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Fig. S6. Examples of the genes that remain significant after adjusting for the Risk-Of-Recurrence for LIBCSP participants.

Table S2 (Excel file). Full list of the genes included in the panel (not showed 6 reference genes: CLTC, GAPDH, GUSB, HPRT1, PGK1 and TUBB). Columns are as follows: 1) HUGO gene symbol; 2) shows association with miR-500a activity by ActMiR algorithm in TCGA dataset; 3) presence in PAM50 panel; 4) differentially expressed in MCF7 cells after modulation of miR-500a (overexpression of mimic or antagonist).

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.

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Purpose: To explore the etiologic role of genetic variants in telomere pathway genes and breast cancer risk.Methods: A population-based case-control study, the Long Island Breast Cancer Study Project, was conducted, and 1,067 cases and 1,110 controls were included in the present study. Fifty-two genetic variants of nine telomere-related genes were genotyped.Results: Seven single nucleotide polymorphisms (SNP) showed significant case-control differences at the level of P < 0.05. The top three statistically significant SNPs under a dominant model were TERT-07 (rs2736109), TERT-54 (rs3816659), and POT1-03 (rs33964002). The odds ratios (OR) were 1.56 [95% confidence interval (95% CI), 1.22-1.99] for the TERT-07 G-allele, 1.27 (95% CI, 1.05-1.52) for the TERT-54 T-allele, and 0.79 (95% CI, 0.67-0.95) for the POT1-03 A-allele. TERT-67 (rs2853669) was statistically significant under a recessive model; the OR of the CC genotype was 0.69 (95% CI, 0.69-0.93) compared with the T-allele. However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P < 0.001 (0.05/52) except for TERT-07. When restricted to Caucasians (94% of the study subjects), a stronger association for the TERT-07 G-allele was observed with an OR of 1.60 (95% CI, 1.24-2.05; P = 0.0002). No effect modifications were found for variant alleles and menopausal status, telomere length, cigarette smoking, body mass index status, and family history of breast cancer risk.Conclusions: Four SNPs in the TERT and POT1 genes were significantly related with overall breast cancer risk. This initial analysis provides valuable clues for further exploration of the biological role of telomere pathway genes in breast cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 219–28

Fig. S8. Survival curves for SUSD3 gene expression. A) current LIBCSP study, B) METABRIC population, C) KMplot combined dataset. From left to right: global population, HR-positive (i.e. positive for ER or/and PR) patients, HR-negative (i.e. negative for both ER and PR) patients.

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.

Fig. S4. Principal component analysis of gene expression levels.

Table S1 (pdf file). Full demographic and clinical characteristics of profiled patients and the LIBCSP parent subset.

Association between 387 SNPs and risk of EA, BE, or EA/BE combined

Fig. S1. Correlation between IHC-defined status and gene expression levels for estrogen receptor (ER, left panel) and progesterone receptor (PR, right panel). Each panel shows, left to right, distribution of gene expression values (vertical axis) for IHC-negative, IHC-positive and IHC-unknown groups. Red lines indicate the cut-off chosen (see below).

Legends for Supplemental Figures

Fig. S2. Function of false-positives (red line), false-negatives (green line) and sum of false-positives and false-negatives (blue line), depending on the cut-off value of gene expression levels. Horizontal line indicates the cut-off chosen as giving the minimal sum of false-positives and false-negatives.

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus.Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn.Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed.Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus.Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev; 24(11); 1801–3. ©2015 AACR.

Supplementary Tables 1-3, Supplementary Figures 1-2 from Multiple Genetic Variants in Telomere Pathway Genes and Breast Cancer Risk

Fig. S7. Validation of the associations found in the current study, by the METABRIC dataset, keeping the cutoff selected by LIBCSP dataset. Horizontal axis displays hazards ratio for given gene in the LIBCSP dataset, vertical axis shows HR for METABRIC dataset. Size of the dot indicates p-value for METABRIC dataset. Pink colors marks the genes of PAM50 panel.

Table S3 (Excel file). Association of profiled genes with breast cancer mortality among participants in the LIBCSP, in different subsets or adjustments. For all analyses, age and tumor stage were included as cofactors; "ERPR_all" - included all patients; "ERPR_pos" - ER|PR+ patients; "ERPR_neg" - ER-/PR- patients; "ERPR_adj" - all patients, with ER/PR status as additional cofactor; "ROR_adj" - all patients, with ROR group as additional cofactor; "ROR_high" - patients assigned to high ROR group; "ROR_low+med" - patients assigned to low and medium ROR groups. For each analysis, columns are as follows: HR - hazard ratio; HR.CI - 95% confidence interval for HR; p - unadjusted p-value; p.BH - Benjamini-Hochberg-adjusted p-value; q - decile threshold for high/low expression level stratification; N.hi - number of patients in "high expression" group.

Supplemental Methods

Fig. S3. Distribution of expression levels among genes and samples. Each dot represents a gene, with horizontal axis showing the percent of samples expressing this gene and vertical axis showing median log2 expression level of this gene.

PDF file - 197K, Table S1. Discovery set study populations. Table S2. Distribution of discovery set subjects by site, case-control status and chip. Table S3. Discovery set quality control summary. Table S4. SNPs with score-based P-values < 4 X 10-8 among 58016 SNPs for which Plink aborted the logistic regressions. Table S5. Replication set study populations. Table S6. Distribution of replication set subjects by site, case-control status and

Fig. S5. Survival curves among the LIBCSP patients, stratified by ROR group (left panel) and molecular subtype (right panel).

Supplementary Methods and Materials from Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22–1.38) and 1.64 (1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10−30], Japanese women [ORs (95% CI) = 1.31 (1.13–1.52) and 1.37 (1.06–1.76), P for trend = 2.51 × 10−4], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99–1.16) and 1.18 (1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63–1.06) and 0.85 (0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r2 = 0.91) and European-ancestry (r2 = 0.83) populations, but not in Africans (r2 = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region. Cancer Res; 71(4); 1344–55. ©2011 AACR.

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.

The association between diet quality and head and neck cancer (HNC) was explored using a population-based case-control study of 1170 HNC cases and 1303 age-, race-, and sex-matched controls from the United States. Diet quality was assessed with three diet quality scores (DQS): (a) Healthy Eating Index 2005 (HEI-2005), (b) Mediterranean Diet Score (MDS), and (c) HNC-specific Mediterranean Diet Score (MDS-HNC), a modified MDS that we developed to be more applicable to HNC. Logistic regression models estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) representing diet quality-incident HNC associations. We examined effect measure modification (EMM) by body mass index (BMI), race, cigarette smoking, and alcohol consumption and associational heterogeneity by HPV-positivity and tumor site. A one standard deviation summary DQS decrement suggested a consistent inverse association (ORs (CIs)) for the HEI-2005, MDS, and MDS-HNC: 1.35 (1.21, 1.50), 1.13 (1.02, 1.25), and 1.17 (1.06, 1.31), respectively. This association did not vary by tumor site or tumor HPV status, though additive EMM by alcohol use and by BMI was observed. Our findings suggest the Mediterranean diet can be used to study HNC in American populations, and that poor diet quality elevates HNC incidence, particularly among alcohol users.

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 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 Telomeres are vital for genomic integrity and telomere length has been linked to many adverse health outcomes. Some hazardous air pollutants, or air toxics, increase oxidative stress and inflammation, two possible determinants of shortened telomere length. No studies have examined air toxic-telomere length associations in a non-occupational setting. Methods This study included 731 Sister Study participants (enrolled 2003-2007) who were randomly selected to assess telomere length in baseline blood samples. Multiplex qPCR was used to determine telomere to single copy gene (T/S) ratios. Census tract concentration estimates of 29 air toxics from the 2005 National Air Toxics Assessment were linked to baseline residential addresses. Air toxics were classified into tertile-based categories of the exposure. Multivariable linear regression was used to estimate β coefficients and 95% confidence intervals (CI) in single pollutant models. Multipollutant groups were identified with regression trees. Results The average T/S ratio was 1.24. Benzidine (T3vsT1 β= -0.08; 95% CI: -0.14, -0.01) and 1,4-dioxane (T3vsT1 β= -0.06; 95% CI: -0.13, 0.00) in particular, as well as carbon tetrachloride, chloroprene, ethylene dibromide, and propylene dichloride, were associated with shorter relative telomere length. Benzidine (p=0.02) and 1,4-dioxane (p=0.06) demonstrated some evidence of a monotonic trend. The regression tree identified age, BMI, physical activity, ethylene oxide, acrylonitrile, ethylidene dichloride, propylene dichloride, and styrene in multipollutant groups related to telomere length. Conclusions In this first study of air toxics and telomere length in a non-occupational setting, several air toxics, particularly 1,4-dioxane and benzidine, were associated with shorter relative telomere length.

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.

Background Much of the marked increase in incidence of non-Hodgkin lymphoma (NHL) over the past few decades remains unexplained. Organochlorines, including organochlorine pesticides (OCPs), have been implicated as possible contributors to the increase, but the evidence is inconsistent. Objectives To investigate the relation between pre-diagnostic levels of OCPs and risk of NHL in a case-control study nested within the population-based Janus Serum Bank Cohort in Norway. Methods Prediagnostic concentrations of 11 OCPs or OCP metabolites were measured in baseline blood samples collected between 1972 and 1978 from 190 cases and 190 controls matched on sex, county, age at blood draw, and date of blood draw. We conducted conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for each quartile of lipid-corrected OCP/metabolite relative to the lowest quartile. Results We observed non-significantly elevated ORs across quartiles of β-hexachlorocyclohexane compared to the lowest quartile (OR range: 1.40–1.82) although with no apparent monotonic exposure-response relationship. We also found an inverse association between risk of NHL and o,p'-DDT (OR for Q4 vs. Q1 = 0.44, 95% CI: 0.19, 1.01; p-trend = 0.05). In analyses stratified by age at blood collection and duration of follow-up, several other analytes, primarily chlordane-related compounds, showed inverse associations among younger participants or those with longer follow-up time between blood draw and NHL diagnosis. Conclusions We found only limited evidence of positive association between selected OCPs and development of NHL.

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.

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 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: 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.