Search

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.

Environmental phenols and phthalates are common ingredients in personal care products and some have been implicated in breast cancer progression. We have previously identified genes differentially expressed in response to low-dose exposure to diethyl phthalate (DEP) and methyl paraben (MPB) in a rat model. Herein we explore if these genes are associated with breast cancer mortality in humans. We profiled MPB- and DEP-responsive genes in tumors by NanoString® from a population-based cohort of 606 women with first primary breast cancer among whom 119 breast cancer-specific deaths occurred within 15+ years of follow-up. For each gene, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results were validated in two publicly available datasets. The following results were obtained. From 107 DEP- and 77 MPB-responsive genes profiled, 44 and 30 genes, respectively, were significantly associated with breast cancer-specific mortality. Some top DEP-responsive genes are novel for breast cancer mortality, such as ABHD14B (for high-vs-low expression, HR 0.36, 95% CI: 0.2–0.5) and TMC4 (HR 0.37, 95% CI: 0.3–0.5); top hits for MPB (SLC40A1 (HR 0.37, 95% CI: 0.3–0.5) and NTN4 (HR 0.39, 95% CI: 0.3–0.6)) are well-known predictors of breast cancer survival. PLEKHA6 was another novel survival predictor, sensitive to hormonal receptor status (HR 0.5, 95% CI 0.3–0.9 for hormonal receptor-positive and HR 3.2, 95% CI 1.7–6.2 for -negative group). In conclusion, tumor expression of DEP- and MPB-responsive genes is associated with breast cancer mortality, supporting that exposure to these chemicals may influence the progression of breast cancer.

Background:Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear.Methods:Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study‐specific odds ratios (ORs) and 95% CIs for self‐reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random‐effects meta‐analysis.Results:Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00‐1.80; I2 = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05‐1.55; I2 = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06‐1.58; I2 = 34.9%). Regurgitation symptoms modified the diabetes‐EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19‐2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74‐1.43). No consistent association was found between diabetes and BE.Conclusions:Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

Background Reproductive characteristics are well-established risk factors for breast cancer, but the underlying mechanisms are not fully resolved. We hypothesized that altered DNA methylation, measured in tumor tissue, could act in concert with reproductive factors to impact breast carcinogenesis. Methods Among a population-based sample of women newly diagnosed with first primary breast cancer, reproductive history was assessed using a life-course calendar approach in an interviewer-administered questionnaire. Methylation-specific polymerase chain reaction and Methyl Light assays were used to assess gene promotor methylation status (methylated vs. unmethylated) for 13 breast cancer-related genes in archived breast tumor tissue. We used case-case unconditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations with age at menarche and parity (among 855 women), and age at first birth and lactation (among a subset of 736 parous women) in association with methylation status. Results Age at first birth > 27 years, compared with CDH1 (OR = 0.44, 95% CI = 0.20–0.99) and TWIST1 (OR = 0.48, 95% CI = 0.28–0.82), and higher odds of methylation of BRCA1 (OR = 1.63, 95% CI = 1.14–2.35). Any vs. no lactation was associated with higher odds of methylation of the PGR gene promoter (OR = 1.59, 95% CI = 1.01–2.49). No associations were noted for parity and methylation in any of the genes assayed. Conclusions Our findings indicate that age at first birth, lactation and, perhaps age at menarche, are associated with gene promoter methylation in breast cancer, and should be confirmed in larger studies with robust gene coverage.

Background The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. Methods Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions. Results All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null. Conclusions The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.

Fish intake and other dietary sources of omega-3 fatty acids have been shown to be associated with a reduced risk for some cancers. Although previous studies of head and neck cancer have reported associations with different dietary factors, including reduced risks for fruits and vegetables and putatively healthy dietary patterns, associations specific to fish intake are unclear. This study investigated the association between fish/shellfish intake and risk of squamous cell carcinoma of the head and neck (SCCHN) using data from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study conducted in 46 North Carolina counties with cases recruited from 2002 through 2006. Controls were frequency matched to the cases on age, sex, and race; the final sample size was 1039 cases and 1375 controls. Demographic, lifestyle, and dietary information were collected using an in-person interviewer-administered structured questionnaire. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with unconditional logistic regression. Patients whose fish/shellfish intake was among the highest tertile had a 20% lower odds of SCCHN compared with those in the lowest tertile (OR: 0.80; 95% CI: 0.60-1.07) after adjustment for the matching and other factors (income, energy intake, fruit intake, cigarette smoking, and alcohol intake). The inverse association was more pronounced for oral cavity and oropharyngeal tumors, for African Americans, and for females, but CIs were wide. To further investigate this potential risk reduction strategy for SCCHN, future studies should consider examining specific fish/shellfish, cooking practices, and other omega-3 fatty acid sources.

Exposure to total hydrocarbons (THC) and volatile organic compounds from air pollution is associated with risk of coronary heart disease. THC exposure from oil spills might be similarly associated, but no research has examined this. We assessed the relationship between THC exposure during the response and cleanup of the Deepwater Horizon oil spill (Gulf of Mexico) and heart attack risk among 24,375 oil spill workers enrolled in the Gulf Long-Term Follow-up Study. There were 312 first heart attacks (self-reported physician-diagnosed myocardial infarction, or fatal coronary heart disease) ascertained during the study period (2010–2016). THC exposures were estimated using a job-exposure matrix incorporating self-reported activities and personal air measurements. We used Cox proportional hazards regression to estimate hazard ratios, with inverse-probability weights to account for confounding and censoring. Maximum THC levels of ≥0.30 parts per million (ppm) were associated with heart attack risk, with a 1.8-fold risk for exposure of ≥3.00 ppm versus

BACKGROUND AND AIMS: Tissue miRNA can discriminate between esophageal adenocarcinoma (EA) and normal epithelium. However, no studies have examined a comprehensive panel of circulating miRNAs in relation to EA diagnosis and survival. METHODS: We used all 62 EA cases from the U.S. Multi-Center case-control study with available serum matched 1:1 to controls. Cases were followed for vital status. miRNAs (n=2,064) were assessed using the HTG EdgeSeq miRNA Whole Transcriptome Assay. Differential expression analysis of miRNAs in relation to case-control status was conducted. In cases, Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. P-values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Predictive performance was assessed using cross validation. RESULTS: 68 distinct miRNAs were significantly upregulated between cases and controls (e.g., miR-1255b-2–3p fold change=1.74, BH-adjusted P=0.01). Assessing the predictive performance of these significantly upregulated miRNAs yielded 60% sensitivity, 65% specificity, and 0.62 AUC. miR-4253 and miR-1238–5p were associated with risk of mortality after EA diagnosis (HR=4.85,95%CI:2.30–10.23, BH-adjusted P=0.04 and HR=3.81,95%CI:2.02–7.19, BH-adjusted P=0.04, respectively). CONCLUSIONS: While they require replication, these findings suggest that circulating miRNAs may be associated with EA diagnosis and survival.

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

Background Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE1) and 16-hydroxyestrone (16-OHE1) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer. Methods This population-based study was initiated in 1996–1997 with spot urine samples obtained shortly after diagnosis (mean = 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE1 and 16-OHE1 using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n = 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided. Results Urinary concentrations of the 2-OHE1 to 16-OHE1 ratio (>median of 1.8 vs ≤median) were inversely associated with all-cause mortality (HR = 0.74, 95% CI = 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR = 0.73, 95% CI = 0.45 to 1.17) and cardiovascular diseases mortality (HR = 0.76, 95% CI = 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n = 118, HR = 0.42, 95% CI = 0.22 to 0.81) than among those who had not (n = 559, HR = 0.98, 95% CI = 0.72 to 1.34; Pinteraction = .008). Conclusions The urinary 2-OHE1 to 16-OHE1 ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection.

Contains fulltext : 229320.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P(BONF) = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P(BONF) = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Phthalates are commonly included as ingredients in personal care products such as cosmetics, shampoos and perfumes. Diethyl phthalate (DEP) has been found to be anti-androgenic and linked with adverse reproductive effects on males, but effects on females are poorly understood. We designed an integrative and translational study to experimentally examine the effects of DEP exposure at a human-equivalent dose on the mammary transcriptome in rats and to subsequently examine the DEP gene signature in breast tissues (both pre-malignant and tumor) from a population study. In Sprague-Dawley rats treated orally with DEP from birth to adulthood, we identified a signature panel of 107 genes predominantly down-regulated by DEP exposure. Univariate analysis of this 107 DEP gene signature in pre-malignant breast tissues revealed that six genes (P4HA1, MPZL3, TMC4, PLEKHA6, CA8, AREG) were inversely associated with monoethyl phthalate (MEP; the urinary metabolite of DEP) concentration (p

Purpose: Breast cancer is among the leading causes of cancer-related death; discovery of novel prognostic markers is needed to improve outcomes. Combining systems biology and epidemiology, we investigated miRNA-associated genes and breast cancer survival in a well-characterized population-based study. Experimental Design: A recently developed algorithm, ActMiR, was used to identify key miRNA “activities” corresponding to target gene degradation, which were predictive of breast cancer mortality in published databases. We profiled miRNA-associated genes in tumors from our well-characterized population-based cohort of 606 women with first primary breast cancer. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI), after 15+ years of follow-up with 119 breast cancer–specific deaths. Results: miR-500a activity was identified as a key miRNA for estrogen receptor–positive breast cancer mortality using public databases. From a panel of 161 miR-500a–associated genes profiled, 73 were significantly associated with breast cancer–specific mortality (FDR < 0.05) in our population, among which two clusters were observed to have opposing directions of association. For example, high level of SUSD3 was associated with reduced breast cancer–specific mortality (HR = 0.3; 95% CI, 0.2–0.4), whereas the opposite was observed for TPX2 (HR = 2.7; 95% CI, 1.8–3.9). Most importantly, we identified set of genes for which associations with breast cancer–specific mortality were independent of known prognostic factors, including hormone receptor status and PAM50–derived risk-of-recurrence scores. These results are validated in independent datasets. Conclusions: We identified novel markers that may improve prognostic efficiency while shedding light on molecular mechanisms of breast cancer progression. Clin Cancer Res; 24(3); 581–91. ©2017 AACR.

Modifiable lifestyle factors have been consistently associated with breast cancer, and risk may vary by menopausal status. However, whether these associations vary according to age among postmenopausal women remains unresolved.Using postmenopausal women from a population-based case-control study (990 cases and 1006 frequency-matched controls), we conducted multivariable-adjusted unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for lifestyle factors (lifetime alcohol intake, body mass index [BMI] in the year before diagnosis, lifetime recreational physical activity [RPA], and nonsteroidal anti-inflammatory drug use) in association with breast cancer stratified by age (65 vs. 65+). We examined estrogen-related subgroups by (1) further stratifying by hormone replacement therapy (HRT) use and (2) restricting cases to estrogen receptor (ER)+/progesterone receptor (PR)+ cancers.Postmenopausal breast cancer incidence in women 65 years and older was positively associated with alcohol intake (OR = 1.79 for 15-30 g/day vs. nondrinkers, 95% CI: 1.03-3.12) and BMI (OR = 1.83 for BMI ≥30 vs.25, 95% CI: 1.29-2.60), and inversely with RPA (OR = 0.69 for fourth quartile vs. inactive, 95% CI: 0.47-1.03). For postmenopausal women younger than 65, ORs were closer to the null. Tests for heterogeneity by age were significant at the p 0.10 level for BMI and RPA, but not alcohol. Among older women, associations were stronger among never users of HRT and for those with ER+/PR+ cancers. The inverse associations with aspirin use did not differ by age.Interventions targeting modifiable lifestyle factors may reduce the burden of postmenopausal breast cancer among older women.

Background During the past 40 years, esophageal/gastric cardia adenocarcinoma (EA/GCA) incidence increased in Westernized countries, but survival remained low. A parallel increase in sugar intake, which may facilitate carcinogenesis by promoting hyperglycaemia, led us to examine sugar/carbohydrate intake in association with EA/GCA incidence and survival. Methods We pooled 500 EA cases, 529 GCA cases and 2027 controls from two US population-based case-control studies with cases followed for vital status. Dietary intake, assessed by study-specific food frequency questionnaires, was harmonized and pooled to estimate 12 measures of sugar/carbohydrate intake. Multivariable-adjusted odds ratios (ORs) and hazard ratios [95% confidence intervals (CIs)] were calculated using multinomial logistic regression and Cox proportional hazards regression, respectively. Results EA incidence was increased by 51-58% in association with sucrose (ORQ5vs.Q1 = 1.51, 95% CI = 1.01-2.27), sweetened desserts/beverages (ORQ5vs.Q1 = 1.55, 95% CI = 1.06-2.27) and the dietary glycaemic index (ORQ5vs.Q1 = 1.58, 95% CI = 1.13-2.21). Body mass index (BMI) and gastro-esophageal reflux disease (GERD) modified these associations (Pmultiplicative-interaction ≤ 0.05). For associations with sucrose and sweetened desserts/beverages, respectively, the OR was elevated for BMI < 25 (ORQ4-5vs.Q1-3 = 1.79, 95% CI = 1.26-2.56 and ORQ4-5vs.Q1-3 = 1.45, 95% CI = 1.03-2.06), but not BMI ≥ 25 (ORQ4-5vs.Q1-3 = 1.05, 95% CI = 0.76-1.44 and ORQ4-5vs.Q1-3 = 0.85, 95% CI = 0.62-1.16). The EA-glycaemic index association was elevated for BMI ≥ 25 (ORQ4-5vs.Q1-3 = 1.38, 95% CI = 1.03-1.85), but not BMI < 25 (ORQ4-5vs.Q1-3 = 0.88, 95% CI = 0.62-1.24). The sucrose-EA association OR for GERD < weekly was 1.58 (95% CI = 1.16-2.14), but for GERD ≥ weekly was 1.01 (95% CI = 0.70-1.47). Sugar/carbohydrate measures were not associated with GCA incidence or EA/GCA survival. Conclusions If confirmed, limiting intake of sucrose (e.g. table sugar), sweetened desserts/beverages, and foods that contribute to a high glycaemic index, may be plausible EA risk reduction strategies.

Barrett’s esophagus (BE) is the key precursor lesion of esophageal adenocarcinoma, a lethal cancer that has increased rapidly in westernized countries over the past four decades. Dietary sugar intake has also been increasing over time, and may be associated with these tumors by promoting hyperinsulinemia. The study goal was to examine multiple measures of sugar/starches intake in association with BE. This pooled analysis included 472 BE cases and 492 controls from two similarly conducted case–control studies in the United States. Dietary intake data, collected by study-specific food frequency questionnaires, were harmonized across studies by linking with the University of Minnesota Nutrient Database, and pooled based on study-specific quartiles. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, total energy intake, study indicator, body mass index, frequency of gastro-esophageal reflux, and fruit/vegetable intake. In both studies, intake of sucrose (cases vs. controls, g/day: 36.07 vs. 33.51; 36.80 vs. 35.06, respectively) and added sugar (46.15 vs. 41.01; 44.18 vs. 40.68, respectively) were higher in cases than controls. BE risk was increased 79% and 71%, respectively, for associations comparing the fourth to the first quartile of intake of sucrose (ORQ4vs.Q1 = 1.79, 95% CI = 1.07–3.02, P trend = 0.01) and added sugar (ORQ4vs.Q1 = 1.71, 95% CI = 1.05–2.80, P trend = 0.15). Intake of sweetened desserts/beverages was associated with 71% increase in BE risk (ORQ4vs.Q1 = 1.71, 95% CI = 1.07–2.73, P trend = 0.04). Limiting dietary intake of foods and beverages that are high in added sugar, especially refined table sugar, may reduce the risk of developing BE.

Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor. We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods. No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association. Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

Background & Aims Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.

We investigated whether the relationship between diabetes and all-cause and CVD-related mortality differed between women with and without breast cancer among a cohort drawn from the same source population. We interviewed 1,363 women newly diagnosed with breast cancer in 1996–1997, and 1,358 age-matched women without breast cancer, to assess history of physician-diagnosed diabetes. All-cause (n = 631) and CVD-specific mortality (n = 234) was determined by the National Death Index through 2009. We estimated multivariable-adjusted hazard ratios (HRs) for the rates of all-cause and CVD-specific mortality and, to account for competing causes of death, and subdistribution HRs (sHRs) for risk of CVD-related death. Among women with and without breast cancer, respectively, diabetes was associated with: all-cause mortality [HR (95% CI) 1.52 (1.13, 2.05) and 2.17 (1.46, 3.22)]; CVD-specific deaths [1.74 (1.06, 2.84) and 2.06 (1.11, 3.84)]; and risk of CVD-related death [sHR 1.36 (0.81, 2.27) and 1.79 (0.94, 3.40)]. Differences in effect estimates between women with and without breast cancer did not reach statistical significance (p-interaction > 0.10). We found that the positive association between a history of physician-diagnosed diabetes and risk of all-cause and CVD-related mortality is of similar magnitude among a population-based cohort of women with or without breast cancer.

BACKGROUND: Epidemiologic studies have reported associations between prenatal and early postnatal air pollution exposure and autism spectrum disorder (ASD); however, findings differ by pollutant and developmental window. OBJECTIVES: We examined associations between early life exposure to PM(2.5) and ozone in association with ASD across multiple US regions. METHODS: Our study participants included 674 children with confirmed ASD and 855 population controls from the Study to Explore Early Development, a multi-site case–control study of children born from 2003 to 2006 in the United States. We used a satellite-based model to assign air pollutant exposure averages during several critical periods of neurodevelopment: 3 months before pregnancy; each trimester of pregnancy; the entire pregnancy; and the first year of life. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs), adjusting for study site, maternal age, maternal education, maternal race/ethnicity, maternal smoking, and month and year of birth. RESULTS: The air pollution–ASD associations appeared to vary by exposure time period. Ozone exposure during the third trimester was associated with ASD, with an OR of 1.2 (95% CI: 1.1, 1.4) per 6.6 ppb increase in ozone. We additionally observed a positive association with PM(2.5) exposure during the first year of life [OR = 1.3 (95% CI: 1.0, 1.6) per 1.6 μg/m(3) increase in PM(2.5)]. CONCLUSIONS: Our study corroborates previous findings of a positive association between early life air pollution exposure and ASD, and identifies a potential critical window of exposure during the late prenatal and early postnatal periods.

Introduction: Potentially carcinogenic hazardous air pollutants (air toxics) have been inconsistently associated with breast cancer. Whether metabolic factors modify these associations is unknown. We studied 29 non-metallic air toxics classified as mammary gland carcinogens in animal studies in relation to breast cancer risk. Methods: Participants included 49,718 women from the Sister Study. Census tract air toxic concentration estimates from the 2005 National Air Toxics Assessment were linked to enrollment residential addresses. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for individual air toxics were estimated using Cox regression. Body mass index (BMI) was considered a potential modifier. Relevant mixtures were identified using classification trees. Results: Over follow-up (average = 8.4 years), 2975 women were newly diagnosed with breast cancer (invasive or ductal carcinoma in situ). Several air toxics, including methylene chloride, polycyclic organic matter, propylene dichloride, and styrene, were associated with increased risk. Of these, methylene chloride was most consistently associated with risk across multiple analyses. It was associated with overall (HRquintile 4vs1 = 1.21 (95%CI = 1.07–1.38)) and estrogen receptor positive (ER+) invasive breast cancer (HRquintile 4vs1 = 1.28 (95%CI = 1.08–1.52)) in individual pollutant models, although no dose-response was observed. Associations were stronger among overweight/obese (vs. non-overweight/obese) women (p

DNA methylation has been implicated in breast cancer aetiology, but little is known about whether reproductive history and DNA methylation interact to influence carcinogenesis. This study examined modification of the association between global DNA methylation and breast cancer risk by reproductive characteristics. A population-based case-control study assessed reproductive history in an interviewer-administered questionnaire. Global DNA methylation was measured from white blood cell DNA using luminometric methylation assay (LUMA) and pyrosequencing assay (long interspersed elements-1 (LINE-1). We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among 1 070 breast cancer cases and 1 110 population-based controls. Effect modification was assessed on additive and multiplicative scales. LUMA methylation was associated with elevated breast cancer risk across all strata (comparing the highest to the lowest quartile), but estimates were higher among women with age at menarche ≤12 years (OR = 2.87, 95%CI = 1.96–4.21) compared to >12 years (OR = 1.66, 95%CI = 1.20–2.29). We observed a 2-fold increase in the LUMA methylation-breast cancer association among women with age at first birth >23 years (OR = 2.62, 95%CI = 1.90–3.62) versus ≤23 years (OR = 1.32, 95% CI = 0.84–2.05). No modification was evident for parity or lactation. Age at menarche and age at first birth may be modifiers of the association between global DNA methylation and breast cancer risk.

Introduction Previous investigations found elevated mortality after breast cancer in association with biomarkers of persistent organochlorine pesticides in non-occupationally exposed women. We hypothesized that lifetime residential pesticide use, which includes persistent and non-persistent pesticides, would also be associated with increased mortality after breast cancer. Methods A population-based cohort of 1505 women with invasive or in situ breast cancer was interviewed in 1996–1997, shortly after diagnosis, about pre-diagnostic lifetime residential pesticide use. Participants were followed for mortality through 2014 (595 deaths from any cause and 236 from breast cancer, after 17.6 years of follow-up). Pesticides were examined as 15 individual categories; a group of seven used for lawn and garden purposes; a group of eight used for nuisance-pest purposes; and all combined. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and breast cancer-specific mortality. Modification by estrogen receptor (ER) status, body mass index, and long-term residence was examined. Results Ever use (HR = 0.77, 95%CI = 0.63–0.95) and higher lifetime applications (4th quartile: HR = 0.62, 95%CI = 0.47–0.81, ptrend = 0.3) of the lawn and garden group of pesticides were inversely associated with all-cause mortality, compared to never use. The inverse association for lawn and garden pesticide use was limited to ER positive (vs. negative) tumors (pinteraction = 0.05). Nuisance-pest pesticides, and all groups combined, were not associated with all-cause or breast cancer-specific mortality. Conclusions Contrary to our hypothesis, lifetime residential use of lawn and garden pesticides, but not all combined or nuisance-pest pesticides, was inversely associated with all-cause mortality after breast cancer.

To examine 143 diabetes risk single nucleotide polymorphisms (SNPs), identified from genome-wide association studies, in association with breast cancer (BC) incidence and subsequent mortality. A population-based sample of Caucasian women with first primary invasive BC (n = 817) and controls (n = 1021) were interviewed to assess diabetes status. Using the National Death Index, women with BC were followed for >18 years during which 340 deaths occurred (139 BC deaths). Genotyping was done using DNA extracted from blood samples. We used unconditional logistic regression to estimate age-adjusted odds ratios and 95% confidence intervals (CIs) for BC incidence, and Cox regression to estimate age-adjusted hazard ratios and CIs for all-cause and BC-specific mortality. Twelve SNPs were associated with BC risk in additive genotype models, at α = 0.05. The top three significant SNPs included SLC30A8-rs4876369 (P = 0.0034), HHEX-rs11187146 (P = 0.0086), and CDKN2A/CDKN2B-rs1333049 (P = 0.0094). Diabetes status modified the associations between rs4876369 and rs2241745 and BC incidence, on the multiplicative interaction scale. Six SNPs were associated with all-cause (CDKAL1-rs981042, P = 0.0032; HHEX-rs1111875, P = 0.0361; and INSR-rs919275, P = 0.0488) or BC-specific (CDKN2A/CDKN2B-rs3218020, P = 0.0225; CDKAL1-rs981042, P = 0.0246; and TCF2/HNF1B-rs3094508, P = 0.0344) mortality in additive genotype models, at α = 0.05. Genetic polymorphisms that increase the risk of developing diabetes may also increase the risk of developing and dying from BC.

Background: Ecologic analyses, case–case comparisons, and animal experiments suggest positive associations between air pollution and tuberculosis. Objectives: We evaluated this hypothesis in a large sample, which yielded results that are applicable to the general population. Methods: We conducted a case–control study nested within a cohort of Kaiser Permanente of Northern California members. All active pulmonary tuberculosis (TB) cases newly diagnosed between 1996 and 2010 (n = 2,309) were matched to two controls (n = 4,604) by age, sex, and race/ethnicity on the index date corresponding with the case diagnosis date. Average individual-level concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) and 10 μm (PM10) for 2 years before diagnosis/entry into the study were estimated using measurements from the California Air Resources Board monitor closest to the participant’s residence. Results: In single-pollutant adjusted conditional logistic regression models, the pulmonary TB odds ratios (95% confidence intervals) for the highest quintile (vs. lowest) were 1.50 (95% CI: 1.15, 1.95) for CO and 1.42 (95% CI: 1.10, 1.84) for NO2. Corresponding estimates were higher among never [1.68 (95% CI: 1.26, 2.24)] than ever [1.19 (95% CI: 0.74, 1.92)] smokers for CO. In contrast, for NO2, estimates were higher among ever [1.81 (95% CI: 1.13, 2.91)] than never [1.29 (95% CI: 0.97, 1.71)] smokers. O3 was inversely associated for smokers [0.66 (95% CI: 0.43, 1.02)] and never smokers [0.65 (95% CI: 0.52, 0.81)]. No other consistent patterns were observed. Conclusions: In this first, to our knowledge, U.S. nested case–control study on air pollution and pulmonary TB, we observed positive associations with ambient CO and NO2, which require confirmation. Citation: Smith GS, Van Den Eeden SK, Garcia C, Shan J, Baxter R, Herring AH, Richardson DB, Van Rie A, Emch M, Gammon MD. 2016. Air pollution and pulmonary tuberculosis: a nested case-control study among members of a Northern California health plan. Environ Health Perspect 124:761–768; http://dx.doi.org/10.1289/ehp.1408166

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.\ud Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.\ud Results: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92–0.95, p = 4.13E−13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02–1.06, p = 1.26E−05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95–0.99, p = 8.05E−04).\ud Conclusions: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

Purpose Experimental studies demonstrate that ω-3 polyunsaturated fatty acids (PUFAs) inhibit inflammatory eicosanoids generated by ω-6 PUFAs. Epidemiologic studies on dietary ω-3 PUFA intake show consistent inverse associations with breast cancer incidence among Asian populations, where ω-3, relative to ω-6, intake is high. In contrast, associations are inconsistent among Western populations, where intake of ω-3, relative to ω-6, is low. We hypothesized that examining interactions between ω-3 and ω-6 would help elucidate the PUFA-breast cancer association in the United States. Methods In a Long Island, New York, population-based study of 1463 breast cancer cases and 1500 controls, we estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression to examine interactions between ω-3 and ω-6 intake. Results We observed a super-additive interaction (relative excess risk due to interaction = 0.41; 95% confidence interval = 0.06–0.76) between ω-3 and ω-6 intake in association with breast cancer incidence, although the CIs for the joint exposure of low ω-3/high ω-6 compared to high ω-3/low ω-6 intake were wide (odds ratio = 1.20; 95% confidence interval = 0.85–1.69). Conclusions Breast cancer risk reduction may be possible for U.S. women with dietary consumption of higher ω-3, which has anti-inflammatory properties, in concert with lower ω-6, which induces inflammation. Replication from future U.S.-based investigations is needed.

Contains fulltext : 215282.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

Background: To examine whether neighborhood deprivation modifies the association between early life air pollution exposure and autism spectrum disorder (ASD), we used resources from a multisite case–control study, the Study to Explore Early Development. Methods: Cases were 674 children with confirmed ASD born in 2003–2006; controls were 855 randomly sampled children born during the same time period and residents of the same geographic areas as cases. Air pollution was assessed by roadway proximity and particulate matter

Background Chemical, physical and psychological stressors due to the 2010 Deepwater Horizon oil spill may impact coronary heart disease (CHD) among exposed populations. Using longitudinal information from two interviews in the Gulf Long Term Follow-up (GuLF) STUDY, we assessed CHD among oil spill workers and community members. Objective To assess the associations between duration of oil spill clean-up work, residential proximity to the oil spill, and incidence of self-reported myocardial infarction or fatal CHD. Methods Among respondents with two GuLF STUDY interviews (n = 21,256), there were 395 first incident heart disease events (self-reported myocardial infarction or fatal CHD) across 5 years. We estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for associations with duration of oil spill clean-up work and residential proximity to the oil spill. To assess potential impacts of non-response, we compared covariate distributions for those who did (n = 21,256) and did not (n = 10,353) complete the second interview and used inverse probability (IP) of censoring weights to correct for potential non-response bias. Results Living in proximity to the oil spill (vs. living further away) was associated with heart disease, with [HR(95%CI) = 1.30(1.01–1.67)] and without [1.29(1.00–1.65)] censoring weights. For work duration, hazard of heart disease appeared to be higher for those who worked > 180 days (vs. 1–30 days), with and without censoring weights [1.43(0.91–2.25) and 1.36(0.88–2.11), respectively]. Associations persisted throughout the 5-year follow-up. Conclusions Residential proximity to the spill and duration of clean-up work were associated with a suggested 29–43% higher hazard of heart disease events. Associations were robust to censoring.

Background: Phthalates, known endocrine disruptors, may play a role in breast carcinogenesis. Few studies have examined phthalates in relation to breast cancer (BC), and, to our knowledge, none have considered survival following BC. Objectives: We examined 11 urinary phthalate metabolites, individually and as molar sum groupings, in association with BC incidence and subsequent survival. Methods: Our study includes 710 women diagnosed with first primary BC in 1996–1997 and 598 women without BC from Long Island, New York. Within 3 mo of diagnosis, participants provided spot urine samples. Nine phthalate metabolites were measured in all women; two [monocarboxyoctyl phthalate (MCOP) and monocarboxy-isononyl phthalate (MCNP)] were measured in 320 women with and 205 without BC. Women with BC were followed since diagnosis using the National Death Index; during follow-up (median=17.6y), we identified 271 deaths (98 BC related). We examined creatinine-corrected metabolite concentrations in association with: BC, using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and all-cause/BC-specific mortality, using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We also examined effect modification by body mass index (BMI) and estrogen receptor (ER) status. Results: The highest (vs. lowest) quintiles of mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), MCNP, and MCOP were associated with BC ORs ranging from 0.71–0.73. The highest (vs. lowest) quintiles of mono(2-ethylhexyl) phthalate (MEHP) and MCOP were associated with BC-specific mortality HRs of 0.54 (95% CI: 0.28, 1.04) and 0.55 (95% CI: 0.23, 1.35), respectively. For BC-specific mortality, interactions were significant between BMI and mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), with positive associations among women with BMI

Background The purpose of this study was to examine whether at-diagnosis smoking and postdiagnosis changes in smoking within five years after breast cancer were associated with long-term all-cause and breast cancer-specific mortality. Methods A population-based cohort of 1508 women diagnosed with first primary in situ or invasive breast cancer in 1996 to 1997 were interviewed shortly after diagnosis and again approximately five years later to assess smoking history. Participants were followed for vital status through December 31, 2014. After 18+ years of follow-up, 597 deaths were identified, 237 of which were breast cancer related. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Compared with never smokers, risk of all-cause mortality was elevated among the 19% of at-diagnosis smokers (HR = 1.69, 95% CI = 1.36 to 2.11), those who smoked 20 or more cigarettes per day (HR = 1.85, 95% CI = 1.42 to 2.40), women who had smoked for 30 or more years (HR = 1.62, 95% CI = 1.28 to 2.05), and women who had smoked 30 or more pack-years (HR = 1.82, 95% CI = 1.39 to 2.37). Risk of all-cause mortality was further increased among the 8% of women who were at-/postdiagnosis smokers (HR = 2.30, 95% CI = 1.56 to 3.39) but was attenuated among the 11% women who quit smoking after diagnosis (HR = 1.83, 95% CI = 1.32 to 2.52). Compared with never smokers, breast cancer–specific mortality risk was elevated 60% (HR = 1.60, 95% CI = 0.79 to 3.23) among at-/postdiagnosis current smokers, but the confidence interval included the null value and elevated 175% (HR = 2.75, 95% CI = 1.26 to 5.99) when we considered postdiagnosis cumulative pack-years. Conclusions Smoking negatively impacts long-term survival after breast cancer. Postdiagnosis cessation of smoking may reduce the risk of all-cause mortality. Breast cancer survivors may benefit from aggressive smoking cessation programs starting as early as the time of diagnosis.

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Results: Three gene regions were associated with breast cancer incidence: FGFR2 (P = 1.23 × 10−5; replication P < 1.00 × 10−6), NEK10 (P = 3.57 × 10−4; replication P < 1.00 × 10−6), and SIVA1 (P = 5.49 × 10−4; replication P < 1.00 × 10−6). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association (P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614–0.659 compared with 0.601; 95% CI, 0.578–0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640–0.684). Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus. Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057–64. ©2018 AACR.

The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

Organochlorine insecticides have been studied extensively in relation to breast cancer incidence, and results from two meta-analyses have been null for late-life residues, possibly due to measurement error. Whether these compounds influence survival remains to be fully explored. We examined associations between organochlorine insecticides [p,p'-DDT (dichlorodiphenyltrichloroethane), its primary metabolite, p,p'-DDE, and chlordane] assessed shortly after diagnosis and survival among women with breast cancer. A population-based sample of women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997 and with available organochlorine blood measures (n = 633) were followed for vital status through 2011. After follow-up of 5 and 15 years, we identified 55 and 189 deaths, of which 36 and 74, respectively, were breast cancer-related. Using Cox regression models, we estimated the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for lipid-adjusted organochlorine concentrations with all-cause and breast cancer-specific mortality. At 5 years after diagnosis, the highest tertile of DDT concentration was associated with all-cause (HR = 2.19; 95% CI: 1.02, 4.67) and breast cancer-specific (HR = 2.72; 95% CI: 1.04, 7.13) mortality. At 15 years, middle tertile concentrations of DDT (HR = 1.42; 95% CI 0.99, 2.06) and chlordane (HR = 1.42; 95% CI: 0.94, 2.12) were modestly associated with all-cause and breast cancer-specific mortality. Third tertile DDE concentrations were inversely associated with 15-year all-cause mortality (HR = 0.66; 95% CI: 0.44, 0.99). This is the first population-based study in the United States to show that DDT may adversely impact survival following breast cancer diagnosis. Further studies are warranted given the high breast cancer burden and the ubiquity of these chemicals.

Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. peerReviewed

Background Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure. Objectives Our study aim was to evaluate the association between residential exposure to vehicular traffic and breast cancer incidence. Methods Residential histories of 1,508 participants with breast cancer (case participants) and 1,556 particpants with no breast cancer (control participants) were assessed in a population-based investigation conducted in 1996–1997. Traffic exposure estimates of benzo[a]pyrene (B[a]P), as a proxy for traffic-related PAHs, for the years 1960–1995 were reconstructed using a model previously shown to generate estimates consistent with measured soil PAHs, PAH–DNA adducts, and CO readings. Associations between vehicular traffic exposure estimates and breast cancer incidence were evaluated using unconditional logistic regression. Results The odds ratio (95% CI) was modestly elevated by 1.44 (0.78, 2.68) for the association between breast cancer and long-term 1960–1990 vehicular traffic estimates in the top 5%, compared with below the median. The association with recent 1995 traffic exposure was elevated by 1.14 (0.80, 1.64) for the top 5%, compared with below the median, which was stronger among women with low fruit/vegetable intake [1.46 (0.89, 2.40)], but not among those with high fruit/vegetable intake [0.92 (0.53, 1.60)]. Among the subset of women with information regarding traffic exposure and tumor hormone receptor subtype, the traffic–breast cancer association was higher for those with estrogen/progesterone-negative tumors [1.67 (0.91, 3.05) relative to control participants], but lower among all other tumor subtypes [0.80 (0.50, 1.27) compared with control participants]. Conclusions In our population-based study, we observed positive associations between vehicular traffic-related B[a]P exposure and breast cancer incidence among women with comparatively high long-term traffic B[a]P exposures, although effect estimates were imprecise. Citation Mordukhovich I, Beyea J, Herring AH, Hatch M, Stellman SD, Teitelbaum SL, Richardson DB, Millikan RC, Engel LS, Shantakumar S, Steck SE, Neugut AI, Rossner P Jr., Santella RM, Gammon MD. 2016. Vehicular traffic–related polycyclic aromatic hydrocarbon exposure and breast cancer incidence: the Long Island Breast Cancer Study Project (LIBCSP). Environ Health Perspect 124:30–38; http://dx.doi.org/10.1289/ehp.1307736

Background In laboratory experiments, ω-3 polyunsaturated fatty acids (PUFAs) reduce inflammatory eicosanoids resulting from ω-6 PUFA metabolism via competitive inhibition; and the ω-3 induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary ω-3 PUFA intake benefits survival following breast cancer, are limited and inconsistent.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Background: Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against oesophageal and gastric cancer. Few epidemiologic studies have examined flavonoid intake and incidence of these cancers, and none have considered survival. Methods: In this USA multicentre population-based study, case participants (diagnosed during 1993–1995 with oesophageal adenocarcinoma (OEA, n=274), gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma (OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and frequency-matched controls (n=662) were interviewed. Food frequency questionnaire responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Case participants were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated, comparing highest with lowest intake quartiles, using polytomous logistic and proportional hazards regressions, respectively. Results: Little or no consistent association was found for total flavonoid intake (main population sources: black tea, orange/grapefruit juice, and wine) and incidence or survival for any tumour type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a 57% reduction in the risk of incident OEA (OR=0.43, 95% CI=0.29–0.66) and OES (OR=0.43, 95% CI=0.26–0.70). The ORs for isoflavones, for which coffee was the main source, were increased for all tumours, except OES. Anthocyanidins were associated with decreased risk of mortality for GCA (HR=0.63, 95% CI=0.42–0.95) and modestly for OEA (HR=0.87, 95% CI=0.60–1.26), but CIs were wide. Conclusions: Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce incidence and improve survival for these cancers.

The role of gene-specific methylation in white blood cells (WBC) as a marker of breast cancer risk is currently unclear. We determined whether promoter hypermethylation in blood DNA of candidate tumor suppressor genes frequently methylated in breast tumors can be used as a surrogate biomarker for breast cancer risk. Promoter methylation of BRCA1, CDH1 and RARβ was analyzed in WBC DNA from a population-based sample of 1,021 breast cancer patients and 1,036 controls by the MethyLight assay. Gene-specific promoter methylation in the DNA of 569 tumor tissue samples was also analyzed to determine the correlation of methylation levels with blood from the same individual. Hypermethylation of BRCA1 (OR: 1.31; 95% CI: 0.98-1.75) in WBC was associated with an increased risk of breast cancer when positive methylation was defined as ≥0.1% methylated. There was lack of concordance between tumor tissue and paired WBC DNA methylation. These results provide limited support that hypermethylation of BRCA1 in WBC DNA may be useful for determination of breast cancer risk. Additional studies with larger numbers of genes are needed to fully understand the relationship between WBC methylation and breast cancer risk.

Introduction: Little is known about how modifiable lifestyle factors interact with the epigenome to influence disease. Body mass index (BMI, weight kg/height m2) and physical activity are associated with postmenopausal breast cancer, but the mechanisms are not well-understood. We hypothesized that BMI or physical activity may modify the association between markers of global DNA methylation and postmenopausal breast cancer risk. Methods: Resources from a population-based case-control study (~1300 postmenopausal women) were used to construct logistic regression models. We explored whether the association between breast cancer and global methylation, assessed using the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) methylation in white blood cell DNA, was modified by BMI or recreational physical activity (RPA). Results: The LUMA-breast cancer association was modified by BMI (multiplicative p=0.03) and RPA (p=0.004). Non-obese women in the highest quartile of LUMA experienced a greater than two-fold increased risk of postmenopausal breast cancer (BMI

Background Grilled, barbecued, and smoked meat intake, a prevalent dietary source of polycyclic aromatic hydrocarbon (PAH) carcinogens, may increase the risk of incident breast cancer. However, no studies have examined whether intake of this PAH source influences survival after breast cancer. Methods We interviewed a population-based cohort of 1508 women diagnosed with first primary invasive or in situ breast cancer in 1996 and 1997 at baseline and again approximately five years later to assess grilled/barbecued and smoked meat intake. After a median of 17.6 years of follow-up, 597 deaths, of which 237 were breast cancer related, were identified. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality as related to prediagnosis intake, comparing high (above the median) to low intake, as well as postdiagnosis changes in intake, comparing every combination of pre-/postdiagnosis intake to low pre-/postdiagnosis intake. All statistical tests were two-sided. Results High prediagnosis grilled/barbecued and smoked meat intake was associated with increased risk of all-cause mortality (HR = 1.23, 95% CI = 1.03 to 1.46). Other associations were noted, but estimates were not statistically significant. These include high prediagnosis smoked beef/lamb/pork intake and increased all-cause (HR = 1.17, 95% CI = 0.99 to 1.38, Ptrend = .10) and breast cancer-specific (HR = 1.23, 95% CI = 0.95 to 1.60, Ptrend = .09) mortality. Also, among women with continued high grilled/barbecued and smoked meat intake after diagnosis, all-cause mortality risk was elevated 31% (HR = 1.31, 95% CI = 0.96 to 1.78). Further, breast cancer-specific mortality was decreased among women with any pre- and postdiagnosis intake of smoked poultry/fish (HR = 0.55, 95% CI = 0.31 to 0.97). Conclusion High intake of grilled/barbecued and smoked meat may increase mortality after breast cancer.

Whether aspirin or other nonsteroidal anti-inflammation drug (NSAID) use is associated with mortality following breast cancer remains unclear. Consideration of use patterns and interaction with obesity may help to clarify the inconsistent results. Pre-diagnosis NSAID use, weight, and height were assessed ~ 3 months after diagnosis through in-person interviews with a population-based cohort of 1,442 women with first primary breast cancer. Vital status was determined through the national death index after ~ 18 years of follow-up (N = 237/597 breast cancer-specific/all-cause deaths). We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multiplicative interaction by body mass index (BMI) was evaluated using the likelihood ratio test. Ever aspirin use was inversely associated with breast cancer-specific mortality (HR 0.87, 95% CI 0.59–1.29), but positively associated with all-cause mortality (HR 1.21, 95% CI 0.99–1.48); the CIs included the null values. The HRs, however, were more pronounced for the highest level of duration, frequency, regularity, and timing for all-cause, but not breast cancer-specific mortality. Interactions with BMI revealed no significant heterogeneity (pinteraction = 0.37 and pinteraction = 0.36, respectively). Pre-diagnosis aspirin use was not strongly associated with mortality following breast cancer. The all-cause mortality associations, however, were slightly stronger when we considered patterns of use.

Background: Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association. Methods: A population-based cohort of women (N = 1,508) diagnosed with first primary invasive or in situ breast cancer in 1996 to 1997 was interviewed shortly after diagnosis and again approximately 5 years later to assess ETS exposure, and women were followed for more than 18 years using the National Death Index; 597 deaths (237 associated with breast cancer) were identified. Multivariable Cox regression was used to estimate adjusted HRs and 95% confidence intervals (CI) for mortality among women with breast cancer as related to at-diagnosis and at-/postdiagnosis changes in ETS exposure. Results: There was little or no association between at-diagnosis ETS exposure and all-cause (HR = 1.04; 95% CI, 0.78–1.40) or breast cancer–specific (HR = 0.98; 95% CI, 0.63–1.52) mortality. Mortality was elevated among women who reported cessation in postdiagnosis ETS exposure up to 1 year before the follow-up assessment, for all-cause (HR = 1.81; 95% CI, 0.87–3.74) and breast cancer mortality (HR = 1.89; 95% CI, 0.68–5.24); however, estimates were imprecise. Conclusions: We found little evidence of an association between at-diagnosis ETS exposure and mortality after breast cancer. Postdiagnosis cessation of ETS exposure was positively associated with mortality, although we could not rule out chance and reverse causation as possible explanations. Impact: Exposure to ETS does not appear to influence mortality after breast cancer. Cancer Epidemiol Biomarkers Prev; 26(2); 278–80. ©2016 AACR.

Studies of vitamin D-pathway genetic variants in relation to cancer risk have been inconsistent. We examined the associations between vitamin D-related genetic polymorphisms, plasma 25-hydroxyvitamin D [25(OH)D], and breast cancer risk. In a population-based case–control study of 967 incident breast cancer cases and 993 controls, we genotyped 25 polymorphisms encoding the vitamin D receptor (VDR) gene, 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D-binding protein (GC) and measured plasma 25(OH)D. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95 % confidence intervals (CIs). Among CYP24A1 polymorphisms, rs6068816 was associated with a 72 % reduction in breast cancer risk (TT vs. CC, OR 0.28, 95 % CI 0.10–0.76; p trend = 0.01), but for rs13038432, the 46 % decrease included the null value (GG vs. AA, OR 0.54, 95 % CI 0.17–1.67; p trend = 0.03). Increased risk that included the null value was noted for CYP24A1 rs3787557 (CC vs. TT, OR 1.34, 95 % CI 0.92–1.89). The VDR polymorphism, TaqI (rs731236), was associated with a 26 % risk reduction (TT vs. CC, OR 0.74, 95 % CI 0.56–0.98; p trend = 0.01). For other polymorphisms, ORs were weak and included the null value. The inverse association for plasma 25(OH)D with breast cancer was more pronounced (OR 0.43, 95 % CI 0.27–0.68) among women with the common allele for CYP24A1, rs927650 (p for interaction on a multiplicative scale = 0.01). Breast cancer risk may be associated with specific vitamin D-related polymorphisms, particularly CYP24A1. Genetic variation in the vitamin D pathway should be considered when designing potential intervention strategies with vitamin D supplementation.

AURKA is a putative low-penetrance tumor susceptibility gene due to its prominent role in cell cycle regulation and centrosomal function. Germline variation in AURKA was evaluated for association with breast cancer and intrinsic breast cancer subtypes in the Carolina Breast Cancer Study (CBCS), a population-based case-control study of African Americans (AA) and Caucasians (Cau). Tag and candidate single nucleotide polymorphisms (SNPs) on AURKA were genotyped in 1946 cases and 1747 controls. In race-stratified analyses adjusted for age and African ancestry, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate SNP associations with breast cancer. In a race-combined analysis with similar adjustment, these associations were also examined by intrinsic breast cancer subtype. Using dominant models, most AURKA SNPs demonstrated no association with breast cancer in the race-stratified analyses. Among AA, rs6092309 showed an inverse association with breast cancer (OR = 0.69, 95% CI = 0.53-0.90). In the race-combined analyses, rs6099128 had reduced ORs for luminal A (OR = 0.76, 95% CI = 0.60-0.95) and basal-like breast cancer (OR = 0.54, 95% CI = 0.37-0.80). Rs6092309 showed a similar pattern of association with each subtype. Three SNPs (rs6014711, rs911162, rs1047972) had positive associations with basal-like breast cancer, and ORs reduced or close to 1.00 for other subtypes. Our results suggest inverse associations between some AURKA SNPs and overall breast cancer in AA. We found differential associations by specific subtypes and by race. Replication of these findings in larger AA populations would allow more powerful race-stratified subtype analyses.

Background: Environmental phenols, compounds used widely in personal care and consumer products, are known endocrine disruptors. Few epidemiologic studies have examined the association of phenol biomarkers with breast cancer incidence and, to our knowledge, none have considered associations with mortality following breast cancer. We examined seven urinary phenol biomarkers in association with breast cancer incidence and subsequent mortality, and examined effect measure modification by body mass index (BMI). Methods: Participants included 711 women with breast cancer and 598 women without breast cancer who were interviewed for the population-based Long Island Breast Cancer Study Project. Among women with breast cancer, phenol biomarkers were quantified in spot urine samples collected on average within three months of a first diagnosis of primary in situ or invasive breast cancer in 1996–1997. Women with breast cancer were monitored for vital status using the National Death Index. After a median follow-up of 17.6 years, we identified 271 deaths, including 98 deaths from breast cancer. We examined creatinine-corrected phenol concentrations and the sum of parabens (Σparabens) in association with breast cancer incidence using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and with mortality using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We evaluated multiplicative effect measure modification using cross-product terms in nested models. Results: The highest (vs lowest) quintiles of urinary methylparaben, propylparaben, and Σparabens were associated with risk of breast cancer with ORs ranging from 1.31 to 1.50. Methylparaben, propylparaben, and Σparabens were also associated with all-cause mortality HRs ranging from 0.68 to 0.77. Associations for breast cancer incidence were more pronounced among women with BMI