Island Breast Cancer Study Project Research Articles

Metabolomics links lifestyle variables to breast cancer in the Long Island Breast Cancer Study Project

Background/Aim: Healthy lifestyle has been associated with decreased risk of developing breast cancer. Using untargeted metabolomics profiling, we aim to identify the molecular mechanisms connecting lifestyle and breast cancer through network analysis. Methods: A total of 50 post-menopausal women with breast cancer and 50 cancer-free controls were selected from the Long Island Breast Cancer Study Project (LIBCSP). We measured untargeted plasma metabolomics using liquid chromatography- high resolution mass spectrometry (LC-HRMS). Using ‘enet’, we retained metabolites found in active molecular network (AMN) clusters for analysis. LASSO was used to explore associations between cancer status and metabolites; 14 lifestyle related variables including smoking, physical activity, alcohol consumption, meat consumption, fruit and vegetables consumption, supplemental vitamin use; and 20 covariates including various reproductive factors. LASSO was repeated to explore associations between selected lifestyle factors and metabolites. Results were displayed as a network to uncover biological pathways linking lifestyle factors to breast cancer. Results: After filtering, 1797 metabolomics peaks in the plasma samples remained. Of these, 851 "active” metabolites were retained in 197 correlation AMN clusters. Through LASSO, breast cancer status was associated with 66 "active” metabolites. Several of these metabolites were also associated with lifestyle variables including meat consumption, alcohol consumption, and supplemental β-carotene, B12 and folate use. No individual lifestyle factors were directly associated with breast cancer status through LASSO, suggesting that metabolites may act as biological intermediaries between healthy lifestyle factors and breast cancer. In particular, 13-HPODE, a metabolite linked with inflammation, was associated with breast cancer status and connected to β-carotene supplement usage through an AMN. Conclusions: We found several plasma metabolites associated with both lifestyle factors and breast cancer status. These results suggest that inflammation may play a mechanistic role linking supplement usage to breast cancer status. Keywords: breast cancer, lifestyle factors, metabolomics, network analysis

Urinary parabens and breast cancer risk: Modification by LINE-1 and LUMA global DNA methylation, and associations with breast cancer defined by tumor promoter methylation status.

Parabens are a group of alkyl esters of p-hydroxybenzoic acid added to consumer products to prevent the growth of harmful bacteria and molds. Parabens are hypothesized to increase the risk of breast cancer (BC); however, no study has examined the interactions between parabens, global DNA methylation (DNAm), and BCrisk. We examined the modifying effects of DNAm on the associations between parabens and BC, and whether parabens were associated with BCdefined by tumor promoter methylation status. Participants included 708 cases and 598 controls from the Long Island Breast CancerStudy Project. Methylparaben (MPB), propylparaben, and butylparabenlevels were measured in spot urine samples. Global DNAm was measured by analysis of long interspersed elementes-1(LINE-1) and the luminometric methylation assay (LUMA). The promoter methylation status of 13 genes was measured in tumor samples from 509 cases. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between parabens and BC stratified by LINE-1/LUMA, and between parabens and gene-specific promoter methylation-defined BC. Outcome heterogeneity was evaluated using ratios of ORs (RORs). We assessed the joint effects of the multiple parabens using quantile g-computation. The highest versus lowest tertile of MPB and a one-quantile increase in all parabens were associated with ORs of 1.46 (95%CI = 0.96-2.23) and 1.32 (95%CI = 1.02-1.71), respectively, among women with hypomethylated LINE-1. A one-ln unit increase in MPB was associated with a 25% increase in the odds of hypomethylated (vs. hypermethylated) CCND2 promoter-defined BC (ROR = 1.25, 95%CI = 1.06-1.48), and a one-quantile increase in all parabens was associated with a 55% increase in the odds of hypomethylated (vs. hypermethylated) CCND2 promoter-defined BC (ROR = 1.55, 95%CI = 1.04-2.32). Exposure to parabens may increase the risk of BC among women with hypomethylated global DNAm and may increase the risk of tumors with gene-specific hypomethylated promoter regions.

The associations of healthy lifestyle index with breast cancer incidence and mortality in a population-based study.

To investigate how a healthy lifestyle index (HLI) is associated with breast cancer risk and survival in a population-based breast cancer study. The study included 1319 breast cancer cases and 1310 controls from the population-based Long Island Breast Cancer Study Project and its follow-up study where vital status was ascertained using the National Death Index (521 deaths, 210 from breast cancer; median follow-up 214.5months). HLI scores were generated from body mass index, physical activity, intake of plant and animal foods, alcohol consumption, breastfeeding, and smoking, with higher values corresponding to healthier behaviors obtained from baseline questionnaire. Multivariable logistic and Cox regression models were used to estimate breast cancer odds ratios (ORs) and mortality hazards ratios (HRs), respectively. Compared to women in the low HLI tertile, a significant reduction in risk of breast cancer was observed for women in the intermediate (OR = 0.78, 95% CI 0.64-0.93) and high (OR = 0.73, 95% CI 0.60-0.88) tertiles; a one-point increase in HLI score was associated with a 14% reduction in breast cancer risk (OR = 0.86, 95% CI 0.80-0.93). For survival, a significant reduction in all-cause mortality was also observed in women in the intermediate (HR = 0.68, 95% CI 0.56-0.84) and high (HR = 0.72, 95% CI 0.58-0.88) HLI tertiles with a 17% reduction in all-cause mortality (HR = 0.83, 95% CI 0.76-0.91) for one-point increase in HLI score. These inverse associations were more prominent among postmenopausal women. A healthy lifestyle is beneficial not only in reducing breast cancer risk but also in improving overall survival after breast cancer diagnosis, especially among postmenopausal women.

Phthalates and Phenols, Leukocyte Telomere Length, and Breast Cancer Risk and Mortality in the Long Island Breast Cancer Study Project.

Phthalates and phenols from the environment have been inconsistently associated with breast cancer risk or mortality. Studies on the potential modifying role of leukocyte telomere length (LTL), a biomarker of biological aging, on these associations are lacking. We included 1,268 women from the Long Island Breast Cancer Study Project with available data on phthalate and phenol analytes and LTL measurements. Twenty-two phthalate and phenol analytes were measured in spot urines and LTL was measured in blood. The modifying effect of LTL on the associations of individual analyte with breast cancer risk as well as mortalities was estimated using interaction terms between LTL and urinary concentrations of analyte in logistic regression and Cox regression models, respectively. ORs, HRs, and corresponding 95% confidence intervals for a one-unit (ln μg/g creatinine) increase of urinary phthalate/phenol level were estimated at 10th, 50th, and 90th percentiles of LTL. LTL significantly (P < 0.05) modified associations between 11 of 22 of urinary phthalate/phenols analytes and breast cancer risk. An inverse association between phthalate/phenols analytes and breast cancer risk at shorter LTL and a positive association at longer LTL was generally suggested. No modifying effect was found for LTL on the association between these phthalate/phenols analytes and breast cancer mortalities. LTL may modify the associations between phthalate and phenol exposures and breast cancer risk. This study is the first study that determined the modifying effect of biological aging in the association between environmental chemical exposure and breast cancer risk.

Dietary Acid Load, Serum Polychlorinated Biphenyl Levels, and Mortality Following Breast Cancer in the Long Island Breast Cancer Study Project.

Dietary acid load (DAL) may be associated with all-cause mortality (ACM) and breast cancer-specific mortality (BCM), and these associations may be modified by serum polychlorinated biphenyl (PCB) levels. Participants included 519 women diagnosed with first primary in situ or invasive breast cancer in 1996/1997 with available lipid-corrected PCB data. After a median of 17 years, there were 217 deaths (73 BCM). Potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores calculated from a baseline food frequency questionnaire estimated DAL. Cox regression estimated covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PRAL and NEAP with mortality. We evaluated effect measure modification by total serum PCB levels (>median vs. ≤median). PRAL quartile 4 versus quartile 1 was associated with an ACM HR of 1.31 (95%CI = 0.90–1.92). In the upper median of PCBs, ACM HRs were 1.43 (95%CI = 0.96–2.11) and 1.40 (95%CI = 0.94–2.07) for PRAL and NEAP upper medians, respectively. In the lower median of PCBs, the upper median of NEAP was inversely associated with BCM (HR = 0.40, 95%CI = 0.19–0.85). DAL may be associated with increased risk of all-cause mortality following breast cancer among women with high total serum PCB levels, but inversely associated with breast cancer mortality among women with low PCB levels.

Urinary parabens and breast cancer risk: Modification and interaction by LINE-1/LUMA methylation in the Long Island Breast Cancer Study Project

BACKGROUND AND AIM: Parabens, ubiquitous endocrine disrupting chemicals used in personal care products, may interact with DNA methylation status to impact breast cancer (BC) risk. We examined whether global DNA methylation modifies or interacts with paraben levels to impact BC risk and whether paraben levels are associated with tumor gene-specific promoter methylation in 12 BC-related genes. METHODS: Participants included 708 cases and 598 controls from the population-based Long Island Breast Cancer Study Project. Levels of methyl-/propyl-/butyl-parabens and parabens were measured in spot urine samples, creatinine-corrected, and dichotomized at the 80th percentiles. Global DNA methylation status (methylated vs. unmethylated) was measured in peripheral blood using LINE-1 and LUMA. Among 509 cases, the promoter methylation status of 12 BC-related genes was measured in tumor samples. For effect measure modification, we used logistic regression to estimate covariate-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the associations between paraben levels and BC stratified by LINE-1/LUMA methylation status. For additive interactions, we used logistic regression to estimate aORs and CIs for the joint associations between paraben levels and LINE-1/LUMA methylation status and BC. To examine outcome heterogeneity, we used multinomial logistic regression to estimate aORs and CIs for the associations between paraben levels and gene-specific promoter methylation status (unmethylated cases vs. controls; methylated cases vs. controls). RESULTS:Propylparaben levels 80th (vs. ≤80th) percentile were associated with a 50% increase in the odds of having a methylated APC promoter than being a control (aOR=1.50, 95%CI=1.02-2.20), but not with having an unmethylated APC promoter than being a control (aOR=0.94, 95%CI=0.63-1.42). LINE-1/LUMA did not modify the associations between parabens and BC and did not interact with parabens to increase BC risk. CONCLUSIONS:Exposure to parabens may increase the risk of BC with methylated promoter regions of APC, a tumor suppressor gene and regulator of the WNT signaling pathway. KEYWORDS: Breast cancer, parabens, endocrine disrupting chemicals, DNA methylation, gene promoter methylation

Associations of Phthalates and Phenols, Telomere Length, and Breast Cancer in the Long Island Breast Cancer Study Project

BACKGROUND AND AIM: Exposure to phthalates or phenols has been of concern as associated with breast cancer due to the endocrine disrupting effects of these chemicals. Studies related to the modifying role of cellular aging on these associations are lacking. We aim to evaluate the modifying effect of leukocyte telomere length (LTL), a biomarker of cellular aging, on the associations between phthalate and phenol exposure and breast cancer incidence and mortality. METHODS: We used data from 1268 women whose urinary phthalates and phenols and LTL measurements were available from the Long Island Breast Cancer Study Project. Twenty-two metabolites of phthalates and phenols were measured in the spot urine collected from the study participants. The modifying effect of LTL on the association between each individual metabolite and breast cancer incidence and mortality was estimated using interaction terms between LTL and the individual metabolites in logistic regression models and Cox regression models. Odds ratios, hazard ratios, and corresponding 95% confidence intervals (CI) for a one-unit (ln ug/g creatinine) increase of urinary metabolite concentration were estimated at 10th, 50th, and 90th percentiles of LTL. RESULTS:LTL significantly (P0.05) modified the associations between breast cancer incidence and metabolites for eleven phthalates and phenols. Metabolites were, in general, inversely and positively associated with breast cancer incidence at shorter and at longer LTL, respectively. No statistically significant modifying effect was found for LTL in the association between these metabolites and breast cancer mortality. CONCLUSIONS:Women with longer LTL were more susceptible to exposure to phthalates and phenols in the development of breast cancer. But shorter LTL can still increase the detrimental effect of certain types of phenols to breast cancer. KEYWORDS: Phthalate, Phenol, Breast Cancer, Leukocyte Telomere Length

PAM50- and immunohistochemistry-based subtypes of breast cancer and their relationship with breast cancer mortality in a population-based study.

We evaluated the prognostic ability of immunohistochemistry (IHC)-based vs. PAM50-based subtypes for breast cancer mortality in a population-based study of breast cancer. We included a total of 463 breast cancer cases from the population-based Long Island Breast Cancer Study Project (LIBCSP). IHC-based markers were abstracted from the medical records, while the PAM50-based intrinsic subtypes were assessed from tumor tissues using NanoString nCounter® Analysis System. Cox proportional hazards models were used to estimate hazards ratios (HRs) for breast cancer-specific mortality associated with subtypes. For IHC-based hormone receptor-positive (HR+) tumors (n = 361), 68.7% were classified as luminal subtypes by PAM50; for HR- tumors (n = 102), 95.1% were classified as non-luminal subtypes. Compared to HR+/HER2- subtype, HR- patients had significantly higher breast cancer mortality (HR-/HER2+: HR = 2.84, 95% CI = 1.58-5.11; triple-negative breast cancer: HR = 2.42, 95% CI = 1.44-4.06). Compared to luminal A, a higher mortality rate was observed for all other PAM50-based subtypes: luminal B (HR = 4.03, 95% CI = 1.97-8.22), HER2-enriched (HR = 6.82, 95% CI = 3.29-14.14) and basal-like (HR = 4.71, 95% CI = 2.24-9.93). Additional subtyping of HR+ patients by PAM50 provided future risk stratification where luminal B patients in this group had significant higher mortality than luminal A patients (HR = 3.93, 95% CI = 1.92-8.03). Similar results were also observed among 291 HR+/HER2- patients, but not among the HR- patients. Our study suggests that for HR+ patients, especially HR+/HER2- patients, additional PAM50-based subtyping would provide better prognostic stratification and improve disease management.

Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.

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.

Urinary concentrations of environmental phenols and their associations with breast cancer incidence and mortality following breast cancer

BackgroundEnvironmental 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). MethodsParticipants 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. ResultsThe 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 < 25.0 kg/m2 than among women with BMI ≥ 25.0 kg/m2; however, associations for mortality were more pronounced among women with BMI ≥ 25 kg/m2 than among women with BMI < 25 kg/m2. ConclusionsSelect parabens may have differential associations with risk of developing breast cancer and mortality following breast cancer.

Genetic polymorphisms of diabetes-related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project.

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.

Abstract 243: Genetic polymorphisms of diabetes-related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project

Abstract Background: Diabetes is associated with increased risk of breast cancer and subsequent mortality; however, whether genetic variants that increase diabetes risk also influence breast cancer has received little attention. Herein, we examined the associations between 143 single nucleotide polymorphisms (SNPs) identified from genome-wide association studies of diabetes risk, and breast cancer incidence and subsequent mortality. For SNPs significantly associated with breast cancer incidence or mortality, we evaluated effect modification by diabetes status. Methods: Caucasian women diagnosed with first primary invasive breast cancer (n=817) and controls (n=1,021) from a population-based case-control study were interviewed to assess diabetes status. Using the National Death Index, women with breast cancer were followed for more than 18 years during which we identified 340 deaths including 139 from breast cancer. Genomic DNA was extracted from blood samples and genotyping was done using high-throughput matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We used logistic regression to estimate age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer incidence and used Cox regression to estimate age-adjusted hazard ratios (HRs) and 95% CIs for all-cause and breast cancer-specific mortality. Results: Twelve SNPs were associated with incident breast cancer in additive models, at an alpha of 0.05. The top three most significantly associated SNPs included SLC30A8 rs4876369 (P=0.0034), HHEX rs11187146 (P=0.0086), and CDKN2A/CDKN2B rs1333049 (P=0.0086). Diabetes status modified two SNP-breast cancer incidence associations: SLC30A8 rs4876369 was associated with a 25% increase (OR=1.25, 95% CI=1.02-1.53) in odds of breast cancer among women without diabetes, and with a 330% increase (OR=4.30, 95% CI=1.66-11.17) in odds of breast cancer among women with diabetes (PInteraction=0.0150). IRS2 rs2241745 was inversely associated (OR=0.76, 95% CI=0.61-0.94) with breast cancer among women without diabetes, and associated with a 76% increase (OR=1.76, 95% CI=0.86-3.58) in odds of breast cancer among women with diabetes (PInteraction=0.0283). Three SNPs were associated with all-cause (CDKAL1 rs981042, P=0.0032; HHEX rs1111875, P=0.0361; and INSR rs919275, P=0.0488) and three with breast cancer-specific (CDKN2A/CDKN2B rs3218020, P=0.0225; CDKAL1 rs981042, P=0.0246; and TCF2/HNF1B rs3094508, P=0.0344) mortality in additive models, at an alpha of 0.05. Conclusions: SNPs identified in GWAS studies of diabetes risk were associated with breast cancer incidence and mortality among a population-based sample of women. These associations may highlight important biological mechanisms of breast carcinogenesis and progression. Citation Format: Humberto Parada, Rebecca J. Cleveland, Kari E. North, June Stevens, Susan L. Teitelbaum, Alfred I. Neugut, Regina M. Santella, Maria E. Martinez, Marilie D. Gammon. Genetic polymorphisms of diabetes-related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 243.

Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project.

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 (), 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 and inverse associations among women with .Conclusions:Consistent with laboratory evidence, we observed inverse associations between urinary concentrations of several phthalate metabolites and BC and subsequent survival; however, these results should be interpreted with caution given that biospecimen collection among women with BC occurred after diagnosis, which may be of particular concern for our case–control findings. https://doi.org/10.1289/EHP2083

Abstract LB-253: Novel prognostic gene profiles in tumors for breast cancer survival

Abstract Recent development in molecular phenotyping of breast cancer to guide treatment strategy has improved breast cancer survival. While several prognostic panels, such as Oncotype DX (21 genes), MammaPrint (70 genes), ProSigna (50 genes), have been approved for clinical use with demonstrated utility, there is still room for improvement. Using a novel bioinformatics approach, we previously demonstrated that higher “activity” (instead of level of expression) of miR-500a-5p in tumor was associated with shorter survival of ER+ breast cancer patients. However, the activity of miR-500a cannot be directly measured and can only be inferred by the expression of its associated genes. Using NanoString platform, we profiled 162 miR-500a-related genes as well as PAM50 genes (22 genes overlapped between PAM50 set and miR-500a-related set) from tumors collected as part of the Long Island Breast Cancer Study Project, where a population-based sample of 1508 women, predominantly Caucasians aged 25-98 (median age 58), newly diagnosed with first primary breast cancer in 1996-1997, were followed up for 15+ years using the National Death Index. We were able to obtain sufficient RNA for profiling from paraffin-embedded tumors tissues for 609 cases, among which 119 breast cancer deaths were reported at the end of follow up. Survival analyses were carried out using Cox proportional hazards models adjusting for known prognostic factors. Consistent with our a priori hypothesis, most of the selected miR-500a related genes (81 out of 162) significantly associated with breast cancer-specific mortality. Co-expression analysis revealed two major clusters of genes with opposite associations with breast cancer-specific mortality. For example, expression of SUSD3 from the first cluster showed inverse associations with breast cancer-specific mortality [high vs low expression: Hazard Ratio (HR) 0.33, 95% CI: 0.23-0.47] while TPX2 from the second cluster showed the opposite [HR 2.64, CI: 1.84-3.80]. These associations were also confirmed in independent combined datasets (described in “KM-Plotter”, kmplot.com). Most importantly, these associations remained significant after adjusting for known prognostic factors including tumor hormonal receptor status and PAM50-derived risk of recurrence category, implicating they are independent markers for breast cancer survival. Our study identified novel predictors that may improve prognostic efficiency of current molecular phenotyping. In addition, these results shed light on molecular mechanism of breast cancer progression and may point to the targets for treatment of the disease. Citation Format: Vasily N. Aushev, Marilie D. Gammon, Humberto Parada, Davide Degli Esposti, Hector Hernandez-Vargas, Zdenko Herceg, Susan Teitelbaum, Jun Zhu, Eunjee Lee, Jia Chen. Novel prognostic gene profiles in tumors for breast cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-253. doi:10.1158/1538-7445.AM2017-LB-253

Abstract 2304: Environmental pollutants and breast cancer: 2006-2016 epidemiological studies designed to evaluate biological hypotheses provide evidence of risk for certain pesticides, organic solvents, and products of combustion

Abstract Common environmental chemicals have plausible links to breast cancer because they are mammary gland carcinogens in animal studies or are known to activate relevant hormonal pathways or enhance susceptibility of the mammary gland to carcinogenesis. An institute of Medicine report prioritized human studies of these exposures. Yet the long latency and multifactorial etiology of breast cancer make evaluation of these chemicals in humans challenging, adding to the importance of study designs that are well-suited to capture hypothesized breast-cancer mechanisms. With this in mind, we updated Brody et al’s 2007 review in Cancer to evaluate the strength of the epidemiologic evidence for several classes of chemicals with widespread exposure. We conducted a systematic search of the PubMed database for articles published in 2006-2016 using 147 terms and the inclusion/exclusion criteria defined in Brody et al’s 2007 review. We critically reviewed articles identified by our search, including whether study designs were suited to the biological evidence. We identified 158 new articles since 2006. In the past 10 years, the strength of evidence for an association between breast cancer and banned but persistent endocrine disrupting chemicals polychlorinated biphenyls (PCBs) and organochlorine pesticides has increased, based on a unique 50-year cohort study that captured exposure during potentially critical windows for breast development (in utero, adolescence, pregnancy) and at the time when the chemicals were still in use. Studies that considered early life exposure to organic solvents and/or exposure of long duration also added to evidence for an association with breast cancer. Solvents are used in dry cleaning, electronics manufacturing, leather and fur processing, and metal, auto, textile, and some military work. Other important reports included the U.S. Agricultural Health Study, which provided the first evidence of an association between organophosphate pesticides and breast cancer. Analyses from the Long Island Breast Cancer Study Project showed higher risk associated with polycyclic aromatic hydrocarbons (PAHs, products of combustion) in women with certain genetic variations. Consumer product chemicals, including BPA, phthalates, per fluorinated compounds, and hair dyes were evaluated in a few studies with inconsistent results; many of these studies had serious methodologic limitations. Animal and mechanistic evidence suggest that timing could be crucial to carcinogenic actions of many environmental chemicals, however we found that most epidemiologic studies in the past 10 years did not evaluate a specific timeframe of exposure prior to diagnosis. Those that did enhanced our understanding of relevant windows for biological activity of certain classes of chemicals. Citation Format: Kathryn M. Rodgers, Julia O. Udesky, Ruthann A. Rudel, Julia G. Brody. Environmental pollutants and breast cancer: 2006-2016 epidemiological studies designed to evaluate biological hypotheses provide evidence of risk for certain pesticides, organic solvents, and products of combustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2304. doi:10.1158/1538-7445.AM2017-2304

Institutes in the Lead: Identifying Environmental Factors in Breast Cancer.

Institutes in the Lead: Identifying Environmental Factors in Breast Cancer.

Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence.

Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes. Residential histories of 1,508 cases and 1,556 controls were assessed in the Long Island Breast Cancer Study Project between 1996 and 1997 and used to reconstruct residential traffic exposures to benzo[a]pyrene, as a proxy for traffic-related PAHs. Likelihood ratio tests from adjusted unconditional logistic regression models were used to assess multiplicative interactions. A gene-traffic interaction was evident (p = 0.04) for ERCC2 (Lys751); when comparing the upper and lower tertiles of 1995 traffic exposure estimates, the odds ratio (95% confidence interval) was 2.09 (1.13, 3.90) among women with homozygous variant alleles. Corresponding odds ratios for 1960-1990 traffic were also elevated nearly 2-3-fold for XRCC1(Arg194Trp), XRCC1(Arg399Gln) and OGG1(Ser326Cys), but formal multiplicative interaction was not evident. When DNA repair variants for ERCC2, XRCC1 and OGG1 were combined, among women with 4-6 variants, the odds ratios were 2.32 (1.22, 4.49) for 1995 traffic and 2.96 (1.06, 8.21) for 1960-1990 traffic. Our study is first to report positive associations between traffic-related PAH exposure and breast cancer incidence among women with select biologically plausible DNA repair genotypes.

Vehicular Traffic–Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP)

Vehicular Traffic–Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP)

Vehicular Traffic-Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP).

BackgroundPolycyclic 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.ObjectivesOur study aim was to evaluate the association between residential exposure to vehicular traffic and breast cancer incidence.MethodsResidential 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.ResultsThe 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].ConclusionsIn 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.CitationMordukhovich 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

Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity.

Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant. We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation. BMI 25-29.9kg/m2, and perhaps BMI≥30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI≥30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84). While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.