Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study.

PURPOSE: Recent studies suggested fine particulate matter (PM2.5) exposure increases the risk of breast cancer, but evidence among racially and ethnically diverse populations remains sparse. MATERIALS AND METHODS: Among 58,358 California female participants of the Multiethnic Cohort (MEC) Study followed for an average of 19.3 years (1993-2018), we used Cox proportional hazards regression to examine associations of time-varying PM with invasive breast cancer risk (n = 3,524 cases; 70% African American and Latino females), adjusting for sociodemographics and lifestyle factors. Subgroup analyses were conducted for race and ethnicity, hormone receptor status, and breast cancer risk factors. RESULTS: Satellite-based PM2.5 was associated with a statistically significant increased incidence of breast cancer (hazard ratio [HR] per 10 µg/m3, 1.28 [95% CI, 1.08 to 1.51]). We found no evidence of heterogeneity in associations by race and ethnicity and hormone receptor status. Family history of breast cancer showed evidence of heterogeneity in PM2.5-associations (Pheterogeneity = .046). In a meta-analysis of the MEC and 10 other prospective cohorts, breast cancer incidence increased in association with exposure to PM2.5 (HR per 10 µg/m3 increase, 1.05 [95% CI, 1.00 to 1.10]; P = .064). CONCLUSION: Findings from this large multiethnic cohort with long-term air pollutant exposure and published prospective cohort studies support PM2.5 as a risk factor for breast cancer. As about half of breast cancer cannot be explained by established breast cancer risk factors and incidence is continuing to increase, particularly in low- and middle-income countries, our results highlight that breast cancer prevention should include not only individual-level behavior-centered approaches but also population-wide policies and regulations to curb PM2.5 exposure.

Association between Airport Ultrafine Particles and Lung Cancer Risk: The Multiethnic Cohort Study.

BACKGROUND: Ultrafine particles (UFP) are unregulated air pollutants abundant in aviation exhaust. Emerging evidence suggests that UFPs may impact lung health due to their high surface area-to-mass ratio and deep penetration into airways. This study aimed to assess long-term exposure to airport-related UFPs and lung cancer incidence in a multiethnic population in Los Angeles County. METHODS: Within the California Multiethnic Cohort, we examined the association between long-term exposure to airport-related UFPs and lung cancer incidence. Multivariable Cox proportional hazards regression models were used to estimate the effect of UFP exposure on lung cancer incidence. Subgroup analyses by demographics, histology and smoking status were conducted. RESULTS: Airport-related UFP exposure was not associated with lung cancer risk [per one IGR HR, 1.01; 95% confidence interval (CI), 0.97-1.05] overall and across race/ethnicity. A suggestive positive association was observed between a one IQR increase in UFP exposure and lung squamous cell carcinoma (SCC) risk (HR, 1.08; 95% CI, 1.00-1.17) with a Phet for histology = 0.05. Positive associations were observed in 5-year lag analysis for SCC (HR, 1.12; 95% CI, CI, 1.02-1.22) and large cell carcinoma risk (HR, 1.23; 95% CI, 1.01-1.49) with a Phet for histology = 0.01. CONCLUSIONS: This large prospective cohort analysis suggests a potential association between airport-related UFP exposure and specific lung histologies. The findings align with research indicating that UFPs found in aviation exhaust may induce inflammatory and oxidative injury leading to SCC. IMPACT: These results highlight the potential role of airport-related UFP exposure in the development of lung SCC.

Association of Endocrine Disrupting Chemicals With the Metabolic Syndrome Among Women in the Multiethnic Cohort Study.

Metabolic syndrome (MetS) is associated with a high risk of cardiovascular disease, a leading cause of death among women. MetS is a diagnosis of at least 3 of the following: high blood pressure, high fasting glucose, high triglycerides, high waist circumference, and low high-density lipoprotein cholesterol. Epidemiological studies suggest that endocrine disrupting chemical (EDC) exposure is positively associated with individual components of MetS, but evidence of an association between EDCs and MetS remains inconsistent. In a cross-sectional analysis within the Multiethnic Cohort Study, we evaluated the association between 4 classes of urinary EDCs (bisphenol A [BPA], triclosan, parabens, and phthalates) and MetS among 1728 women. Multivariable logistic regression was used to estimate odds ratios and 95% CI for the association between tertiles of each EDC and MetS adjusting for age, body mass index (BMI), racial and ethnic group, and breast cancer status. Stratified analyses by race and ethnicity and BMI were conducted. MetS was identified in 519 (30.0%) women. We did not detect statistically significant associations of MetS with BPA, triclosan, or phthalate metabolite excretion. MetS was inversely associated with total parabens (Ptrend = .002). Although there were suggestive inverse associations between EDCs and MetS among Latino and African American women, and women with BMI < 30 kg/m2, there was no statistically significant heterogeneity in associations by race and ethnicity or BMI. These findings suggest an inverse association between parabens and MetS in larger multiethnic studies. Prospective analyses to investigate suggested differences in associations by race, ethnicity, and BMI are warranted.

Effect of Chemotherapy on the Gut Microbiome of Breast Cancer Patients During the First Year of Treatment.

Introduction: There is accumulating information of the effects of chemotherapy and weight changes on the gut microbiome of breast cancer patients. Methods: In this 1-year follow-up study, we investigated gut microbiome of 33 breast cancer patients who donated fecal samples at baseline and after completion of treatment. We compared alpha diversity and mean taxa abundance at baseline and absolute taxa abundance changes (final-baseline) by treatment (16 neoadjuvant [neoADJ], 13 adjuvant [ADJ], 4 no chemotherapy [noC]) and specific chemotherapy agent using Wilcoxon rank sum and negative binomial mixed model (NBMM) analysis. Results: All four gut alpha diversity measures changed in association with chemotherapy treatment; they increased in the neoADJ (+16.4% OTU p = 0.03; +51.6% Chao1 p = 0.03; +7.0% Shannon index p = 0.02; +11.0% PD whole tree p = 0.09) but not in the ADJ and noC group (ADJ+noC). The difference in Chao1 index change between groups was statistically significant (pneoADJ vs. ADJ+noC=0.04). Wilcoxon p values of 0.03-0.003 were observed for five taxa. In NBMM analysis, changes in taxa abundance differed (Bonferroni-adjusted p ≤ 0.0007) for two Bacteroidetes taxa (g_Alistipes, f_S24-7) and two Firmicutes taxa (g_Catenibacterium, g_Eubacterium). NBMM analysis results remained unchanged with adjustment for weight changes. Alpha diversity changes were also found by receipt of chemotherapy agents. Consistent increases in alpha diversity were observed among those treated with TCHP (OTU p = 0.009; Chao1 p = 0.02; Shannon p = 0.02; PD whole tree p = 0.05) but not AC, Taxol or Herceptin. Those treated with TCHP or Herceptin showed increases in Verrucomicrobia (g_Akkermansia) but decreases of Bacteroidetes(g_Alistipes); the differences in changes in taxa abundance were statistically significant. Conclusion: Results from this pilot longitudinal study support an effect of chemotherapy, particularly neoADJ on the gut microbiome of breast cancer patients even after adjustment for weight changes. Further investigations are needed to confirm these findings in larger studies and with longer follow-up and to assess the impact of these microbiome changes on patient outcome.

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Traffic-related Air Pollution and Lung Cancer Incidence: The California Multiethnic Cohort Study.

Rationale: Although the contribution of air pollution to lung cancer risk is well characterized, few studies have been conducted in racially, ethnically, and socioeconomically diverse populations. Objectives: To examine the association between traffic-related air pollution and risk of lung cancer in a racially, ethnically, and socioeconomically diverse cohort. Methods: Among 97,288 California participants of the Multiethnic Cohort Study, we used Cox proportional hazards regression to examine associations between time-varying traffic-related air pollutants (gaseous and particulate matter pollutants and regional benzene) and lung cancer risk (n = 2,796 cases; average follow-up = 17 yr), adjusting for demographics, lifetime smoking, occupation, neighborhood socioeconomic status (nSES), and lifestyle factors. Subgroup analyses were conducted for race, ethnicity, nSES, and other factors. Measurements and Main Results: Among all participants, lung cancer risk was positively associated with nitrogen oxide (hazard ratio [HR], 1.15 per 50 ppb; 95% confidence interval [CI], 0.99-1.33), nitrogen dioxide (HR, 1.12 per 20 ppb; 95% CI, 0.95-1.32), fine particulate matter with aerodynamic diameter <2.5 µm (HR, 1.20 per 10 µg/m3; 95% CI, 1.01-1.43), carbon monoxide (HR, 1.29 per 1,000 ppb; 95% CI, 0.99-1.67), and regional benzene (HR, 1.17 per 1 ppb; 95% CI, 1.02-1.34) exposures. These patterns of associations were driven by associations among African American and Latino American groups. There was no formal evidence for heterogeneity of effects by nSES (P heterogeneity > 0.21), although participants residing in low-SES neighborhoods had increased lung cancer risk associated with nitrogen oxides, and no association was observed among those in high-SES neighborhoods. Conclusions: These findings in a large multiethnic population reflect an association between lung cancer and the mixture of traffic-related air pollution and not a particular individual pollutant. They are consistent with the adverse effects of air pollution that have been described in less racially, ethnically, and socioeconomically diverse populations. Our results also suggest an increased risk of lung cancer among those residing in low-SES neighborhoods.

Outdoor ambient air pollution and breast cancer survival among California participants of the Multiethnic Cohort Study.

BACKGROUND: Within the Multiethnic Cohort (MEC), we examined the association between air pollution and mortality among African American, European American, Japanese American, and Latina American women diagnosed with breast cancer. METHODS: We used a land use regression (LUR) model and kriging interpolation to estimate nitrogen oxides (NOx , NO2) and particulate matter (PM2.5, PM10) exposures for 3,089 breast cancer cases in the MEC, who were diagnosed from 1993 through 2013 and resided largely in Los Angeles County, California. Cox proportional hazards models were used to examine the association of time-varying air pollutants with all-cause, breast cancer, cardiovascular disease (CVD), and non-breast cancer/non-CVD mortality, accounting for key covariates. RESULTS: We identified 1,125 deaths from all causes (474 breast cancer, 272 CVD, 379 non-breast cancer/non-CVD deaths) among the 3,089 breast cancer cases with 8.1 years of average follow-up. LUR and kriged NOX (per 50 ppb) and NO2 (per 20 ppb), PM2.5 (per 10 µg/m3), and PM10 (per 10 µg/m3) were positively associated with risks of all-cause (Hazard Ratio (HR) range = 1.13-1.25), breast cancer (HR range = 1.19-1.45), and CVD mortality (HR range = 1.37-1.60). Associations were statistically significant for LUR NOX and CVD mortality (HR = 1.60; 95% CI: 1.08-2.37) and kriged NO2 and breast cancer mortality (HR = 1.45; 95% CI 1.02-2.07). Gaseous and PM pollutants were positively associated with breast cancer mortality across racial/ethnic group. CONCLUSION: In this study, air pollutants have a harmful impact on breast cancer survival. Additional studies should evaluate potential confounding by socioeconomic factors. These data support maintaining clean air laws to improve survival for women with breast cancer.

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.

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.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

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.

The association between ambient air pollutants and pancreatic cancer in the Multiethnic Cohort Study.

BACKGROUND: Prior 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. METHODS: To 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. RESULTS: A 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 10 µg/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 10 µg/m3), NOx (HR = 1.14; 95% CI, 0.88, 1.48, per 50 ppb), or NO2 (HR = 1.14; 95% CI, 0.85, 1.54, per 20 ppb). CONCLUSIONS: Our 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.

Association between Airport-Related Ultrafine Particles and Risk of Malignant Brain Cancer: A Multiethnic Cohort Study.

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.

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

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 × 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 × 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.

Risk of breast cancer and prediagnostic urinary excretion of bisphenol A, triclosan and parabens: The Multiethnic Cohort Study.

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.

Urinary phthalate exposures and risk of breast cancer: the Multiethnic Cohort study.

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.

Gut microbiome associations with breast cancer risk factors and tumor characteristics: a pilot study.

OBJECTIVE: To investigate the association between gut microbiome with breast tumor characteristics (receptor status, stage and grade) and known breast cancer risk factors. METHODS: In 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. RESULTS: There 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 index p = 0.034], lower abundance of Firmicutes (p = 0.005) and higher abundance of Bacteroidetes (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 of Firmicutes (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 RELEVANCE: Further 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.

Association Between Outdoor Air Pollution and Risk of Malignant and Benign Brain Tumors: The Multiethnic Cohort Study.

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.

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

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 < 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). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.

Serum Levels of Commonly Detected Persistent Organic Pollutants and Per- and Polyfluoroalkyl Substances (PFASs) and Mammographic Density in Postmenopausal Women.

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.

Association between ambient air pollution and breast cancer risk: The multiethnic cohort study.

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.

The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium.

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.