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Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk.Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index.Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype.Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes.Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.

Summary results for all SNPs at the 4q24 locus associated with breast cancer risk at P

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

Background: Filipina Americans have one of the highest breast cancer incidence rates among Asian Americans for poorly understood reasons.Methods: Breast cancer risk factors were investigated in a population-based study of Filipina (790 cases, 587 controls), Japanese (543 cases, 510 controls), and Chinese (913 cases, 904 controls) Americans. Cases were identified by the Los Angeles County Cancer Surveillance Program, and controls were matched to cases on age, ethnicity, and neighborhood. Multivariable conditional logistic regression was performed by Asian ethnicity.Results: In Filipina, Chinese, and Japanese Americans, breast cancer risk decreased significantly with increasing parity (all Ptrend < 0.0001). Breast cancer risk increased with increasing quartiles of cumulative menstrual months in premenopausal (Ptrend = 0.019) and postmenopausal Filipina (Ptrend = 0.008), in premenopausal (Ptrend = 0.0003) but not postmenopausal Chinese (Ptrend = 0.79), and in neither premenopausal (Ptrend = 0.092) nor postmenopausal (Ptrend = 0.75) Japanese Americans. For postmenopausal Filipina and Japanese, greater weight gain since age 18 (Ptrend = 0.019 and 0.053, respectively), high current body mass index (both Ptrend < 0.01), and greater waist circumferences (both Ptrend < 0.04) were statistically significant; these associations were weaker for postmenopausal Chinese women.Conclusions: Cumulative menstrual months and body size factors were statistically significant risk factors for Filipina. Total menstrual months were associated with breast cancer among Chinese but not for Japanese, while body size factors were significantly associated with risk among Japanese but not among Chinese.Impact: Characterization of breast cancer risk factors in Filipina will help to generate hypotheses for their high breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 25(12); 1572–86. ©2016 AACR.

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993–1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98–1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm3) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07–1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers.Significance:Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer.

Supplemental table 1 presents reproductive factors in Filipina, Chinese, and Japanese migrants by timing of birth Supplemental table 2 presents select risk factors by tumor stage at diagnosis (in situ, localized, and advanced stage) Supplemental table 3 presents select menstrual and reproductive factors by hormone receptor status Supplemental table 4 compares interviewed and non-interviewed breast cancer cases by age, neighborhood SES, and tumor stage at diagnosis

Supplemental Table S1. Pooled Odds Ratios and 95% Confidence Intervals Representing the Association Between Physical Inactivity and Epithelial Ovarian Cancer by Menopause Status. Supplemental Table S2. Age-Adjusted And Multivariable-Adjusted Pooled Odds Ratios And 95% Confidence Intervals (CI) Representing The Association Between Physical Inactivity And Epithelial Ovarian Cancer By Race. Supplemental Table S3. Pooled odds ratios and 95% confidence intervals representing the association between physical inactivity and epithelial ovarian cancer by standard BMI classification. Supplemental Table S4. Pooled odds ratios and 95% confidence intervals representing the association between physical inactivity and epithelial ovarian cancer by dichotomous BMI classification

Purpose Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). Results The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. Conclusion PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Background Frailty status has been sparsely studied in some groups including Native Hawaiians and Asian Americans. Methods We developed a questionnaire-based deficit accumulation frailty index (FI) in the Multiethnic Cohort (MEC) and examined frailty status (robust, FI 0 to Results After adjustment for age, demographic, lifestyle factors, and chronic conditions, relative to White men, odds of being frail was significantly higher (34%–54%) among African American, Native Hawaiian, and other Asian American men, whereas odds was significantly lower (36%) in Japanese American men and did not differ in Latino men. However, among men who had high school or less, none of the groups displayed significantly higher odds of prefrail or frail compared with White men. Relative to White women, odds of being frail were significantly higher (14%–33%) in African American and Latino women, did not differ for other Asian American women and lower (14%–36%) in Native Hawaiian and Japanese American women. These racial and ethnic differences in women were observed irrespective of education. Risk of all-cause mortality was higher in prefrail and frail men than robust men (adjusted hazard ratio [HR] = 1.69, 1.59–1.81; HR = 3.27, 3.03–3.53); results were similar in women. All-cause mortality was significantly positively associated with frailty status and frailty score across all sex, race, and ethnic groups, Conclusions Frailty status differed significantly by race and ethnicity and was consistently associated with all-cause mortality. The FI may be a useful tool for aging studies in this multiethnic population.

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Objective: The effects of chemotherapy and weight changes on the gut microbiome of breast cancer patients are not well understood. Methods: We conducted a 1-year follow-up study of 33 breast cancer patients and investigated gut microbiome before initiation of chemotherapy and after completion of treatment. We compared alpha diversity and mean taxa abundance at baseline and absolute changes (Δ; final-baseline) in taxa abundance by treatment (16 neoadjuvant- neoADJ, 13 adjuvant- ADJ, 4 no chemotherapy-noC) using Wilcoxon rank sum and negative binomal tests and evalauted whether these changes were affected by weight changes during follow-up. Results: Alpha diversity measures increased in the neoADJ (+16.4% in OTU p =0.03; +51.6% in Chao1 p =0.03; +7.0% in Shannon index P=0.02; +11.0% in PD whole tree p =0.09) but not in the non-neoADJ group (ADJ+noC). The difference in change in Chao1 index between groups was statistically significant ( p NEOADJ vs ADJ+noC =0.04). Wilcoxon p values of 0.03 to 0.003 were observed for five taxa: Bacteroidetes (g _Alistipes) , Firmicutes (g_Clostridium, g_Eubacterium, g_Bilophila) and Preteobacteria g_Haemophilus). In the negative binomial analysis, changes in abundance differed at Bonferroni-adjusted p values ≤0.0007 for four taxa: two Bacteroidetes taxa ( g_Alistipes, f _S247 ) and two Firmicutes taxa (g_Catenibacterium, g_Eubacterium ). The negative binomial results remained largely the same when we adjusted for weight changes. Conclusions and Relevance: This pilot longitudinal study showed changes in alpha diversity measures and abundance of select taxa that appeared to differ by chemotherapy type. Further investigations are needed to confirm these findings and to assess the impact of these microbiome changes on patient outcome.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993–1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98–1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm3) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07–1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers. Significance: Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer.

BackgroundPrior studies examining the association between ambient air pollutants and pancreatic cancer have been conducted in racially/ethnically homogeneous samples and have produced mixed results, with some studies supporting evidence of an association with fine particulate matter.MethodsTo further investigate these findings, we estimated exposure levels of particulate matter (PM2.5, PM10) and oxides of nitrogen (NOX, and NO2) using kriging interpolation for 100,527 men and women from the Multiethnic Cohort Study, residing largely in Los Angeles County from 1993 through 2013. We measured the association between these air pollutants and incident pancreatic cancer using Cox proportional hazards models with time-varying pollutant measures, with adjustment for confounding factors.ResultsA total of 821 incident pancreatic cancer and 1,660,488 person-years accumulated over the study period, with an average follow-up time of over 16 years. PM2.5 (per 10μg/m3) was associated with incident pancreatic cancer (hazard ratio [HR]=1.61; 95% CI, 1.09, 2.37). This PM2.5 -association was strongest among Latinos (HR=3.59; 95% CI, 1.60, 8.06) and ever smokers (HR=1.76; 95% CI, 1.05, 2.94). There was no association for PM10 (HR=1.12; 95% CI, 0.94, 1.32, per 10μg/m3), NOx (HR=1.14; 95% CI, 0.88, 1.48, per 50ppb), or NO2 (HR=1.14; 95% CI, 0.85, 1.54, per 20ppb).ConclusionsOur findings support prior research identifying an association between fine particulate matter, PM2.5, and pancreatic cancer. Although not statistically heterogeneous, this association was most notable among Latinos and smokers. Future studies are needed to replicate these results in an urban setting and in a racially/ethnically diverse population.

Exposure to bisphenol A (BPA), triclosan and parabens is widespread but their impact on breast cancer risk remains unclear. This nested case-control study investigated endocrine-disrupting chemicals (EDCs) and breast cancer risk within the Multiethnic Cohort (MEC). We measured prediagnostic urinary BPA, triclosan and parabens in 1032 postmenopausal women with breast cancer (48 African American, 77 Latino, 155 Native Hawaiian, 478 Japanese American and 274 White) and 1030 individually matched controls, using a sensitive and validated liquid chromatography mass spectrometry assay. Conditional logistic regression was used to examine risk with these EDCs with adjustment for creatinine and potential confounders. In all women, breast cancer risk was not associated with BPA (Ptrend = 0.53) and was inversely associated with triclosan (ORT3 vs T1 = 0.83, 95% CI: 0.66-1.04, Ptrend = 0.045) and total parabens (ORT3 vs T1 = 0.77, 95% CI: 0.62-0.97, Ptrend = 0.03). While risk of hormone receptor positive (HR+) cancer was 20% to 23% lower among women in the upper two tertiles of paraben exposure (Ptrend = 0.02), risk of HR negative (HR-) was reduced 27% but only among those in the upper tertile of exposure. Although risk associations did not differ significantly by ethnicity or by body mass index (BMI), the inverse association with triclosan was observed mainly among overweight/obese women (ORT3 vs T1 = 0.76, 95% CI: 0.56-1.02, Ptrend = 0.02). In summary, breast cancer risk in a multiethnic population was unrelated to BPA and was weakly inversely associated with triclosan and paraben exposures. Studies with multiple urine samples collected before breast cancer diagnosis are needed to further investigate these EDCs and breast cancer risk.

Simple Summary Breast cancer is the most common cancer in females worldwide. To date, many gene-environment interaction (GxE) studies have been conducted to better understand how genetic factors combine with environmental factors to influence risk. However, previous studies have not found or found only a few interactions by using SNPs which were discovered from genome-wide association studies and have been conducted, for the most part, within European populations. In this study, we focused on estrogen-related lifestyle factors that have been identified for breast cancer, including several well-established reproductive factors that are mediated by hormonal mechanisms. We aimed to examine whether there are any gene and environmental factor interactions related to estrogen exposure or metabolism using a candidate approach in Korean women. We found two interactions in this study, although they were not replicated in the independent large consortium data. These findings suggest specificity in Koreans for breast cancer risk. In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 x 10(-3)). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 x 10(-4)). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ) and California Line Source Dispersion model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 μg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [95% CI]: 1.02-1.79), NO2 (HR = 1.44, 95% CI: 1.04-1.99), PM10 (HR = 1.29, 95% CI: 1.07-1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01-1.45) and NO2 (HR = 1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near-roadway exposures, on the risk of breast cancer is warranted.

Background Medicare claims record linkage has been used to identify diagnosed dementia cases in order to estimate dementia prevalence and cost of care. Claims records in the 1990 s and early 2000 s have been found to provide 85% - ∼90% sensitivity and specificity. Objective Considering that dementia awareness has improved over time, we sought to examine sensitivity and specificity of more recent Medicare claims records against a standard criterion, clinical diagnosis of dementia. Methods For a sample of patients evaluated at the University of Southern California Alzheimer Disease Research Center (ADRC), we performed database linkage with Medicare claims files for a six-year period, 2007-2012. We used clinical diagnosis at the ADRC as the criterion diagnosis in order to calculate sensitivity and specificity. Results Medicare claims correctly identified 85% of dementia patients and 77% of individuals with normal cognition. About half of patients clinically diagnosed with mild cognitive impairment had dementia diagnoses in Medicare claims. Misclassified dementia patients (i.e., missed diagnosis by Medicare claims) had more favorable Mini-Mental State Examination and Clinical Dementia Rating scores and were less likely to present behavioral symptoms than correctly-classified dementia patients. Conclusions Database linkage to Medicare claims records is an efficient and reasonably accurate tool to identify dementia cases in a population-based cohort. However, possibilities of obtaining biased results due to misclassification of dementia status need to be carefully considered to use Medicare claims diagnosis for etiologic research studies. Additional confirmation of dementia diagnosis may also be considered. A larger study is warranted to confirm our findings.

Previous epidemiological evidence on air pollution and prostate cancer risk is limited, with few studies examining the time varying effects of air-pollution, and primarily among whites in the US and Canada. To further our understanding on this topic, we assessed ambient air pollutants in relation to prostate cancer incidence in a large multi-ethnic population. We included 33,830 men aged 45 years or older at baseline (1993-1996) who resided in Southern California at enrollment in the Multiethnic Cohort (24.5% African American, 15.1% Japanese American, 48.4% Latino, 0.2% Native Hawaiian, and 11.8% White). Until 2016, with a median of 20 years of follow-up, 4,540 prostate cancer cases were identified by linkage to the California SEER cancer registry. Monthly exposures to particulate matter with aerodynamic diameter ≤ 10 μm (PM10) and nitrogen oxides (NOx) per participant were estimated by Kriging interpolation based on air-monitoring data and residential addresses. We used Cox proportional hazards models to estimate the association between time-varying air-pollutant levels and prostate cancer risk, using age in months as the time metric. We adjusted for neighborhood socioeconomic status (nSES) at baseline and current nSES at event, education, race/ethnicity, smoking pack years, BMI, diabetes status, asthma history, and family history of prostate cancer, using age at cohort entry as the strata variable. The average NOx and PM10 over the study period was 73.1 parts per billion (ppb) and 38.1 μg/m3 in prostate cancer cases, respectively, and 60.9 ppb and 35.5 μg/m3 in men without prostate cancer, respectively. Across racial/ethnic groups, African Americans had the highest average NOx levels (74.3ppb) and Latinos had the highest average PM10 levels (39.0 μg/m3) over the study period. In the overall population, NOx per 50 ppb was statistically significantly associated with an increased risk of prostate cancer [hazard ratio (HR)=1.12, 95% confidence interval (CI): 1.01-1.25] and PM10 per 10 μg/m3 was associated with a suggestive increased risk (HR=1.07, 95%CI: 0.99-1.16). In analysis by race/ethnicity, statistically significant positive associations with NOx (HR=1.25, 95%CI: 1.07-1.46) and PM10 (HR=1.21, 95%CI: 1.07-1.38) were detected among African American, but not consistently in other racial/ethnic groups. In a subset of 21,537 men with no residential moves over the follow-up period, we observed positive associations for both NOx and PM10 similar to those among all men. In conclusion, our results suggest that both NOx and PM10 are associated with an increased risk of prostate cancer. Analyses of other air pollutants in relation to prostate cancer risk and disease aggressiveness are ongoing. Citation Format: Anqi Wang, Chiu-chen Tseng, Heather Rose, Iona Cheng, Anna H. Wu, Christopher A. Haiman. Ambient air pollution and risk of prostate cancer: The multiethnic cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1437.

Background The epidemiologic evidence from observational studies on breast cancer risk and phthalates, endocrine disrupting chemicals, has been inconsistent. In the only previous study based on pre-diagnostic urinary phthalates and risk of breast cancer, results were null in mostly white women. Methods We examined the association between pre-diagnostic urinary phthalates and breast cancer in a nested case-control study within the Multiethnic Cohort (MEC) study, presenting the first data from five major racial/ethnic groups in the USA. We measured 10 phthalate metabolites and phthalic acid, using a sensitive liquid chromatography mass spectrometry assay on 1032 women with breast cancer (48 African Americans, 77 Latinos, 155 Native Hawaiians, 478 Japanese Americans, and 274 Whites) and 1030 matched controls. Conditional logistic regression was used to examine risk with individual metabolites and ratios of primary (MEHP, mono-2-ethylhexyl-phthalate) to secondary (MEHHP, mono(2-ethyl-5-hydroxyhexyl); MEOHP, mono(2-ethyl-5-oxohexy)) metabolites of di-2-ethylhexyl phthalate (DEHP), a widely used plasticizer. In addition, we investigated risk associations with high (∑HMWP) and low molecular weight (∑LMWP) phthalates, as well as total phthalates which included high and low molecular weight phthalates with phthalic acid (∑LMHMPA) or without phthalic acid in molar ratios (∑LMHMmolar) and adjusted for creatinine and potential confounders. Results Among all women, breast cancer risk was higher for those in tertile 2 and tertile 3 of primary to secondary metabolites of DEHP (MEHP/(MEHHP + MEOHP)) in comparison to those in tertile 1; the respective odds ratios were 1.32 (95% CI 1.04–1.68) and 1.26 (95% CI 0.96–1.66) (Ptrend = 0.05). Risk among Native Hawaiian women increased with exposures to eight of ten individual phthalates and total phthalates (∑LMHMPA ORT3 vs T1 = 2.66, 95% CI 1.39–5.12, Ptrend = 0.001). In analysis by hormone receptor (HR) status, exposure above the median of ∑LMWP was associated with an increased risk of HR-positive breast cancer (OR = 1.30, 95% CI 1.05–1.60) while above the median exposure to phthalic acid was associated with an increased risk of HR-negative breast cancer (ORabove vs below median = 1.59, 95% CI 1.01–2.48). Conclusions Further investigations of suggestive associations of elevated breast cancer risk with higher ratios of primary to secondary metabolites of DEHP, and differences in risk patterns by race/ethnicity and HR status are warranted.

Background: Benzene is classified as a Group 1 carcinogen in humans. A major pathway of benzene exposure is through the inhalation of ambient air contaminated by emissions from motor vehicle exhaust, gas stations, industries, tobacco smoke, and other consumer products. Past studies on benzene and breast cancer based on job titles or occupational history have yielded mixed results and the role of ambient benzene and breast cancer risk has been sparsely studied. Within the California component of the Multiethnic Cohort study, we examined the association between outdoor exposure to benzene and breast cancer risk among four major U.S. racial/ethnic groups―African Americans, Latinos, Japanese Americans, and Whites. Methods: Outdoor ambient benzene exposure was estimated from U.S. EPA measurements from air monitoring stations that were within 15 km of residences of 57,589 female MEC participants, largely from Los Angeles County, from time of recruitment (1993-1996) through study end date (12/31/2010). Cox proportional hazards models were used to examine the associations between time-varying benzene exposure and invasive breast cancer risk (cases=2,388), adjusting for age, race/ethnicity, education, smoking pack-years, family history of breast cancer, body mass index, physical activity, parity and age at first live birth, age at menarche, menopausal status, use of hormone therapy, alcohol consumption, intake of total calories, and neighborhood (block group) socioeconomic status. Stratified analyses were conducted by race/ethnicity, smoking history, and hormone receptor status. Results: Outdoor ambient benzene exposure (average median level from 1993-2010 was 0.94 ppb) was associated with an increased risk of breast cancer (per 1 ppb hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.24-1.58). This positive association was observed across all racial/ethnic groups; HR ranged from 1.23 to 1.67 (p values were Citation Format: Ugonna Ihenacho, Jun Wu, Chiu-Chen Tseng, Juan Yang, Scott Fruin, Timothy Larson, Salma Shariff-Marco, Loic Le Marchand, Daniel Stram, Beate Ritz, Iona Cheng, Anna H. Wu. Association between outdoor ambient benzene and invasive breast cancer incidence: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-170.

There are little epidemiological data on the impact of persistent organic pollutants (POPs) and endocrine disruptors on mammographic density (MD), a strong predictor of breast cancer. We assessed MD in 116 non-Hispanic white post-menopausal women for whom serum concentrations of 23 commonly detected chemicals including 3 polybrominated diphenyl ethers (PBDEs), 8 per- and polyfluoroalkyl substances (PFASs), and 12 polychlorinated biphenyls (PCBs) had been measured. Linear regression analyses adjusting for potential confounders were used to examine the associations between the levels of the chemical compounds, modeled as continuous and dichotomized (above/below median) variables, and square-root-transformed MD. None of the associations were statistically significant after correcting for multiple testing. Prior to correction for multiple testing, all chemicals with un-corrected p-values < 0.05 had regression coefficients less than zero, suggesting inverse associations between increased levels and MD, if any. The smallest p-value was observed for PCB-153 (regression coefficient for above-median vs. below-median levels: −0.87, un-corrected p = 0.008). Neither parity nor body mass index modified the associations. Our results do not support an association between higher MD and serum levels of PBDEs, PCBs, or PFASs commonly detected in postmenopausal women.

ObjectiveTo investigate the association between gut microbiome with breast tumor characteristics (receptor status, stage and grade) and known breast cancer risk factors.MethodsIn a pilot cross-sectional study of 37 incident breast cancer patients, fecal samples collected prior to chemotherapy were analyzed by 16S ribosomal RNA (rRNA) gene-based sequencing protocol. Alpha diversity and specific taxa by tumor characteristics and breast cancer risk factors were tested by Wilcoxon rank sum test, and by differential abundance analysis, using a zero-inflated negative binomial regression model with adjustment for total counts, age and race/ethnicity.ResultsThere were no significant alpha diversity or phyla differences by estrogen/progesterone receptor status, tumor grade, stage, parity and body mass index. However, women with human epidermal growth factor receptor 2 positive (HER2+) (n = 12) compared to HER2− (n = 25) breast cancer showed 12–23% lower alpha diversity [number of species (OTU)p = 0.033, Shannon indexp = 0.034], lower abundance ofFirmicutes(p = 0.005) and higher abundance ofBacteroidetes(p = 0.089).Early menarche (ages ≤ 11) (n = 11) compared with later menarche (ages ≥ 12) (n = 26) was associated with lower OTU (p = 0.036), Chao1 index (p = 0.020) and lower abundance ofFirmicutes(p = 0.048). High total body fat (TBF) (> 46%) (n = 12) compared to lower (≤ 46%) TBF was also associated with lower Chao 1 index (p = 0.011). There were other significant taxa abundance differences by HER2 status, menarche age, as well as other tumor and breast cancer risk factors.Conclusions and relevanceFurther studies are needed to identify characteristics of the human microbiome and the interrelationships between breast cancer hormone receptor status and established breast cancer risk factors.

Increasing parity and duration of combined oral contraceptive (COC) use provide substantial protection against ovarian carcinoma (cancer). There are limited data on the impact of the age of the births or age of COC use on reducing ovarian cancer risk. Here, we examined the effects of age at first and last births and age at use of COCs using data from studies conducted in Los Angeles County, California, USA (1,632 cases, 2,340 controls). After adjusting for the number of births, every 5 years that a first birth was delayed reduced the risk of ovarian cancer by 13% (95% CI 5-21%; p = 0.003); a first birth after age 35 was associated with a 47% lower risk than a first birth before age 25. COC use before age 35 was associated with greater protection per year of use than COC use at older ages. Considering previously published results as well as the results presented here, increasing parity and a later age at births are both important protective factors against ovarian cancer and the protection extends over 30 or more years from last birth. Current models of the etiology of ovarian cancer do not encompass an effect of late age at births. Our result of an attenuation of the protective effect with COC use after around age 35 needs further investigation as it has not been seen in all studies.

Accumulating evidence suggests that the aggregation of common metabolic conditions (high blood pressure, diabetes and dyslipidemia) is a risk factor for breast cancer. Breast cancer incidence has risen steadily in Asian American women, and whether these metabolic conditions contribute to breast cancer risk in certain Asian American subgroups is unknown. We investigated the role of physician-diagnosed hypertension, high cholesterol and diabetes separately, and in combination, in relation to the risk of breast cancer in a population-based case-control study of 2,167 Asian Americans diagnosed with breast cancer and 2,035 age and ethnicity matched control women in Los Angeles County. Compared to Asian American women who did not have any of the metabolic conditions, those with 1, 2 or 3 conditions showed a steady increase in risk (respective odds ratios were 1.12, 1.42 and 1.62; P trend = 0.001) with adjustment for covariates including body mass index. Similar significant trends were observed in Filipina Americans (P trend = 0.021), postmenopausal women (P trend =0.001), Asian women who were born in the United States (US) (P trend = 0.052) and migrants who have lived in the US for at least 20 years (P trend = 0.004), but not migrants who lived in the US for

Background There are increasing concerns about the potential impact of air pollution on chronic brain inflammation and microglia cell activation, but evidence of its carcinogenic effects is limited. Methods We used kriging interpolation and land use regression models to estimate long-term air pollutant exposures of oxides of nitrogen (NOx, NO2), kriging interpolation for ozone (O3), carbon monoxide, and particulate matter (PM2.5, PM10), and nearest monitoring station measurements for benzene for 103 308 men and women from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993–1996) through 2013. We used Cox proportional hazards models to examine the associations between time-varying pollutants and risk of malignant brain cancer (94 men, 116 women) and meningioma (130 men, 425 women) with adjustment for sex, race and ethnicity, neighborhood socioeconomic status, smoking, occupation, and other covariates. Stratified analyses were conducted by sex and race and ethnicity. Results Brain cancer risk in men increased in association with exposure to benzene (hazard ratio [HR] = 3.52, 95% confidence interval [CI] = 1.55 to 7.55) and PM10 (HR = 1.80, 95% CI = 1.00 to 3.23). Stronger associations with PM10 (HR = 3.02, 95% CI = 1.26 to 7.23), O3 (HR = 2.93, 95% CI = 1.09 to 7.88), and benzene (HR = 4.06, 95% CI = 1.17 to 18.2) were observed among Latino men. Air pollution was unrelated to risk of meningioma except that O3 exposure was associated with risk in men (HR = 1.77, 95% CI = 1.02 to 3.06). Brain cancer risk in women was unrelated to air pollution exposures. Conclusions Confirmation of these sex differences in air pollution–brain cancer associations and the stronger findings in Latino men in additional diverse populations is warranted.

Common genetic variants in 183 loci have been identified in relation to breast cancer risk in genome-wide association studies (GWAS). These risk variants combined explain only a relatively small proportion of breast cancer heritability, particularly in Asian populations. To search for additional genetic susceptibility loci for breast cancer, we performed a meta-analysis of data from GWAS conducted in Asians (24,206 cases and 24,775 controls). Variants showing an association with breast cancer risk at P < 0.01 were evaluated in GWAS conducted in European women including 122,977 cases and 105,974 controls. In the combined analysis of data from both Asian and European women, the lead variant in 28 loci not previously reported showed an association with breast cancer risk at P < 5 ×10−8. In the meta-analysis of all GWAS data from Asian and European descendants, we identified SNPs in three additional loci in association with breast cancer risk at P < 5 ×10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). Expression quantitative trait locus (eQTL) and gene-based analyses provided evidence for the possible involvement of the YBEY, MAN2C1, SNUPN, TBX1, SEMA4A, STC1, MUTYH, LOXL2, and LINC00886 genes underlying the associations observed in eight of these 28 newly identified risk loci. In addition, we replicated the association for 78 of the 166 previously reported risk variants at P < 0.05 in women of Asian descent using GWAS data. These findings improve our understanding of breast cancer genetics and etiology and extend to Asian populations previous findings from studies of European women.

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P, In breast cancer, genome-wide associations studies (GWAS) have highlighted loci associated with disease risk. Here, the authors perform a meta-analysis of GWAS data from Asian populations, discovering 31 potential new risk loci, 10 of which are validated in an independent disease cohort.

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium.METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

Background: There are limited studies that have investigated the association between ambient gaseous and particulate matter (PM) air pollutants and risk of pancreatic cancer. Results from published studies are inconsistent, the strongest evidence was a significant, 16% increase in risk of pancreatic cancer mortality per 10 µg/m3 increase in PM Citation Format: David Bogumil, Anna H. Wu, Daniel Stram, Chiu-Chen Tseng, Iona Cheng, Veronica Wendy Setiawan. Air pollution in relation to risk of pancreatic cancer in the Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-184.

Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype. Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18–1.52) and without (HR=1.22, 95% CI: 1.12–1.33) further adjustment for residual disease, respectively. Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Contains fulltext : 170949.pdf (Publisher’s version ) (Closed access) BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

Background: There are now 3.1 million breast cancer (BC) survivors with 4.5 million survivors projected by 2030. This high and growing burden speaks to the need of identifying modifiable factors that influence BC survival. Particulate matter (PM) air pollutants have been associated with increased mortality for cardiovascular disease (CVD) and several cancers. However, few studies have examined the impact of air pollution on mortality among BC cases. Within the Multiethnic Cohort (MEC), we examined the association between outdoor air pollution and mortality among African American (AA), Latino (LA), Japanese American (JA), and White (WH) women diagnosed with BC. Methods: Kriging interpolation of air pollution data from air monitoring stations was used to estimate PM2.5, PM10, and nitrogen oxides (NOx, NO2) exposures for 3,089 BC cases in the MEC, residing largely in Los Angeles County, linked to residential histories from date of diagnosis to date of death or 12/31/2013. Cox proportional hazard models were used to examine the association between time-varying air pollutants and mortality, accounting for age at diagnosis, race/ethnicity, marital status, chemotherapy, hormone therapy, radiation, surgery, stage, grade, hormone receptor status, tumor size, body mass index, smoking, alcohol, age at first birth, diabetes, CVD, and neighborhood socioeconomic status. All-cause, BC, CVD, non-BC/non-CVD mortality outcomes were evaluated. Stratified analyses were conducted by race/ethnicity, hormone receptor status, and stage. Results: Among the 3,089 BC cases, there were 1,125 all-cause deaths (474 BC, 272 CVD, and 379 non-BC/non-CVD) with an average of 8.1 years of follow-up. PM2.5 (per 10μg/m3), PM10 (per 10μg/m3), NOx (per 50 ppb), and NO2 (per 20 ppb) were associated with risk of all-cause (hazard ratios (HRs) range=1.25-1.72; p’s Citation Format: Iona Cheng, Juan Yang, Chiuchen Tseng, Jun Wu, Shannon M Conroy, Salma Shariff-Marco, Scarlett Lin Gomez, Alice Whittemore, Daniel O Stram, Loic Le Marchand, Lynne R Wilkens, Beate Ritz, Anna H Wu. Association between outdoor air pollution and breast cancer survival: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C050.

Background: Phthalates (Phth), known endocrine-disruptors, may play a role in breast carcinogenesis. Low-molecular-weight phthalates (LMWPhth) are commonly found in personal care products while high MWPhth (HMWPhth) are used primarily as plasticizers. Individual Phth may disrupt normal mammary gland development and promote tumorigenesis by binding to and activating the estrogen receptor (ER). Methods: We prospectively examined the association between pre-diagnostic urinary levels of Phth metabolites and breast cancer risk in a case-control study nested within the Multiethnic Cohort (MEC). We measured 11 Phth metabolites and phthalic acid from overnight/first morning urine samples of 798 women with invasive breast cancer (355 Japanese Americans, 218 Whites, 125 Native Hawaiians, 62 Latinos, and 38 African Americans; the latter three groups were combined due to small numbers) and 796 matched controls using an ultrasensitive isotope dilution orbitrap LCMS assay after hydrolysis from conjugation, extraction, and concentration. Average time between urine collection and breast cancer diagnosis was 5.5 years (SD=3.3). Cases and controls were 1:1 matched on area (Hawaii or California), birth year (± 1 year), race/ethnicity, urine type (overnight or first morning), and date of urine collection (± 1 year). Association of LMWPhth (MBP, MiBP, MEP, MMP), HMWPhth (MBzP, MEHP, MEHHP, MEOHP, MECPP, MCMHP, MCHP), and total Phth exposure (LMWPhth + HMWPhth), and phthalic acids with breast cancer risk were examined using conditional logistic regression. All models were adjusted for creatinine levels, demographics, and potential confounders (e.g., education and established breast cancer risk factors). Stratified analyses were conducted by race/ethnicity and ER and progesterone receptor (PR) status. Results: Women in the highest tertile (T3) of total Phth exposure showed a significant increased risk of breast cancer compared to women in the lowest tertile (T1) (HR=1.36, 95% CI: 1.02-1.82). The association was suggested across race/ethnicity with a statistically significant positive association observed in the three smaller groups combined (Native Hawaiians, Latinos, and African Americans) with HR for T2=2.29 (95% CI: 1.27-4.41) and HR for T3=2.42 (95% CI: 1.25-4.70); Ptrend=0.006. By ERPR status, risk associations tended to be stronger for ER-PR- (n=96 cases) (HR=1.13, 95% CI: 0.89-1.45) than for ER+PR+ (n=694 cases) (HR=1.06, 95% CI: 0.94-1.19) breast tumors. Among the three smaller groups combined, total Phth exposure was associated with a significant increased risk of ER-PR- breast cancer (n=38 cases) (P=0.045). Conclusion: This is one of the first studies of Phth exposure and breast cancer to include large numbers of diverse populations in a single study. Risk patterns were stronger among the combined group of Native Hawaiians, Latinos, and African American and for ER-PR- breast cancer. Better understanding of these differences in risk associations by race/ethnicity and ERPR status is needed. This abstract is also being presented as Poster D100. Citation Format: Anna H. Wu, Adrian A. Franke, Chiuchen Tseng, Shannon M. Conroy, Yuqing S. LI, Mindy DeRouen, Linda Polfus, Christian Caberto, Daniel Stram, Chris Haiman, Lynne R. Wilkens, Loic Le Marchand, Iona Cheng. Exposure to phthalates and risk of invasive breast cancer: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR06.

Background: The etiology of malignant brain cancer remains largely unknown. The two established risk factors, ionizing radiation and a history of allergies or atopic disease, explain less than 10% of the disease. In 2012, the International Agency for Research on Cancer classified air pollution and particulate matter (PM) as carcinogenic to humans (Group 1). The carcinogenic effects of air pollution may reach the brain via the systemic circulation, crossing the blood-brain barrier. There are increasing concerns about the potential impact of air pollution on outcomes of central nervous system (CNS), including chronic brain inflammation and microglia cell activation, but evidence of its carcinogenic effects is still limited. Methods: Kriging interpolation of air pollution data from monitoring stations were used to estimate long-term exposures of particulate matter pollutants (PM2.5, PM10), gaseous pollutants (oxides of nitrogen (NOx, NO2), ozone (O3), carbon monoxide (CO), and air toxics (benzene) for 103,308 men and women from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) at age 45-75 through 12/31/2013. Cox proportional hazards models were used to examine the associations between time-varying air pollutant levels and risk of malignant brain cancer (95 men, 116 women) and meningioma (130 men, 425 women) with adjustment for sex, race/ethnicity, neighborhood socioeconomic status, smoking, occupation, and other covariates. Stratified analyses were conducted by sex and race/ethnicity (African Americans, Japanese Americans, Latinos, Whites). Results: In men and women combined, risk of malignant brain cancer appeared to be increased in association with higher exposure to benzene (per 1 ppb HR=1.68, 95% CI:1.00-2.83), O3 (per 10 ppb HR=1.54, 95% CI: 0.95-2.51) and PM10(per 10 μg/m3 HR=1.24, 95% CI: 0.84-1.82) Malignant brain cancer associations with benzene (P=0.002) as well as PM10 (P=0.03) were driven by the results in men, although the interaction by sex did not reach statistical significance. Brain cancers in Latino men and women accounted for about half of the number of malignant brain cancers in this analysis. Subgroup analyses suggested stronger associations of risk of malignant brain cancer and exposure to PM10 (P=0.03), O3 (P=0.01), and benzene (P=0.03) in Latino men but not in Latino women. There were no significant associations between air pollution and risk of meningioma, except for a positive association with O3 exposure (P=0.04) in men. Conclusions: To our knowledge, this is one of the first studies of air pollution and malignant and benign brain cancers to include large numbers of nonwhites and to examine risk patterns by sex. The stronger findings in Latino men and the suggestive male/female differences in results are intriguing as there are parallel sex differences in rates of brain diseases and in survival. Confirmation of these air pollution-brain cancer associations in additional diverse populations is warranted. Citation Format: Anna H Wu, Jun Wu, Chiuchen Tseng, Juan Yang, Salma Shariff-Marco, Veronica W Setiawan, Shahir Masri, Jennifer Jain, Jacqueline Porcel, Scott Fruin, Timothy Larson, Florence Hofman, Thomas Chen, Loic Le Marchand, Daniel Stram, Beate Ritz, Iona Cheng. Association between outdoor air pollution and risk of malignant and benign brain diseases: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C068.

Background: Benzene is classified as a Group 1 carcinogen in humans. A major pathway of benzene exposure is through inhalation of ambient air contaminated by emissions from motor vehicle exhaust, gas stations, industry, tobacco smoke, and other consumer products. Prior studies of benzene and lung cancer have been limited largely to occupational studies. We examined the association between outdoor air exposure to benzene and lung cancer risk in the large population-based Multiethnic Cohort Study (MEC), including four major U.S. racial/ethnic groups—African Americans, Latinos, Japanese Americans, and Whites. Methods: Ambient benzene exposure was estimated from EPA data from air monitoring stations that were within 20 km of residences of 97,288 MEC participants, largely from Los Angeles County, from the time-period of recruitment (1993-1996) through 12/31/2013. Cox proportional hazards models were used to examine the associations between time-varying benzene exposure and lung cancer risk (cases=2796), adjusting for age, sex, race/ethnicity, smoking, family history of lung cancer, marital status, education, occupation, use of nonsteroidal anti-inflammatory drugs, body mass index, alcohol consumption, physical activity, intake of total calorie, red and processed meats, and neighborhood (block group) socioeconomic status. Stratified analyses were conducted by sex, race/ethnicity, and smoking status. In addition, subgroup analysis was conducted by histologic cell-type (adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell, and not otherwise specified carcinoma). Results: Ambient benzene exposure was associated with increased risk of lung cancer (per 1 ppb hazard ratio (HR)=1.18; 95% CI: 1.03-1.35). Slightly higher hazard ratios were observed in females (HR=1.28; 95% CI: 1.05-1.56) in comparison to males (HR=1.12; 95% CI: 0.92-1.35). There was evidence of heterogeneity in associations by race/ethnicity (p heterogeneity=0.02). Specifically, benzene exposure was associated with increased lung cancer risk among African Americans, Japanese Americans, and Latinos (HR ranged 1.18 to 1.42 per 1 ppb), but was inversely associated with risk among Whites. Also, similar associations were seen among ever smokers (HR=1.19; 95% CI: 1.03-1.37) and never smokers (HR=1.25; 95% CI: 0.82-1.89). Across histologic-cell types, a borderline statistically significant association was seen with adenocarcinoma, the most common cell type (HR=1.25, 95% CI: 0.99-1.58). A smaller hazard ratio was observed for squamous cell carcinoma, the stronger smoking-related cell type (HR=1.09, 95% CI: 0.81-1.47). Conclusions: Benzene exposure adversely impacts the risk of lung cancer in the general population but particularly in non-Whites after adjusting for smoking, occupational and other exposures. Additional large population-based studies are needed to confirm this finding and reinforce the need for stringent clear air laws. Citation Format: Iona Cheng, Chiuchen Tseng, Jun Wu, Juan Yang, Salma Shariff-Marco, Jennifer Jain, S. Lani Park, Scott Fruin, Timothy Larson, Scarlett Lin Gomez, Lynne Wilkens, Daniel Stram, Loic Le Marchand, Beate Ritz, Anna H Wu. Association between benzene, a hazardous air pollutant, and lung cancer risk: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C052.

Introduction: California has one of the highest levels of air pollution in the nation. Vehicle exhaust contains a mixture of gases and particulate matter that are known to have mutagenic and carcinogenic effects. Our objective was to examine the association between specific traffic-related air pollutants and lung cancer risk by race/ethnicity and sex among participants of the Multiethnic Cohort Study (MEC), residing predominately in Los Angeles County. Methods: Residential addresses from baseline, 1993-1996, through 2013 for over 112,000 California MEC participants were geocoded to latitude and longitude coordinates and used to estimate air pollutant exposures of NO2, NOX, PM10, CO, and O3 based on Bayesian kriging interpolation of state and national government air monitoring data. A total of 2,994 incident lung cancer cases (1,415 African Americans, 732 Latinos, 516 Whites, and 327 Japanese Americans) were identified by linkage to the California Cancer Registry. Cox proportional hazard regression was conducted to examine the long-term effects of NO2, NOX, PM10, CO, and O3 adjusting for age, race/ethnicity, sex, education, health behaviors, smoking, and other established lung cancer risk factors. Stratified analyses were conducted by sex, race/ethnicity, and smoking status. Results: Lung cancer risk increased per 20 ppb NO2 among women (HR=1.29; 95% CI: 1.02-1.64) with consistent patterns of associations observed among African American, Japanese American, and White women. A slightly larger increased risk was observed among ever-smoking women (HR=1.33; 95% CI: 1.02-1.74), particularly ever-smoking African American women (HR=1.54; 95% CI: 1.06, 2.24). In addition, a statistically significant increased lung cancer risk was observed per 10ug/m3 increase in PM10 among ever-smoking women (HR=1.16; 95% CI: 1.01-1.34) and per 100 ppb increase in CO among women (HR=1.05; 95% CI: 1.01-1.09). No significant associations with lung cancer were detected among men. Conclusion: These preliminary findings suggest that women of diverse racial/ethnic groups may be particularly vulnerable to the effects of long-term exposures of NO2, PM10, and CO on lung cancer risk. These findings among women in contrast to men may relate to differences in residential exposures with higher sensitivity or more time spent in residential neighborhoods for women in comparison to men. Future analyses will examine associations with other pollutants using different exposure assessment approaches and examine differences in associations by neighborhood- and individual-level factors. Citation Format: Iona Cheng, Shannon M. Conroy, Chiuchen Tseng, Juan Yang, Shahir Masri, Timothy Larson, Scott Fruin, Jennifer Jain, Loic Le Marchand, Jonathan Samet, Scarlett Lin Gomez, Veronica Wendy Setiawan, Sung-Shim Lani Park, Daniel O. Stram, Salma Shariff-Marco, Beate Ritz, Jun Wu, Anna H. Wu. Ethnic and sex differences in exposure to traffic-related air pollutants and lung cancer incidence: The Multiethnic Cohort [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A119.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology., Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Background:\ud \ud Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.\ud Methods:\ud \ud We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.\ud Results:\ud \ud Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01–1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01–1.11) and borderline (pOR = 1.15; 95% CI: 1.02–1.29) tumours.\ud Conclusions:\ud \ud Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Background: Risk factors for invasive epithelial ovarian cancer (IEOC) among Hispanics and African Americans are understudied despite notable differences in incidence relative to non-Hispanic whites. Methods: We used multivariate logistic regression to examine parity, oral contraceptive use, tubal ligation, endometriosis, family history of ovarian cancer, and talc use and risk of IEOC among Hispanics (308 cases and 380 controls), African Americans (128 cases and 143 controls), and non-Hispanic whites (1,265 cases and 1,868 controls) using four case–control studies we conducted in Los Angeles County. We expressed each of these factors in the form of increasing risk and calculated population attributable risk percentage (PAR%) estimates for the six risk factors separately and jointly in the three groups. Results: The risk associations with these six well-accepted factors were comparable in the three groups. The significant racial/ethnic differences in the prevalence of these factors and differences in their oophorectomy rates explained 31% of the lower incidence in African Americans compared with non-Hispanic whites, but only 13% of the lower incidence in Hispanics. The PAR%s ranged from 27.5% to 31.0% for no tubal ligation, 15.9% to 22.2% for not using oral contraceptives, and 12.2% to 15.1% for using talc in the three groups. Conclusions: All six risk factors are comparably important in the three groups. Differences in the prevalence of these factors and their oophorectomy rates explained approximately one third of the difference in incidence between African Americans and non-Hispanic whites. Impact: Devising strategies to lessen the burden of IEOC will be applicable to all three racial/ethnic groups. Cancer Epidemiol Biomarkers Prev; 24(7); 1094–100. ©2015 AACR.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

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

Accumulating evidence suggests that the aggregation of common metabolic conditions (high blood pressure, diabetes and dyslipidemia) is a risk factor for breast cancer. Breast cancer incidence has risen steadily in Asian American women, and whether these metabolic conditions contribute to breast cancer risk in certain Asian American subgroups is unknown. We investigated the role of physician-diagnosed hypertension, high cholesterol and diabetes separately, and in combination, in relation to the risk of breast cancer in a population-based case-control study of 2,167 Asian Americans diagnosed with breast cancer and 2,035 age and ethnicity matched control women in Los Angeles County. Compared to Asian American women who did not have any of the metabolic conditions, those with 1, 2 or 3 conditions showed a steady increase in risk (respective odds ratios were 1.12, 1.42 and 1.62; P trend = 0.001) with adjustment for covariates including body mass index. Similar significant trends were observed in Filipina Americans (P trend = 0.021), postmenopausal women (P trend =0.001), Asian women who were born in the United States (US) (P trend = 0.052) and migrants who have lived in the US for at least 20 years (P trend = 0.004), but not migrants who lived in the US for20 years (P trend = 0.64). These results suggest that westernization in lifestyle (diet and physical inactivity) and corresponding increase in adiposity have contributed to the rising prevalence of these metabolic conditions, which in turn, are associated with an increase in breast cancer.