks

BACKGROUND: Prior research suggests that stress plays role in the etiology and progression of hypertension. To lend a more accurate depiction of the underlying mechanisms between stress and hypertension, this study aims to assess the associations between perceived stress and hypertension across varying levels of social support and social network among Asian Americans. METHODS: We conducted a cross-sectional study using data on 530 Chinese, Korean and Vietnamese Americans recruited from a liver cancer prevention program in the Washington D.C. – Baltimore metropolitan area. RESULTS: Hypertension prevalence was 29.1%. Individuals with high perceived stress were 61% more likely to have hypertension compared to those with low levels of perceived stress (Odds Ratio (OR): 1.61, 95% Confidence interval (CI): 1.15, 2.46). There was no evidence that social support and social network acted as effect modifiers. Social support had a direct beneficial effect on hypertension, irrespective of whether individuals were under stress. The relationship between perceived stress and hypertension was modified by gender and ethnicity whereby a significant positive association was only observed among male or Chinese participants. CONCLUSION: Our study highlights the importance of understanding the associations between stress, social support, and hypertension among Asian American subgroups. Findings from the study can be used to develop future stress management interventions, and incorporate culturally and linguistically appropriate strategies into community outreach and education to decrease hypertension risk within the Asian population.

Syndemic methodology has been employed in several studies of HIV-related outcomes affecting Black men who have sex with men (BMSM) and rarely in Black heterosexual men. In contrast to the most common method for assessing syndemics, the use of a syndemic component index, latent class analysis can identify unique combinations of risk factors that may form a syndemic. Analyzing a primarily heterosexual sample of 1,786 Black men from the 2015 Behavioral Risk Factor Surveillance System (BRFSS), we used a 4 latent class model based on depression diagnosis, poverty, and healthcare access to predict ever having been HIV tested. Class 1 was characterized by low proportions of all the risk factors. Class 2 had relatively high healthcare barriers, being the most likely to not have a personal doctor (.8175) and the most likely to have no routine checkup in the past year (.6327) but had relatively low depression diagnosis and poverty. Class 3 had relatively high poverty (.8853), but generally low barriers to healthcare access. Class 4 was characterized by high proportions of all the risk factors. Using log-binomial regression models, there was a significantly lower prevalence of ever having been HIV tested among class 3 (PR = 0.69, 95% CI 0.49, 0.98) and class 4 (PR = 0.49, 95% CI 0.28, 0.84) compared to class 1. When adjusting for education, age, and marital status, the associations were attenuated but still significant for class 3 (aPR = 0.71, 95% CI 0.52, 0.96) and class 4 (aPR = 0.60, 95% CI 0.46, 0.78). Latent class analysis may better serve syndemic research aims in understanding HIV-related outcomes among high-risk populations. Future research using this method to evaluate HIV testing outcomes among BMSM is recommended.

Black populations in the United States are disproportionately affected by HIV. This disparity may be affected by social and structural barriers to HIV testing, leading to undiagnosed infection and prolonged HIV transmissibility. Using data from a nationally representative sample of 1,727 Black men in the 2015 Behavioral Risk Factor Surveillance System we tested for differences in poverty, depression, and health care barriers between Black men who had been HIV tested in the past year and those who had not. We also tested a syndemic index of these factors. Number of syndemic factors was linearly associated with less HIV testing (aPR=0.79, 95% CI 0.66-0.95). Assumptions of unidimensionality were met. The use of a syndemic index was a superior approach to analyzing these factors individually, both in terms of model fit and associations detected. The accumulation of poverty, depression, and health care barriers has an adverse impact on HIV testing among Black men.

Background and Objectives The intersection of cancer, treatment, and aging accelerates functional decline. Social networks, through the provision of social support and resources, may slow the progression of functional deterioration. Socioemotional selectivity theory posits that aging and major life events, like cancer, cause an intentional social network pruning to procure and maintain emotionally fulfilling bonds, while shedding weaker, less supportive relationships. However, it is relatively unknown if such network changes impact functional impairment in cancer survivors. This study examined the relationships between changes in the egocentric social network and functional impairment in older adult cancer survivors and a similarly aged group without cancer (older adults). Research Design and Methods Data were analyzed from 1,481 community dwelling older adults (n = 201 cancer survivors) aged 57–85 years, from Waves 1 and 2 (2005–2006 and 2010–2011) of the National Social Life, Health and Aging Project. Associations were analyzed with multiple logistic regression. Results Cancer survivors and older adults reported similar levels of functional impairment and social network change. Adding 2 new relationships exhibited protective effects against functional impairment, irrespective of cancer status (odds ratio [OR]: 0.64, 95% confidence interval [CI]: 0.41–0.99). Declines in frequent contact were associated with higher odds of functional impairment among cancer survivors (OR: 1.92, 95% CI: 1.15–3.20). Social network components were not significantly associated with functional impairment in older adults. Discussion and Implications Adding new relationships may reduce disability in older adults and increasing network contact may help cancer survivors remain independent. Social network interventions may improve quality of life for older adults.

Background: Of the 1.8 million global incident lung cancer cases estimated in 2012, approximately 60% occurred in less developed regions. Prior studies suggest sex differences in lung cancer risk and a potential role for reproductive and hormonal factors in lung cancer among women. However, the majority of these studies were conducted in developed regions. No prior study has assessed these relationships among Nepali women. Methods: Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009-2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23-85 years. Lung cancer cases (n = 268) were frequency-matched to controls (n = 226) based on age (±5 years), ethnicity and residential area. The main exposures in this analysis included menopausal status, age at menarche, age at menopause, menstrual duration, gravidity, and age at first live-birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Results: Among postmenopausal women, those with a younger age at menopause (

Caregiving stress may play a role in the pathogenesis of Metabolic Syndrome (MetS). However, few studies have investigated the consequences of caregiving on this objectively measured health outcome. This study used population based longitudinal data to examine the causal relationship between caregiving trajectory and MetS among Chinese women. This is a retrospective analysis of 741 women using three waves of data from the Ever-Married Women Survey component of the China Health and Nutrition Survey (2004, 2006, and 2009). Group-based trajectory analysis was used to examine the caregiving trajectories among women in China. Three caregiving trajectories were identified. In multivariate analyses adjusting for potential covariates, ‘rising to high-intense’ caregivers (Odds Ratio (OR) = 3.78; 95% Confidence Interval (CI): 1.10, 12.93) and ‘stable low-intense’ caregivers (OR = 2.07; 95% CI: 1.09, 3.92) were associated with higher risk of MetS compared with non-caregivers. Moreover, caregivers who provided ‘stable low-intense’ parental care were found to be associated with hypertension, high glucose and high triglycerides than those awho did not provide caregiving for their parents. Our results demonstrate that the caregiving trajectories were significantly associated with the risk of MetS. Findings from the study can be used to develop future stress management interventions to decrease MetS risk among women who provide care to their parents.

Key Points Question Are circulating levels of progesterone and progesterone metabolites associated with incident breast cancer in postmenopausal women? Findings In this case-cohort study of 405 incident breast cancer cases, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Meaning This study’s findings suggest that further research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolite levels, as well as their interactions with estradiol levels., Importance The role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties. Objective To evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk. Design, Setting, and Participants Using a sensitive liquid chromatography–tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018. Exposures Circulating concentrations of pregnenolone, progesterone, and their major metabolites. Main Outcomes and Measures Development of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori. Results The present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (, This case-cohort study examines the association of circulating progesterone and progesterone metabolite concentrations with breast cancer in postmenopausal women.

Estrogen metabolites may have different genotoxic and mitogenic properties yet their relationship with endometrial and ovarian cancer risk remains unclear. Within the Breast and Bone Follow-up to the Fracture Intervention Trial (B ∼ FIT, n = 15,595), we conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Participants included 66 endometrial and 67 ovarian cancer cases diagnosed during follow-up (∼ 10 years) and subcohorts of 346 and 416 women, respectively, after relevant exclusions. Serum concentrations were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. Exposures were categorized in tertiles (T) and analyzed individually, as metabolic pathways (C-2, -4, or -16) and as ratios to parent estrogens (estradiol, estrone). Estradiol was significantly associated with increased endometrial cancer risk (BMI-adjusted HRT3vsT1 = 4.09, 95% CI 1.70, 9.85; p trend = 0.003). 2-Hydroxyestrone and 16α-hydroxyestrone were not associated with endometrial risk after estradiol adjustment (2-OHE1:HRT3vsT1 = 1.97, 95% CI 0.78, 4.94; 16-OHE1:HRT3vsT1 = 1.50, 95% CI 0.65, 3.46; p trend = 0.16 and 0.36, respectively). Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment (2-pathway catechols-to-methylated: HRT3vsT1 = 4.02, 95% CI 1.60, 10.1; 4-pathway catechols-to-methylated: HRT3vsT1 = 4.59, 95% CI 1.64, 12.9; p trend = 0.002 for both). Estrogens and estrogen metabolites were not associated with ovarian cancer risk; however, larger studies are needed to better evaluate these relationships. Estrogen metabolism may be important in endometrial carcinogenesis, particularly with less extensive methylation of 2- or 4-pathway catechols associated with elevated endometrial cancer risk.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample ( n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA ( n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable.

Purpose Physical activity may reduce endogenous estrogens, but few studies have assessed effects on estrogen metabolism and none have evaluated sedentary behavior in relation to estrogen metabolism. We assessed relationships between accelerometer-measured physical activity and sedentary behavior and 15 urinary estrogens and estrogen metabolites (EM) among postmenopausal controls from a population-based breast cancer case-control study conducted in Poland (2000-2003). Methods Postmenopausal women (N = 542) were ages 40 to 72 yr and not currently using hormone therapy. Accelerometers, worn for 7 d, were used to derive measures of average activity (counts per day) and sedentary behavior (

Background: Interindividual differences in estrogen metabolism may partially account for differences in risks of estrogen-responsive cancers. We conducted a proof-of-performance study to assess the reproducibility of a LC/MS-MS method for measurement of 15 serum estrogens and metabolites (all 15 termed EM) in total (conjugated+unconjugated) and unconjugated forms and describe interindividual variation. Methods: Interindividual variation in serum EM profiles was evaluated for 20 premenopausal women, 15 postmenopausal women, and 10 men. Replicate aliquots from 10 premenopausal women, 5 postmenopausal women, and 5 men were assayed eight times over 4 weeks. Components of variance were used to calculate coefficients of variation (CV) and intraclass correlation coefficients (ICC). Results: In postmenopausal women and men, median EM concentrations were similar and substantially lower than that in premenopausal women. Within each sex/menopausal group, the sum of all EM varied 5- to 7-fold across extreme deciles. Some EM had greater variation; total estrone varied approximately 12-fold in premenopausal and postmenopausal women. Unconjugated estradiol varied 17-fold in postmenopausal women but only 5-fold in premenopausal women and men. CVs reflecting variation across replicate measures for individuals were 99% for all EM in each group. Conclusions: The serum EM assay has excellent laboratory reproducibility. In premenopausal women, postmenopausal women, and men, interindividual variation in EM measures is substantially greater than laboratory variation. Impact: The serum EM assay is suitable for epidemiologic application. See all the articles in this CEBP Focus section, “Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology.” Cancer Epidemiol Biomarkers Prev; 23(12); 2649–57. ©2014 AACR.

Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992-93, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatography-tandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HRQ5vsQ1 = 1.86; 95% CI: 1.19-2.90; P trend = 0.04). An elevated ratio of the 2-hydroxylation pathway (HRQ5vsQ1 = 0.69; 95% CI: 0.46-1.05; P trend = 0.01) and 4-hydroxylation pathway (HRQ5vsQ1 = 0.61; 95% CI: 0.40-0.93; P trend = 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HRQ5vsQ1 = 0.60; 95% CI: 0.40-0.90; P trend = 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.

Risk factor associations for rare breast cancer variants are often imprecise, obscuring differences between tumor types. To clarify differences, we examined risk factors for 5 histological types of breast cancer in the National Institutes of Health-AARP Diet and Health Study. Risk factor information was self-reported. We followed 192,076 postmenopausal women aged 50–71 years from 1995–1996 through 2006. During that time period, 5,334 ductal, 836 lobular, 639 mixed ductal-lobular, 216 mucinous, and 132 tubular breast cancers were diagnosed. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Heterogeneity was evaluated using case-only logistic regression. The strongest differences were for menopausal hormone therapy (Pheterogeneity < 0.01) and age at first birth (Pheterogeneity < 0.01). Risk of tubular cancer in relation to current menopausal hormone therapy (for current use vs. never use, hazard ratio (HR) = 4.39, 95% confidence interval (CI): 2.77, 6.96) was several times stronger than risk of other histological types (range of HRs, 1.39–1.75). Older age at first birth was unassociated with risk of mucinous (for ≥30 years vs. 20–24 years, HR = 0.62, 95% CI: 0.27, 1.42) or tubular (HR = 1.08, 95% CI: 0.51, 2.29) tumors, in contrast to clear positive associations with lobular (HR = 1.82, 95% CI: 1.39, 2.37) and mixed ductal-lobular (HR = 1.87, 95% CI: 1.39, 2.51) tumors. Differing associations for hormonal factors and mucinous and tubular cancers suggest etiologies distinct from those of common breast cancers.

Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918–25. ©2017 AACR.

Comparing risk factor associations between invasive breast cancers and possible precursors may further our understanding of factors related to initiation versus progression. Accordingly, among 190,325 postmenopausal participants in the National Institutes of Health-AARP Diet and Health Study (1995-2011), we compared the association between risk factors and incident ductal carcinoma in situ (DCIS; n = 1,453) with that of risk factors and invasive ductal carcinomas (n = 7,525); in addition, we compared the association between risk factors and lobular carcinoma in situ (LCIS; n = 186) with that of risk factors and invasive lobular carcinomas (n = 1,191). Hazard ratios and 95% confidence intervals were estimated from multivariable Cox proportional hazards regression models. We used case-only multivariable logistic regression to test for heterogeneity in associations. Younger age at menopause was associated with a higher risk of DCIS but lower risks of LCIS and invasive ductal carcinomas (P for heterogeneity < 0.01). Prior breast biopsy was more strongly associated with the risk of LCIS than the risk of DCIS (P for heterogeneity = 0.04). Increased risks associated with use of menopausal hormone therapy were stronger for LCIS than DCIS (P for heterogeneity = 0.03) and invasive lobular carcinomas (P for heterogeneity < 0.01). Associations were similar for race, age at menarche, age at first birth, family history, alcohol consumption, and smoking status, which suggests that most risk factor associations are similar for in situ and invasive cancers and may influence early stages of tumorigenesis. The differential associations observed for various factors may provide important clues for understanding the etiology of certain breast cancers.

Epidemiologic evidence regarding the relationship between smoking and breast cancer risk is inconsistent. Some studies suggest that the relationship depends on interaction with other factors, such as alcohol use, body mass index (BMI), and menopausal hormone therapy (MHT). We investigated the relationship between smoking and breast cancer risk and interactions with breast cancer risk factors in the NIH-AARP Diet and Health Study, a large prospective cohort. Postmenopausal women ages 50–71 years (N = 192,076) in six US states and two metropolitan areas were followed from 1995–1996 through 2006. Risk factor information was self-reported at baseline. Smoking status was based on whether participants smoked ≥ 100 cigarettes in their lifetime and whether they currently smoked (current −15%, former −40%, never −45%). Alcohol use was estimated from a dietary questionnaire, and categorized based on drinking ≤ 5 or > 5 g/day. BMI was calculated from reported height and weight and categorized as ≥ 30 or < 30 kg/m2. MHT use was categorized as current, former, or never use of any estrogen or progestin preparation. Cancer diagnosis, estrogen receptor (ER), and progesterone receptor (PR) data were reported by state registries. After a mean 9.6 years of follow-up, 7,698 women were diagnosed with primary invasive breast cancer. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression. Multiplicative interactions between smoking and covariates were evaluated using the likelihood ratio test (LRT). Overall, smokers were at an increased risk of breast cancer compared to women who never smoked (current HR 1.19, 95% CI 1.10, 1.28; former HR 1.08, 95% CI 1.02, 1.13). Excess risk diminished as time since quitting increased and was close to null for women who quit smoking ≥ 10 years prior to study enrollment compared to never smokers (HR 1.04, 95% CI 0.98, 1.11). Relative risks differed significantly based on alcohol use (P-LRT < 0.01), but not BMI or MHT use (P-LRT > 0.05). The HR associated with current smoking was 1.15 (95% CI 1.05, 1.25) among women who drank ≤ 5 g/day, but was higher among women who drank > 5 g/day (HR 1.41, 95% CI 1.22, 1.61). The relationship for those who drank > 5 g/day persisted after adjustment for the amount of alcohol (5–10, 10–20, 20–35, >35 g/day) consumed (HR 1.36, 95% CI 1.18, 1.56). Among women who drank > 5 g/day, current smoking was associated with increased risks of hormone receptor-positive tumors (ER+/PR+ HR 1.29, 95% CI 1.01, 1.64; ER+/PR- HR 2.11, 95% CI 1.27, 3.50), but not ER−/PR− tumors (HR 1.07, 95% CI 0.64, 1.79). In summary, we found that smoking was associated with elevated breast cancer risk which was strongest among women who drank > 5 g of alcohol per day. Among these women, smoking-associated increases in breast cancer risk were limited to hormone receptor-positive tumors, consistent with the known relationship between alcohol use and ER+ breast cancer risk. Findings were similar after additional adjustment for the amount of alcohol consumed, suggesting that the increased risks were not due to residual confounding by alcohol dose, although further analyses are needed to fully understand the interaction between these two factors. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-04.

Epidemiologic studies suggest that physical activity reduces breast cancer risk by 20-40 %. However, prior studies have relied on measures of self-report. In a population-based case-control study, we evaluated accelerometer measures of active and sedentary behavior in relation to breast cancer among 996 incident cases and 1,164 controls, residents of Warsaw, Poland (2000-2003), who were asked to wear an accelerometer for 7 days. Accelerometer values were averaged across valid wear days and summarized as overall activity (counts [ct]/min/day); in minutes spent in sedentary behavior (0-99 ct/min); and light (100-759 ct/min) and moderate-to-vigorous (760+ ct/min) activity. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression. Comparing women in the highest quartile (Q4) of activity to those in the lowest (Q1), time spent in moderate-to-vigorous activity was inversely associated with breast cancer odds after adjustment for known risk factors, sedentary behavior and wear time (OR(Q4vsQ1) 0.39, 95 % CI 0.27-0.56; P-trend.0001). Sedentary time was positively associated with breast cancer, independent of moderate-to-vigorous activity (OR(Q4vsQ1) 1.81, 95 % CI 1.26-2.60; P-trend = 0.001). Light activity was not associated with breast cancer in multivariable models including both moderate-to-vigorous activity and sedentary behavior. Our findings support an inverse association between accelerometer-based measures of moderate-to-vigorous physical activity and breast cancer while also suggesting potential increases in risk with sedentary time.

Background: Previous research indicates that certain breast cancer risk factor associations vary by histologic tumor type. However, most studies have been too small to examine risk factors for uncommon histologic types. We examined the association between body mass index (BMI), physical activity, and the relative risk of breast cancer histologic types in a large prospective cohort study to determine whether associations for these risk factors varied by histology. Methods: This analysis included women in the NIH-AARP Diet and Health Cohort Study who were 50 to 71 years old, postmenopausal at baseline, and not previously diagnosed with cancer (N=190,348). The study cohort was established in 1995–1996 when participants completed a baseline questionnaire regarding health and nutritional information. BMI (kg/m2) was calculated from self-reported height and weight. Daily routine physical activity at work or home was derived from a question asking women what best described their daily routine at work, or throughout the day if they did not work at a job. Choices were mostly sitting with little walking, sitting with a fair amount of walking, mostly standing or walking, light lifting or climbing stairs/hills, or heavy work/carrying heavy loads. Cancer diagnosis and histology were obtained from state cancer registries. This analysis includes participant follow-up through December 31, 2006. After a median 11.2 years of follow-up, 7,631 invasive breast cancers were diagnosed: 5,278 ductal, 831 lobular, 640 mixed ductal-lobular, 214 mucinous, 132 tubular, and 536 other types. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Results: Compared to women with a BMI of 18.5 to 24.9, obese women had increased risks of ductal (HR and 95% CI for BMI 30 to 34.9: 1.24, 1.14 — 1.36; BMI ≥ 35: 1.45, 1.30 — 1.62) and mucinous (HR and 95% CI for BMI 30 to 34.9: 1.58, 1.04 — 2.39; BMI ≥ 35: 1.93, 1.16 — 3.20) cancers. For both histologic types, the relative risk increased with increasing BMI (P-trend: ductal P Conclusions: High BMI was associated with increased risk of ductal and mucinous breast cancers. Women who spent their daily routine activity mostly standing or walking or doing heavy work had a reduced risk of ductal and mixed ductal-lobular cancers. These differences suggest that associations of BMI and physical activity vary by breast cancer histologic type in postmenopausal women and may have different roles in the etiology of these cancers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-03.

Background: A potential protective role for estrogen in colon carcinogenesis has been suggested based on exogenous hormone use, but it is unclear from previous studies whether endogenous estrogens are related to colorectal cancer risk. These few prior studies focused on parent estrogens; none evaluated effects of estrogen metabolism in postmenopausal women. Methods: We followed 15,595 women (ages 55–80 years) enrolled in the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT) who donated blood between 1992 and 1993 for cancer through December 2004. A panel of 15 estrogen metabolites (EM), including estradiol and estrone, were measured in serum from 187 colorectal cancer cases and a subcohort of 501 women not using exogenous hormones at blood draw. We examined EM individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 position) and by ratios of the groupings using Cox proportional hazards regression models. Results: No significant associations were seen for estrone (HRQ4 vs. Q1 = 1.15; 95% CI, 0.69–1.93; Ptrend = 0.54), estradiol (HRQ4 vs. Q1 = 0.98; 95% CI, 0.58–1.64; Ptrend > 0.99), or total EM (the sum of all EM; HRQ4 vs. Q1 = 1.35; 95% CI, 0.81–2.24; Ptrend = 0.33). Most metabolites in the 2-, 4-, or 16-pathway were unrelated to risk, although a borderline trend in risk was associated with high levels of 17-epiestriol. Conclusion: Circulating estrogens and their metabolites were generally unrelated to colorectal cancer risk in postmenopausal women. Impact: Additional studies are needed to understand how exogenous estrogen may prevent colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(9); 1419–22. ©2015 AACR.

Divergent risk factors exist for premenopausal and postmenopausal breast cancers, but it is unclear whether differences by age exist among postmenopausal women.We examined relationships among 190,872 postmenopausal women, ages 50-71 years recruited during 1995-1996 for the NIH-AARP Diet and Health Study, in whom 7,384 incident invasive breast carcinomas were identified through 2006. Multivariable Cox regression hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for breast cancer risk factors by age (50-59, 60-69, ≥70 years).The only factor showing significant statistical heterogeneity by age (p(het) = 0.001) was menopausal hormone therapy duration, but trends were apparent across all ages and the strongest association prevailed among women 60-69 years. Although other risk factors did not show statistically significant heterogeneity by age, we did observe attenuated relations for parity and late age at first birth among older women [e.g., HR for age at first birth ≥30 vs. 20-24 = 1.62 (95% CI 1.23-2.14) for women 50-59 years vs. 1.12 (0.96-1.31) for ≥70 years]. In contrast, risk estimates associated with alcohol consumption and BMI tended to be slightly stronger among the oldest subjects [e.g., HR for BMI ≥35 vs. 18.5-24.9 = 1.24 (95% CI 0.97-1.58) for 50-59 years vs. 1.46 (1.26-1.70) for ≥70 years]. These differences were somewhat more pronounced for estrogen receptor positive and ductal cancers, tumors predominating among older women. Breast cancer family history, physical activity, and previous breast biopsies did not show divergent associations by age.Although breast cancer risk factor differences among older women were not large, they may merit further consideration with respect to individualized risk prediction.

Background: The relationship between cigarette smoking and breast cancer risk has been inconsistent, potentially due to modification by other factors or confounding. Methods: We examined smoking and breast cancer risk in a prospective cohort of 186 150 female AARP (formerly American Association of Retired Persons) members, ages 50–71 years, who joined the study in 1995–96 by responding to a questionnaire. Through 2006, 7481 breast cancers were diagnosed. Multivariable-adjusted hazard ratios (HRs) were estimated, overall and stratified by breast cancer risk factors, using Cox proportional hazards regression. Multiplicative interactions were evaluated using the likelihood ratio test. Results: Increased breast cancer risk was associated with current (HR 1.19, 95% confidence interval (CI) 1.10–1.28) and former (HR 1.07, CI 1.01–1.13) smoking. The current smoking association was stronger among women without (HR 1.24, CI 1.15–1.35) as compared to those with a family history of breast cancer (HR 0.94, CI 0.78–1.13) (P-interaction=0.03). The current smoking association was also stronger among those with later (⩾15 years: HR 1.52, CI 1.20–1.94) as compared with earlier (⩽12 years: HR 1.14, CI 1.03–1.27; 13–14 years: HR 1.18, CI 1.05–1.32) ages at menarche (P-interaction=0.03). Conclusions: Risk was elevated in smokers, particularly in those without a family history or late menarche. Research into smoking's effects on the genome and breast development may clarify these relationships.

Background: Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively. Methods: We conducted a nested case–control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw, and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). ORs and 95% confidence intervals (CIs) for the associations of adiponectin, leptin, and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels. Results: Adiponectin levels were inversely associated with risk of endometrial cancer [ORT3vsT1 = 0.48; 95% CI, 0.29–0.80); Ptrend < 0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60–4.79); Ptrend < 0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.25 (0.08–0.75); Ptrend = 0.01 and 4.72 (1.15–19.38); Ptrend = 0.02, respectively]. Nonsignificant positive associations were observed for visfatin. Conclusion: Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT. Impact: Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity–endometrial cancer association. Cancer Epidemiol Biomarkers Prev; 22(7); 1304–12. ©2013 AACR.

Endometrial cancer risk is strongly influenced by obesity, but the mechanisms of action remain unclear. Leptin and adiponectin, secreted from adipose tissue, reportedly play a role in such carcinogenic processes as cell proliferation, angiogenesis, and insulin regulation. In this case–control study, nested within the Breast and Bone Follow-up of the Fracture Intervention Trial (n=15 595), we assessed pre-diagnostic serum leptin, total adiponectin, and high-molecular-weight (HMW) adiponectin in relation to endometrial cancer among postmenopausal women. During the 10-year follow-up, 62 incident endometrial cases were identified and matched to 124 controls on age, geographical site, time of fasting blood draw at baseline (1992–1993), and trial participation status. Adipokines and C-peptide were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated via conditional logistic regression, with exposures categorized in tertiles (T). Multivariable models considered C-peptide, BMI (kg/m2), and estradiol (E2) as potential confounders. Endometrial cancer risk was significantly associated with higher leptin levels, adjusted for E2 and C-peptide (ORT3 vs T1=2.96; 95% CI, 1.21–7.25; P trend T3 vs T1=2.11; 95% CI, 0.69–6.44; P trend=0.18). No significant associations were observed with adiponectin or HMW adiponectin and endometrial cancer. Our findings with leptin suggest that the leptin–BMI axis might increase endometrial cancer risk through mechanisms other than estrogen-driven proliferation. Continued exploration of these pathways in larger prospective studies may help elucidate mechanisms underlying observed obesity–endometrial cancer associations.

Of the 1.8 million global incident lung cancer cases estimated in 2012, approximately 58% occurred in less developed regions (LDRs). Studies conducted in more developed regions suggest potential gender differences in lung cancer risk, whereby women may be more susceptible to the carcinogenic effects of tobacco. However, studies of reproductive and hormonal factors and lung cancer among women have been inconsistent and to date, no prior study has assessed these relationships among Nepali women. Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009-2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23-85 years. Lung cancer cases (n = 268) were frequency-matched to controls (n = 226), on the basis of age (±5 years), ethnicity and residential area. Controls were selected from visitors of non-lung cancer patients within the same hospital. Participants completed an interviewer-administered questionnaire and provided detailed information on demographics, medical history, smoking history, and reproductive and hormonal factors. The main exposures in this analysis included menopausal status, age at menarche, age at menopause, menstrual duration, gravidity, and age at first live-birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Final models include adjustment for key confounders including age and smoking status. Among postmenopausal women, those with a younger age at menopause ( Citation Format: Sanah N. Vohra, Amir Sapkota, Mei-Ling T. Lee, Mia Hashibe, Bhola Siwakoti, Chin B. Pun, Cher M. Dallal. Reproductive and hormonal factors in relation to lung cancer among Nepali women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1737.

Background: Prospective studies have consistently found that postmenopausal breast cancer risk increases with circulating estrogens; however, findings from studies of estrogens and mammographic density (MD), an intermediate marker of breast cancer risk, have been inconsistent. We investigated the cross-sectional associations of urinary estrogens, and their 2-, 4-, and 16-hydroxylated metabolites with MD. Methods: Postmenopausal women without breast cancer (n = 194), ages 48 to 82 years, and reporting no current menopausal hormone therapy use were enrolled at a clinic in Western NY in 2005. Urinary estrogens and estrogen metabolites were measured using mass spectrometry. Percent MD and dense area (cm2) were measured using computer-assisted analyses of digitized films. Linear regression models were used to estimate associations of log-transformed estrogen measures with MD while adjusting for age, body mass index (BMI), parity, and past hormone therapy use. Results: Urinary concentrations of most individual estrogens and metabolites were not associated with MD; however, across the interdecile range of the ratio of parent estrogens (estrone and estradiol) to their metabolites, MD increased by 6.8 percentage points (P = 0.02) and dense area increased by 10.3 cm2 (P = 0.03). Across the interdecile ranges of the ratios of 2-, 4-, and 16-hydroxylation pathways to the parent estrogens, MD declined by 6.2 (P = 0.03), 6.4 (P = 0.04), and 5.7 (P = 0.05) percentage points, respectively. All associations remained apparent in models without adjustment for BMI. Conclusion: In this study of postmenopausal women, less extensive hydroxylation of parent estrogens was associated with higher MD. Impact: Hydroxylation of estrogens may modulate postmenopausal breast cancer risk through a pathway involving MD. Cancer Epidemiol Biomarkers Prev; 21(9); 1582–91. ©2012 AACR.

Background Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and their ratio (2:16α-OHE1) in relation to breast cancer risk. Methods Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using enzyme linked immunosorbent assays. Study-specific and combined multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated based on tertiles of estrogen metabolites. Multinomial logistic regression models were fit according to hormone receptor status. Results Higher premenopausal 2:16α-OHE1 was suggestive of reduced breast cancer risk overall (study-adjusted ORIIIvsI=0.80; 95% CI: 0.49-1.32) and for estrogen receptor negative (ER-) subtype (ORIIIvsI=0.33; 95% CI: 0.13-0.84). Among postmenopausal women, 2:16α-OHE1 was unrelated to breast cancer risk (study-adjusted ORIIIvsI=0.93; 95% CI: 0.65-1.33); however, the association between 2-OHE1 and risk varied by body mass index (p-interaction=0.003). Conclusions Premenopausal urinary 2:16α-OHE1 may play a role in breast carcinogenesis; however, larger studies are needed. Our findings do not support reduced breast cancer risk with higher postmenopausal 2:16α-OHE1 overall, although obesity may modify associations with 2-OHE1.

Background: A role for estrogen in colon carcinogenesis is suggested by the lower incidence of colorectal cancer (CRC) in women than men; the protective effect of exogenous hormones on risk; and reduced levels of estrogen receptor beta (ERβ) expression, the predominant ER in the colon, in cancerous compared to healthy colonic tissue. Nonetheless, the few cohort studies of endogenous hormones have not found reduced risks associated with circulating estradiol or estrone levels in postmenopausal women. We hypothesized that specific metabolites in the estrogen metabolic pathway may preferentially bind to and activate colonic ERβ, and analyzed a panel of 15 estrogen metabolites (EM), including estradiol and estrone, in a case-cohort study of CRC. Methods: We prospectively followed 15,595 women enrolled in B∼FIT (Breast and Bone Follow-up to the Fracture Intervention Trial (FIT)) who had completed questionnaires and donated blood between 1992 and 1993 for incident CRC through December 2004. Using liquid chromatography-tandem mass spectrometry, EM were measured in serum from 197 CRC cases and a subcohort of 491 women who were not using exogenous hormones at the time of blood draw. EM were examined individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring), and by ratios of the groupings. Cox proportional hazard regression models adjusted for clinical site and age (grouped in ten year intervals) were used to calculate quartile-specific hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Significant risks were not observed for individual EM, and HR for quartiles of total EM (sum of all EM) were elevated but not significant (HRQ4 v Q1=1.23, 95% CI=0.8-2.0, ptrend=0.53). No associations were seen for estrone (HRQ4 v Q1=1.05, 95% CI=0.6-1.7) or estradiol (HRQ4 v Q1=0.90. 95% CI=0.5-1.5). When represented as a ratio to the parent estrogens (estrone and estradiol), risks of CRC for women with higher levels of 2-pathway EM or 4-pathway EM were reduced in each quartile, but neither HR nor trends were significant (ratio 2-pathway: parent, HRQ4 v Q1=0.88, 95 CI=0.6-1.4 ptrend=0.56; ratio 4-pathway: parent, HRQ4 v Q1=0.92, 95% CI=0.6, 1.5 ptrend=0.46). Conclusions: Levels of circulating estrone and estradiol and their metabolites are not associated with CRC risk in the B∼FIT cohort. Citation Format: Roni T. Falk, Cher M. Dallal, James V. Lacey, Douglas C. Bauer, Diana SM Buist, Jane A. Cauley, Trisha F. Hue, Andrea LaCroix, Jeffrey A. Tice, Ruth M. Pfeiffer, Xia Xu, Timothy D. Veenstra, Louise A. Brinton. Estrogen metabolites and colorectal cancer risk in postmenopausal women in the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1603. doi:10.1158/1538-7445.AM2014-1603

Studies suggest that higher levels of physical activity may reduce the risk of breast cancer among postmenopausal women, potentially by lowering endogenous estrogen levels. However, few studies have assessed the influence of physical activity on estrogen metabolism; these studies mainly used self-reported measures and focused on only two metabolites, 2-hydroxyestrone and 16α-hydroxyestrone. Estrogen metabolism occurs via hydroxylation at the C-2,-4, or -16 positions, resulting in at least 13 metabolites with potentially different genotoxic and mitogenic effects. In the NCI Polish Breast Cancer Study, we previously reported significant reductions in breast cancer risk with objective measures of activity. Here we present the first study to date to assess the role of accelerometer-measured physical activity on a comprehensive profile of 15 urinary estrogens and estrogen metabolites (EM) among postmenopausal women (N=540) ages 40 to 74 years, not currently on menopausal hormone therapy. Participants were controls from a population-based case-control study conducted in Warsaw, Poland from 2000 to 2003. Women wore an accelerometer on their waist during waking hours for 7 days and provided a 12-hour urine sample. Overall activity was defined by counts per day and was averaged for monitored days with at least 10 hours of wear time. Urinary EM were measured using liquid chromatography-tandem mass spectrometry; EM were standardized by creatinine, assessed by enzyme linked immunoassay. EM were log transformed and analyzed individually, in metabolic pathways (C-2, -4, or -16), and as ratios relative to the parent estrogens (estradiol and estrone). Geometric means of EM by tertiles of activity, adjusted for age and body mass index, were computed based on linear models. Statistical heterogeneity in mean EM levels across activity tertiles was assessed using a Wald test (p-het). High overall activity was associated with lower mean levels of estrone (p-het=0.02) and estradiol (p-het=0.009). With regard to individual metabolites, high activity was inversely associated with 2-methoxyestrone (p-het=0.02), 2-methoxyestradiol (p-het=0.04), estriol (p-het=0.03), and 17-Epiestriol (p-het=0.03). No other significant associations were observed for the individual EM. Examination of specific hydroxylation pathways relative to the parent estrogens revealed that women in the highest tertile of activity had increased hydroxylation at the C-2, -4, and -16 sites (p-het ≤ 0.03). Analyses by intensity of activity and sedentary behavior are ongoing. Our findings with accelerometer-measured physical activity are consistent with prior studies reporting a reduction in estrogen levels with increased activity. Furthermore, our results suggest that increased physical activity may lower endogenous estrogens by increasing hydroxylation, and subsequent metabolism, of estrogens. Citation Format: Cher M. Dallal, Louise A. Brinton, Charles E. Matthews, Ruth Pfeiffer, Terryl Hartman, Jolanta Lissowska, Roni Falk, Montserrat Garcia-Closas, Xia Xu, Timothy D. Veenstra, Gretchen L. Gierach. Is accelerometer-measured physical activity associated with urinary estrogens and estrogen metabolites among postmenopausal women?. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2519. doi:10.1158/1538-7445.AM2013-2519

Background: While elevated circulating estrogens are consistently associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. Estrogen metabolism occurs via hydroxylation at the C-2,-4, or -16 positions, resulting in metabolites with potentially different genotoxic and mitogenic effects. To date, only two prior studies have examined comprehensive estrogen metabolism profiles in relation to postmenopausal breast cancer risk. Methods: We conducted a case-cohort study within B∼FIT (n=15,595), the Breast and Bone Follow-up to the Fracture Intervention Trial, to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites in relation to postmenopausal breast cancer risk. Participants included 387 breast cancer cases diagnosed during the 10-year follow-up and a subcohort of 492 women randomly selected from the cohort within 10-year age and geographical strata. At the screening visit (1992-1993), female volunteers ages 55-80 completed a baseline questionnaire and provided a blood sample. For cases, the average (SD) time between blood draw and diagnosis was 6 years (3.0). Serum concentrations of estrogens and estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression with robust variance adjustment. Exposures were categorized in quintiles (Q) based on the subcohort distribution; multivariable models were adjusted for study design variables (age, geographical site, and trial participation status). Known breast cancer risk factors were not included in the final models as additional adjustment did not alter the results. Estrogens were analyzed individually, as metabolic pathways (C-2, -4, or -16), and as ratios relative to the parent estrogens (estradiol and estrone). Results: Elevated circulating estradiol was significantly associated with increased breast cancer risk (HRQ5vsQ1=1.70; 95% CI: 1.08-2.69), although no dose-response was observed (p-trend=0.12). No significant associations were observed in the analysis of individual metabolites or the 2- and 4-hydroxylation pathways. However, women in the highest quintile of the 16-hydroxylation pathway were significantly more likely to develop breast cancer as compared to those in the lowest (HRQ5vsQ1=1.59; 95% CI: 1.02-2.48; p-trend=0.09). When analyzing each hydroxylation pathway relative to the parent estrogens, the ratio of the 2-hydroxylation pathway (HRQ5vsQ1=0.76; 95% CI: 0.50-1.17; p-trend=0.06), 4-hydroxylation pathway (HRQ5vsQ1=0.69; 95% CI: 0.45-1.06; p-trend=0.03) and 16-hydroxylation pathway (HRQ5vsQ1=0.72; 95% CI: 0.47-1.10; P-trend=0.29) to parent estrogens was suggestive of inverse associations. Additionally, a higher ratio of the 2- to 16-hydroxylation pathways was significantly associated with reduced risk (HRQ5vsQ1=0.66; 95% CI: 0.43-0.99; p-trend=0.009). Conclusions: Our results suggest that women with increased 2- or 4-hydroxylation, relative to their circulating parent estrogens, may be at lower risk of postmenopausal breast cancer. Analyses of metabolic pathways, in addition to individual metabolites, may help elucidate the role of estrogen metabolism in breast carcinogenesis. Citation Format: Cher M. Dallal, Jeffrey A. Tice, Diana S.M. Buist, Douglas C. Bauer, James V. Lacey, Jane A. Cauley, Trisha F. Hue, Andrea LaCroix, Roni Falk, Ruth Pfeiffer, Barbara J. Fuhrman, Timothy D. Veenstra, Xia Xu, Louise A. Brinton. Estrogen metabolism and postmenopausal breast cancer risk in the B∼FIT cohort. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B86.

Background: Data comparing risk factors for in situ and invasive breast cancer, particularly with additional differentiation by ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), are limited. Some previous studies have found similar risk relations for DCIS and invasive carcinoma, consistent with molecular and clinical data showing that DCIS lesions are non-obligate precursors of invasive breast cancer. However, some risk factors may act as promoters at later stages of carcinogenesis and may show differential associations with invasive as compared with in situ disease. We therefore evaluated the relationship between established breast cancer risk factors and the risk of DCIS, LCIS, and ductal and lobular invasive breast carcinomas. Methods: Among 192,315 postmenopausal women ages 50–71 years, enrolled in the NIH-AARP Diet and Health Cohort study, who did not have a prior history of any cancer, we identified 1,228 in situ (1,085 DCIS, 143 LCIS) and 6,185 invasive (5,345 ductal, 840 lobular) incident breast carcinomas from enrollment (1995–96) through last follow-up (2006). Participants provided information on established breast cancer risk factors via mailed questionnaires including: ages at menarche and first birth, breast cancer family history, alcohol use, and body mass index (BMI) or kg/m2. Relative risks (RR) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards regression. Results: Risk associations for age at menarche, age at first live birth, and family history of breast cancer were similar for DCIS, LCIS, and their invasive counterparts. Later age at menarche and earlier age at first live birth were associated with significant risk reductions while family history of breast cancer increased risk. Alcohol intake (>35 grams/day vs. none) was significantly associated with an increased risk of invasive breast cancer (RRductal=1.31, 95% CI: 1.13, 1.51; RRlobular=1.50, 95% CI: 1.04, 2.15) and suggestive of an increased risk of LCIS (RRLCIS=1.32, 95% CI: 0.51, 3.43); in contrast, no association was observed with DCIS (RRDCIS=1.04, 95% CI: 0.73, 1.50). BMI of 35 kg/m2 or greater was related to increased risk of invasive ductal carcinoma (RR=1.45, 95% CI: 1.31, 1.60) but not for in situ or invasive lobular cancers. These differences, however, did not translate into any statistically significant differences in risk factor associations for DCIS vs. LCIS, DCIS vs. ductal invasive, or LCIS vs. lobular invasive (p-heterogeneity >.10 for all comparisons). Conclusions: In this analysis, most established breast cancer risk factors showed similar associations for in situ and invasive ductal and lobular cancers among postmenopausal women, apart from marked obesity, which only increased risk for invasive ductal carcinoma. These data support the view that many of the risk factors considered in predicting risk of invasive breast cancer are also applicable to estimating risk of in situ breast cancer. Furthermore, obesity was differentially associated with increased risk of ductal invasive breast cancer, suggesting that this exposure may act as a promoter later in carcinogenesis. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A71.

Estrogens play important roles in the pathophysiology of breast tumors and are recognized causal factors in the etiology of breast cancer. Parent estrogens (estrone and estradiol) can be hydroxylated at the 2, 4, or 16 position of the steroid ring, resulting in metabolites with different biological activity and availability. Estrogen metabolism shows great inter-individual variation, is modifiable, and may contribute to differences among women at risk of breast cancer. We conducted a cross-sectional study to investigate whether urinary estrogens and estrogen metabolites (jointly referred to as EM) are associated with mammographic density (MD), the strongest predictor of sporadic breast cancer risk among women apart from age. Methods: Postmenopausal women without breast cancer, aged 48–82 y, and reporting no current use of exogenous hormones were recruited and interviewed at a mammography clinic in Western NY in 2005. Concentrations of 15 EM were measured in first morning urine samples from 195 participants using liquid chromatography-tandem mass spectrometry. MD (%) was measured using computer-assisted analyses of digitized films. Linear models were used to assess associations of log-transformed EM concentrations and ratios with MD while adjusting for age, body mass index (BMI, kg/m2), and history of combination menopausal hormone therapy. We assessed effect modification by these factors and by years since menopause. Results: The median age of participants was 58, and median time since menopause was 8 years; 35% of participants were obese (BMI ≥30), and 33% had previously used combination menopausal hormones. Among all participants, urinary concentrations of parent estrogens were not associated with MD while some individual 2-pathway and 4-pathway EM had significant inverse associations with MD. Associations between EM profiles and MD were modified by years since menopause (≤8 or >8 y) and by obesity. Among women with a recent menopause, MD was positively associated with parent estrogens (p=0.02), and inversely associated with 2- and 4-hydroxylation pathway EM (p=0.03 and 0.02); these associations were not observed in women with a more distant menopause (pinteraction=0.02, 0.18, 0.16, respectively). Similarly, parent estrogens were directly associated with MD (p=0.003) among women who were obese but not among thinner counterparts (pinteraction=0.08). Conclusion: This is the first study to examine the relations between 15 EM and MD in postmenopausal women. EM profiles were most strongly associated with MD in subgroups with higher estrogen levels including obese women and those with a more recent menopause. In these groups, more extensive 2- and 4-hydroxylation of parent estrogens was associated with reduced MD. This pattern of metabolism may influence MD by facilitating clearance of estrogens from breast tissues. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A8.

Background Long-term physical activity may affect breast cancer risk. Few prospective studies have evaluated in situ or invasive breast cancer risk, or breast cancer receptor subtypes, in relation to long-term activity. Methods We examined the association between recreational physical activity and risk of invasive and in situ breast cancer in the California Teachers Study, a cohort of women established in 1995-1996. Of 110 599 women aged 20 to 79 years with no history of breast cancer followed up through December 31, 2002, 2649 were diagnosed as having incident invasive breast cancer and 593 were diagnosed as having in situ breast cancer. Information was collected at cohort entry on participation in strenuous and moderate recreational activities during successive periods from high school through the current age or age 54 years (if older at enrollment) and in the past 3 years. A summary measure of long-term activity up to the current age, or age 54 years if older, was constructed for each woman. Results Invasive breast cancer risk was inversely associated with long-term strenuous activity (>5 vs ≤0.5 h/wk per year: relative risk, 0.80; 95% confidence interval, 0.69-0.94; P trend = .02), as was in situ breast cancer risk (>5 vs ≤0.5 h/wk per year: relative risk, 0.69; 95% confidence interval, 0.48-0.98; P trend = .04). Strenuous and moderate long-term activities were associated with reduced risk of ER-negative (strenuous: P trend = .003; moderate: P trend = .003) but not ER-positive (strenuous: P trend = .23; moderate: P trend = .53) invasive breast cancer. Conclusion These results support a protective role of strenuous long-term exercise activity against invasive and in situ breast cancer and suggest differing effects by hormone receptor status.

Background The leptin receptor gene (LEPR) polymorphism Q223R is one of the most common in the general population, and is thought to be associated with an impaired signaling capacity of the leptin receptor and with higher mean circulating levels of leptin. Leptin is a hormone primarily produced in adipose tissue. Increased levels of leptin have been positively correlated with obesity. We have determined the frequency of the leptin receptor polymorphism (LEPR Q223R) in healthy populations from various ethnic groups, and compared plasma leptin levels across the LEPR Q223R polymorphism in healthy African-Caribbean and Caucasian women. Results The study population consists of 1,418 healthy subjects from various ethnic groups. The LEPR Q223R homozygous variant was observed overall in 19% of subjects (n = 1,418), with significant differences based on self reported ethnicity: the proportion of subjects with the homozygous variant was lower in Caucasians (14%, n = 883) than in African-Caribbean (n = 194), African-American (n = 36) and Asian/other ethnic groups (n = 26), (35%, 33% and 34.6% respectively); the frequency in Africans (20%), was similar to the overall study population. The mean ± standard deviation (SD), circulating leptin levels for African-Caribbean women was 44.7 ± 31.4 ng/ml, while for Caucasian women the mean was 42.4 ± 34.8 ng/ml. Adjusted circulating leptin levels in post-menopausal Caucasian women who were LEPR Q223R homozygous variant were marginally statistically significantly higher than in women with the wild-type genotype (p = 0.098). No significant differences in leptin levels by genotype were observed for African-Caribbean women, (heterozygous: p = 0.765, homozygous variant: p = 0.485). Conclusion These findings suggest an association between mean circulating leptin levels and the LEPR Q223R genotype among post-menopausal Caucasian women.