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Study Question: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations?Summary Answer: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals.What Is Known Already: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women.Study Design, Size, Duration: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication.Participants/materials, Setting, Methods: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry.Main Results and the Role Of Chance: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals.Large Scale Data: N/A.Limitations, Reasons For Caution: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited.Wider Implications Of the Findings: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations.Study Funding/competing Interest(s): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare. [ABSTRACT FROM AUTHOR]

Background:Alcohol is an important risk factor for breast cancer in Caucasian women, but the evidence in African-American (AA) women is limited and results are inconclusive.Methods:Associations between recent and lifetime drinking and breast cancer risk were evaluated in a large sample of AA women from a case-control study in New York and New Jersey. Multivariable logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs).Results:There was no association between recent drinking and breast cancer risk, even when stratified by menopausal status or by hormone receptor status. A borderline decreased risk with increased lifetime consumption was found (OR=0.77; 95% CI: 0.58-1.03), which was stronger among women who drank when under 20 years of age (OR=0.65; 95% CI: 0.47-0.89), regardless of menopausal or hormone receptor status.Conclusion:Breast cancer risk associated with recent alcohol consumption was not apparent in AA women, while early age drinking seemed to decrease risk. This is the first investigation on recent and lifetime drinking in subgroups and drinking during different age periods in AA women. If findings are replicated, racial differences in biological pathways involving alcohol and its metabolites should be explored. [ABSTRACT FROM AUTHOR]

Abstract Background Inverse associations between cruciferous vegetable intake and lung cancer risk have been consistently reported. However, associations within smoking status subgroups have not been consistently addressed. Methods We conducted a hospital-based case-control study with lung cancer cases and controls matched on smoking status, and further adjusted for smoking status, duration, and intensity in the multivariate models. A total of 948 cases and 1743 controls were included in the analysis. Results Inverse linear trends were observed between intake of fruits, total vegetables, and cruciferous vegetables and risk of lung cancer (ORs ranged from 0.53-0.70, with P for trend < 0.05). Interestingly, significant associations were observed for intake of fruits and total vegetables with lung cancer among never smokers. Conversely, significant inverse associations with cruciferous vegetable intake were observed primarily among smokers, in particular former smokers, although significant interactions were not detected between smoking and intake of any food group. Of four lung cancer histological subtypes, significant inverse associations were observed primarily among patients with squamous or small cell carcinoma - the two subtypes more strongly associated with heavy smoking. Conclusions Our findings are consistent with the smoking-related carcinogen-modulating effect of isothiocyanates, a group of phytochemicals uniquely present in cruciferous vegetables. Our data support consumption of a diet rich in cruciferous vegetables may reduce the risk of lung cancer among smokers.

Importance: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 are associated with increased breast cancer risk. However, it is unknown whether breast cancer risk differs by PV type or location in carriers ascertained from the general population., Objective: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 ., Design: Age adjusted case-control association analysis for all participants, subsets of PV carriers, and women with no breast cancer family history in population-based and clinical testing cohorts., Setting: Twelve US population-based studies within the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium, and breast cancer cases from the UK-Biobank and an Ambry Genetics clinical testing cohort., Participants: 32,247 women with and 32,544 age-matched women without a breast cancer diagnosis from CARRIERS; 237 and 1351 women with BRCA2 PVs and breast cancer from the UKBB and Ambry Genetics, respectively., Exposures: PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2., Main Outcomes and Measures: PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and p-values) using logistic regression. Mean ages at diagnosis were compared using linear regression., Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex13-27 PTVs (OR=2.7, 95%CI 1.1-7.9) and ex1-10 PTVs (OR=1.6, 95%CI 0.8-3.5) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9; ex1-10 OR=0.5, 95%CI 0.1-1.0), and earlier age of breast cancer diagnosis (ex13-27 5.5 years, p<0.001; ex1-10 2.4 years, p=0.17). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort and the population-based UK Biobank cohort. No differences in risk or age at diagnosis by gene region were observed for PTVs in other predisposition genes., Conclusions and Relevance: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced risk of breast cancer, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs., Key Points: Question: Does ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 pathogenic variant type and location influence breast cancer risk in population-based studies? Findings: Breast cancer risk and estrogen receptor status differ based on the type and location of pathogenic variants in BRCA2 . Women carrying protein truncating variants in exon 11 have a lower breast cancer risk in the population-based cohorts, older age at diagnosis and higher rates of estrogen receptor negative breast cancer than women with exon 1-10 or exon 13-27 truncation variants in population-based and clinical testing cohorts. Meaning: Incorporating pathogenic variant type and location in cancer risk models may improve individualized risk prediction.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity., Methods: Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm., Results: In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality., Conclusions: This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs., Methods: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG)., Results: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16)., Conclusion: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Obesity is an established risk factor for multiple myeloma (MM). Relatively few prior studies, however, have evaluated associations in Black populations., Methods: Among 55,276 participants in the Black Women's Health Study, a prospective U.S. cohort established in 1995, we confirmed 292 incident diagnoses of MM over 26 years of follow-up. Multivariable Cox proportional hazard models, adjusted for age and putative MM risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of usual body mass index (BMI), BMI at age 18, height, and waist-to-hip ratio with MM., Results: Compared to women with a usual adult BMI < 25 kg/m 2 , the HR associated with a usual adult BMI ≥ 35 kg/m 2 was 1.38 (95% CI: 0.96, 1.98). For early adult BMI, the HR comparing women with BMI ≥ 25 vs. <25 kg/m 2 was 1.57 (95% CI: 1.08, 2.28). Women who were heavy in both early and later life had the highest risk compared to those who were lean at both time points (HR: 1.60; 95% CI: 1.02, 2.52). Height was also associated with the risk of MM; the HR per 10 cm was 1.21 (95% CI: 1.02, 1.43)., Conclusions: These results indicate that high early adult BMI is associated with a 57% increased risk of MM in Black women and potentially highlight the importance of weight control as a preventive measure., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: African American women have a disproportionate burden of disease compared to US non-Hispanic white women. Exposure to psychosocial stressors may contribute to these health disparities. Racial discrimination, a major stressor for African American women, could affect health through epigenetic mechanisms., Methods: We conducted an epigenome-wide association study (EWAS) to examine the association of interpersonal racism (in daily life and in institutional settings) with DNA methylation in blood in 384 participants of the Black Women's Health Study (BWHS). We also evaluated whether a greater number of perceived experiences of racism was associated with epigenetic aging as measured using different methylation clocks. Models were adjusted for chronological age, body mass index, years of education, neighborhood SES, geographic region of residence, alcohol drinking, smoking, and technical covariates., Results: Higher scores of racism in daily life were associated with higher methylation levels at the cg04494873 site in chromosome 5 (β = 0.64%; 95% CI = 0.41%, 0.87%; P = 6.35E-08). We also replicated one CpG site, cg03317714, which was inversely associated with racial discrimination in a previous EWAS among African American women. In the BWHS, higher scores of racism in daily life were associated with lower methylation levels at that CpG site (β = -0.94%; 95% CI = -1.37%, -0.51%; P = 2.2E-05). Higher racism scores were associated with accelerated epigenetic aging in more than one methylation clock., Conclusions: Exposure to discriminatory events may affect the epigenome and accelerate biological aging, which may explain in part the earlier onset of disease in African American women., (© 2024. W. Montague Cobb-NMA Health Institute.)

Purpose: Risk factors for monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor to multiple myeloma, are largely unknown. We hypothesized that low vitamin D levels might be associated with higher MGUS prevalence in a national cohort of U.S. Black women., Methods: We screened archived serum samples (collected 2014-2017) from 3896 randomly selected participants in the Black Women's Health Study ages 50-79 for evidence of MGUS; samples had been assayed for 25-hydroxyvitamin D [25(OH)D] shortly after blood draw. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D level and MGUS status, adjusting for age, body mass index, and season of blood draw., Results: We identified 334 MGUS cases (8.6%) in the study population. The adjusted OR comparing women with vitamin D deficiency (25(OH)D < 20 ng/mL) to those with 25(OH)D levels ≥ 30 ng/mL was 1.27 (95% CI: 0.95, 1.72)., Conclusion: MGUS was more prevalent among Black women with vitamin D deficiency compared to those with 25(OH)D ≥ 30 ng/mL; however, the association was not statistically significant. Future prospective studies are warranted to clarify the possible association between vitamin D and MGUS., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor., Methods: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet., Results: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05)., Conclusions: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

Background: Excessive energy intake has been shown to affect the mammalian target of the rapamycin (mTOR) signaling pathway and breast cancer risk. It is not well understood whether there are gene-environment interactions between mTOR pathway genes and energy intake in relation to breast cancer risk., Methods: The study included 1642 Black women (809 incident breast cancer cases and 833 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes and quartiles of energy intake in relation to breast cancer risk overall and by ER- defined subtypes using Wald test with a 2-way interaction term., Results: AKT1 rs10138227 (C > T) was only associated with a decreased overall breast cancer risk among women in quartile (Q)2 of energy intake, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.40, 0.91 (p-interaction = 0.042). Similar results were found in ER- tumors. AKT rs1130214 (C > A) was associated with decreased overall breast cancer risk in Q2 (OR = 0.63, 95% CI 0.44, 0.91) and Q3 (OR = 0.65, 95% CI 0.48, 0.89) (p-interaction = 0.026). HIF-1α C1772T rs11549465 (C > T) was associated with decreased overall breast cancer risk in Q4 (OR = 0.29, 95% CI 0.14, 0.59, p-interaction = 0.007); the results were similar in ER+ tumors. These interactions became non-significant after correction for multiple comparisons., Conclusion: Our findings suggest that mTOR genetic variants may interact with energy intake in relation to breast cancer risk, including the ER- subtype, in Black women. Future studies should confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women., Methods: The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term., Results: The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05)., Conclusion: We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Physical activity has been shown to affect the mammalian target of rapamycin (mTOR) signaling pathway and consequently breast carcinogenesis. Given that Black women in the USA are less physically active, it is not well understood whether there are gene-environment interactions between mTOR pathway genes and physical activity in relation to breast cancer risk in Black women., Methods: The study included 1398 Black women (567 incident breast cancer cases and 831 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with levels of vigorous physical activity in relation to breast cancer risk overall and by ER-defined subtypes using Wald test with 2-way interaction term and multivariable logistic regression., Results: AKT1 rs10138227 (C > T) and AKT1 rs1130214 (C > A) were only associated with a decreased risk of ER + breast cancer among women with vigorous physical activity (odds ratio [OR] = 0.15, 95% confidence interval (CI) 0.04, 0.56, for each copy of the T allele, p-interaction = 0.007 and OR = 0.51, 95% CI 0.27, 0.96, for each copy of the A allele, p-interaction = 0.045, respectively). MTOR rs2295080 (G > T) was only associated with an increased risk of ER + breast cancer among women with vigorous physical activity (OR = 2.24, 95% CI 1.16, 4.34, for each copy of the G allele; p-interaction = 0.043). EIF4E rs141689493 (G > A) was only associated with an increased risk of ER- breast cancer among women with vigorous physical activity (OR = 20.54, 95% CI 2.29, 184.17, for each copy of the A allele; p-interaction = 0.003). These interactions became non-significant after correction for multiple testing (FDR-adjusted p-value > 0.05)., Conclusion: Our findings suggest that mTOR genetic variants may interact with physical activity in relation to breast cancer risk in Black women. Future studies should confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 ., Methods: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status., Results: Germline BRCA1 , BRCA2 , and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1 , 27% for BRCA2 , and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1 , 9% for BRCA2 , and 4% for CHEK2 ., Conclusion: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1 , BRCA2 , CHEK2 , or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Background: Terminal duct lobular units (TDLUs) are the structures in the breast that give rise to most breast cancers. Previous work has shown that TDLU involution is inversely associated with TDLU metrics, such as TDLU count/100mm 2 , TDLU span (µm), and number of acini/TDLU, and that these metrics may be elevated in the normal breast tissue of women diagnosed with triple-negative (TN) compared with luminal A breast tumors. It is unknown whether this relationship exists in Black women, who have the highest incidence of TN breast cancer and the highest overall breast cancer mortality rate. We examined relationships between TDLU metrics and breast cancer molecular subtype among breast cancer cases in the Black Women's Health Study (BWHS)., Methods: We assessed quantitative TDLU metrics (TDLU count/100mm 2 , TDLU span (µm), and number of acini/TDLU) in digitized 247 hematoxylin and eosin-stained adjacent normal tissue sections from 223 BWHS breast cancer cases, including 65 triple negative (TN) cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor-2 (HER2) negative) and 158 luminal A cancers (ER positive, HER2 negative). We evaluated associations of least square mean TDLU metrics adjusted for age and body mass index (BMI) with patient and clinical characteristics. In logistic regression models, we evaluated associations between TDLU metrics and breast cancer subtype, adjusting for age, BMI, and tumor size., Results: Older age and higher BMI were associated with lower TDLU metrics and larger tumor size and lymph node invasion with higher TDLU metrics. The odds of TN compared with luminal A breast cancer increased with increasing tertiles of TDLU metrics, with odds ratios (95% confidence intervals) for tertile 3 versus tertile 1 of 2.18 (0.99, 4.79), 2.77 (1.07, 7.16), and 1.77 (0.79, 3.98) for TDLU count, TDLU span, and acini count/TDLU, respectively., Conclusion: Associations of TDLU metrics with breast cancer subtypes in the BWHS are consistent with previous studies of White and Asian women, demonstrating reduced TDLU involution in TN compared with luminal A breast cancers. Further investigation is needed to understand the factors that influence TDLU involution and the mechanisms that mediate TDLU involution and breast cancer subtype., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Studies in women of European descent showed an inverse association of dietary vitamin A (retinol and carotenoids) intake with breast cancer risks, mainly in premenopausal women., Objectives: We examined whether higher compared with lower levels of dietary vitamin A are associated with reduced breast cancer risks among Black women by estrogen receptor (ER) and menopausal statuses., Methods: In this pooled analysis, data were from 3564 breast cancer cases and 11,843 controls (mean ages = 56.4 and 56.3 years, respectively) in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Dietary intake was assessed by FFQs. Multivariable logistic regressions were performed to estimate ORs and 95% CIs for study-specific quintiles of total vitamin A equivalents and individual carotenoids, and a pooled OR was estimated by a random-effect model., Results: We observed an inverse association of total vitamin A equivalents with ER-positive breast cancer (quintiles 5 compared with 1: pooled OR: 0.82; 95% CI: 0.67-1.00; P-trend = 0.045). The association was seen among premenopausal women (pooled OR: 0.60; 95% CI: 0.43-0.83; P-trend = 0.004), but not among postmenopausal women (pooled OR: 0.99; 95% CI: 0.77-1.28; P-trend = 0.78). Additionally, there were inverse associations of dietary β-carotene (quintiles 5 compared with 1: pooled OR: 0.70; 95% CI: 0.51-0.95; P-trend = 0.08) and lutein (pooled OR: 0.63; 95% CI: 0.45-0.87; P-trend = 0.020) with ER-positive breast cancer among premenopausal women. There was no evidence for an association of total vitamin A equivalents or individual carotenoids with ER-negative breast cancer, regardless of menopausal status., Conclusions: Our findings on dietary vitamin A and breast cancer risks in Black women are consistent with observations in women of European descent and advance the literature showing an inverse association for ER-positive disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Purpose: Breast cancer risk prediction models are used to identify high-risk women for early detection, targeted interventions, and enrollment into prevention trials. We sought to develop and evaluate a risk prediction model for breast cancer in US Black women, suitable for use in primary care settings., Methods: Breast cancer relative risks and attributable risks were estimated using data from Black women in three US population-based case-control studies (3,468 breast cancer cases; 3,578 controls age 30-69 years) and combined with SEER age- and race-specific incidence rates, with incorporation of competing mortality, to develop an absolute risk model. The model was validated in prospective data among 51,798 participants of the Black Women's Health Study, including 1,515 who developed invasive breast cancer. A second risk prediction model was developed on the basis of estrogen receptor (ER)-specific relative risks and attributable risks. Model performance was assessed by calibration (expected/observed cases) and discriminatory accuracy (C-statistic)., Results: The expected/observed ratio was 1.01 (95% CI, 0.95 to 1.07). Age-adjusted C-statistics were 0.58 (95% CI, 0.56 to 0.59) overall and 0.63 (95% CI, 0.58 to 0.68) among women younger than 40 years. These measures were almost identical in the model based on estrogen receptor-specific relative risks and attributable risks., Conclusion: Discriminatory accuracy of the new model was similar to that of the most frequently used questionnaire-based breast cancer risk prediction models in White women, suggesting that effective risk stratification for Black women is now possible. This model may be especially valuable for risk stratification of young Black women, who are below the ages at which breast cancer screening is typically begun., Competing Interests: Tracy BattagliaResearch Funding: American Cancer Society, Patient Centered Outcomes Research Institute, NIH NCATs (Inst) Elisa V. BanderaConsulting or Advisory Role: PfizerNo other potential conflicts of interest were reported.

Background: Polygenic risk scores (PRSs) have been demonstrated to identify women of European, Asian, and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry., Methods: We assembled genotype data for women of African ancestry, including 9241 case subjects and 10 193 control subjects. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve. We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry and estimated lifetime absolute risk of BC in African Americans by PRS category., Results: For overall BC, the odds ratio per SD of the 313-variant PRS (PRS313) was 1.27 (95% confidence interval [CI] = 1.23 to 1.31), with an area under the receiver operating characteristic curve of 0.571 (95% CI = 0.562 to 0.579). Compared with women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38-fold to 1.72-fold). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction., Conclusion: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared with that reported in European, Asian, and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.

Objective: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN., Patients and Methods: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus

Background: Reproductive factors, particularly parity, have differential effects on breast cancer risk according to estrogen receptor (ER) status, especially among African American (AA) women. One mechanism could be through DNA methylation, leading to altered expression levels of genes important in cell fate decisions., Methods: Using the Illumina 450K BeadChip, we compared DNA methylation levels in paraffin-archived tumor samples from 383 AA and 350 European American (EA) women in the Women's Circle of Health Study (WCHS). We combined 450K profiles with RNA-seq data and prioritized genes based on differential methylation by race, correlation between methylation and gene expression, and biological function. We measured tumor protein expression and assessed its relationship to DNA methylation. We evaluated associations between reproductive characteristics and DNA methylation using linear regression., Results: 410 loci were differentially methylated by race, with the majority unique to ER- tumors. FOXA1 was hypermethylated in tumors from AA versus EA women with ER- cancer, and increased DNA methylation correlated with reduced RNA and protein expression. Importantly, parity was positively associated with FOXA1 methylation among AA women with ER- tumors (P = 0.022), as was number of births (P = 0.026), particularly among those who did not breastfeed (P = 0.008). These same relationships were not observed among EA women, although statistical power was more limited., Conclusions: Methylation and expression of FOXA1 is likely impacted by parity and breastfeeding. Because FOXA1 regulates a luminal gene expression signature in progenitor cells and represses the basal phenotype, this could be a mechanism that links these reproductive exposures with ER- breast cancer.

Exposures to carcinogens in hair products have been explored as breast cancer risk factors, yielding equivocal findings. We examined hair product use (hair dyes, chemical relaxers and cholesterol or placenta-containing conditioners) among African American (AA) and White women, and explored associations with breast cancer. Multivariable-adjusted models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to describe the associations of interest among 2280 cases (1508 AA and 772 White) and 2005 controls (1290 AA and 715 White). Among controls, hair dye use was more common among Whites than AAs (58 versus 30%), while relaxer (88 versus 5%) and deep conditioner use (59 versus 6%) was more common among AAs. Among AAs, use of dark hair dye shades was associated with increased breast cancer risk (OR = 1.51, 95% CI: 1.20-1.90) and use of dark shades (OR = 1.72, 95% CI: 1.30-2.26) and higher frequency of use (OR = 1.36, 95% CI: 1.01-1.84) were associated with ER+ disease. Among Whites, relaxer use (OR = 1.74, 95% CI: 1.11-2.74) and dual use of relaxers and hair dyes (OR = 2.40, 95% CI: 1.35-4.27) was associated with breast cancer; use of dark hair dyes was associated with increased ER+ disease (OR = 1.54, 95% CI: 1.01-2.33), and relaxer use was associated with increased ER- disease (OR = 2.56, 95% CI: 1.06-6.16). These novel findings provide support a relationship between the use of some hair products and breast cancer. Further examinations of hair products as important exposures contributing to breast cancer carcinogenesis are necessary., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Ki-67 has been proposed to be used as a surrogate marker to differentiate luminal breast carcinomas (BCs). The purpose of this study was to determine the utility of and best approaches for using tissue microarrays (TMAs) and Ki-67 staining to distinguish luminal subtypes in large epidemiology studies of luminal/human epidermal growth factor receptor 2 (HER2)-negative BC., Methods: Full-section and TMA (three 0.6-mm cores and two 1.0-mm cores) slides of 109 cases were stained with Ki-67 antibody. We assessed two ways of collapsing TMA cores: a weighted approach and mitotically active approach., Results: For cases with at least a single 0.6-mm TMA core (n = 107), 16% were misclassified using a mitotically active approach and 11% using a weighted approach. For cases with at least a single 1.0-mm TMA core (n = 101), 5% were misclassified using either approach. For the 0.6-mm core group, there were 33.3% discordant cases. The number of discordant cases increased from 18% in the group of two cores to 40% in the group of three cores (P = .039)., Conclusions: Ki-67 tumor heterogeneity was common in luminal/HER2- BC. Using a weighted approach was better than using a mitotically active approach for core to case collapsing. At least a single 1.0-mm core or three 0.6-mm cores are required when designing a study using TMA., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Vitamin D may have anticancer activities. The high prevalence of vitamin D deficiency in African Americans (AAs) may be a contributing factor to the cancer health disparities between AAs and European Americans (EAs). Objectives: We compared concentrations of 25(OH)D and vitamin D-binding protein (VDBP) in AA and EA women and investigated determinants of the vitamin D-biomarker concentrations in both populations. Design: We used data and biospecimens from 909 AA and 847 EA healthy control subjects from the Carolina Breast Cancer Study (CBCS) and the Women's Circle of Health Study (WCHS) in the African American Breast Cancer Epidemiology and Risk Consortium. We measured plasma 25(OH)D and VDBP concentrations in all participants and genotyped 67 vitamin D-related genes in AA women only. Results: AA women had lower 25(OH)D concentrations than did EA women (mean ± SD: 14.2 ± 8.1 compared with 21.1 ± 11.5 ng/mL, respectively; P < 0.0001) but similar concentrations of VDBP (mean ± SD: 344 ± 133 compared with 336 ± 124 μg/mL, respectively; P = 0.25). With VDBP and other factors controlled for, the observed racial difference in 25(OH)D concentrations did not diminish. Relations of demographic and lifestyle factors with 25(OH)D were similar between AA and EA women. Although none of the genetic variants that have been identified in previous genome-wide association studies of 25(OH)D concentrations in EAs were significant ( P > 0.05) in AAs, AA women who carried the allele of a functional single nucleotide polymorphism rs4988235, which has been previously associated with lactase expression and lactose tolerance, had higher dietary vitamin D intake and higher measured 25(OH)D concentrations. Conclusions: AA women have lower concentrations of total 25(OH)D than EA women do, but both groups have similar VDBP concentrations, suggesting that there are lower concentrations of free 25(OH)D in AAs. Although demographic and lifestyle determinants of 25(OH)D concentrations are similar between the 2 groups, genetic determinants may be ethnicity specific. Larger studies in AAs will be needed to fully elucidate the underlying determinants of low vitamin D concentrations in AA populations., (© 2017 American Society for Nutrition.)

Purpose: Our previous work has shown low serum 25-hydroxyvitamin D concentrations in association with aggressive breast cancer subtypes. Vitamin D receptor (VDR) is central for vitamin D-mediated transcription regulation. Few studies have examined breast VDR expression with tumor characteristics or patient survival., Experimental Design: VDR expression in breast tumor tissue microarrays was determined by immunohistochemistry in 1,114 female patients as low, moderate, and strong expression based on an immunoreactive score, and examined with histopathologic tumor characteristics and survival outcomes including progression-free survival, breast cancer-specific survival, and overall survival., Results: A majority (58%) of breast tumors showed moderate or strong VDR expression. VDR expression was inversely related to aggressive tumor characteristics, including large tumor size, hormonal receptor (HR) negativity, and triple-negative subtype (P < 0.05). In addition, VDR expression was also inversely related to Ki-67 expression among patients older than 50 years. Nevertheless, VDR expression was not associated with any patient survival outcomes examined., Conclusions: In a large patient population, VDR expression is inversely associated with more aggressive breast cancer, but not with breast cancer survival outcomes. The present findings of VDR expression are consistent with our previous results of circulating vitamin D biomarkers, which provide two converging lines of evidence supporting the putative benefits of vitamin D against aggressive breast cancer. Because of the observational nature of our analyses, future studies are warranted to establish the causality of the reported associations. Clin Cancer Res; 23(1); 97-103. ©2016 AACR., (©2016 American Association for Cancer Research.)

The relationship between physical activity and breast cancer risk has been extensively studied among women of European descent, with most studies reporting inverse associations. However, data on American women of African ancestry (AA) and by tumor subtypes are sparse. Thus, we examined associations of vigorous exercise and breast cancer risk overall, and by estrogen receptor (ER) status, in the African American Breast Cancer Epidemiology and Risk Consortium. We pooled data from four large studies on 2482 ER+ cases, 1374 ER- cases, and 16,959 controls. Multivariable logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for the risk of breast cancer overall, and polytomous logistic regression was used to model the risk of ER+ and ER- cancer. Recent vigorous exercise was associated with a statistically significant, modestly decreased risk for breast cancer overall (OR 0.88, 95 % CI 0.81-0.96) and for ER+ cancer (OR 0.88, 95 % CI 0.80-0.98), but not for ER- cancer (OR 0.93, 95 % CI 0.82-1.06). Overall, there was no strong evidence of effect modification by age, menopausal status, body mass index, and parity. However, our data were suggestive of modification by family history, such that an inverse association was present among women without a family history but not among those with a relative affected by breast cancer. Results from this large pooled analysis provide evidence that vigorous physical activity is associated with a modestly reduced risk of breast cancer in AA women, specifically ER+ cancer.

Purpose: Positive energy imbalance and growth factors linked to obesity promote the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. As the obesity-breast cancer associations differ between European American (EA) and African-American (AA) women, we investigated genetic variants in the mTOR pathway and breast cancer risk in these two racial groups., Methods: We examined 400 single-nucleotide polymorphisms (SNPs) in 31 mTOR pathway genes in the Women's Circle of Health Study with 1263 incident breast cancers (645 EA, 618 AA) and 1382 controls (641 EA, 741 AA). Multivariable logistic regression was performed separately within racial groups. Effect modification was assessed for measured body size and weight gain since age 20., Results: In EA women, variants in FRAP1 rs12125777 (intron), PRR5L rs3740958 (synonymous coding), and CDKAL1 rs9368197 (intron) were associated with increased breast cancer risk, while variants in RPTOR rs9900506 (intron) were associated with decreased risk (nominal p-trend for functional and FRAP1 SNPs or p adjusted for correlated test [p ACT] < 0.05). For AA women, variants in RPTOR rs3817293 (intron), PIK3R1 rs7713645 (intron), and CDKAL1 rs9368197 were associated with decreased breast cancer risk. The significance for FRAP1 rs12125777 and RPTOR rs9900506 in EA women did not hold after correction for multiple comparisons. The risk associated with FRAP1 rs12125777 was higher among EAs who had body mass index ≥30 kg/m(2) (odds ratio = 7.69, 95 % CI 2.11-28.0; p-interaction = 0.007) and gained weight ≥35 lb since age 20 (odds ratio = 3.34, 95 % CI 1.42-7.85; p-interaction = 0.021), compared to their counterparts., Conclusions: The mTOR pathway may be involved in breast cancer carcinogenesis differently for EA and AA women.

Purpose: Invasive ductal carcinoma (IDC) is diagnosed with or without a ductal carcinoma in situ (DCIS) component. Previous analyses have found significant differences in tumor characteristics between pure IDC lacking DCIS and mixed IDC with DCIS. We will test our hypothesis that pure IDC represents a form of breast cancer with etiology and risk factors distinct from mixed IDC/DCIS., Methods: We compared reproductive risk factors for breast cancer risk, as well as family and smoking history between 831 women with mixed IDC/DCIS (n = 650) or pure IDC (n = 181), and 1,620 controls, in the context of the Women's Circle of Health Study (WCHS), a case-control study of breast cancer in African-American and European-American women. Data on reproductive and lifestyle factors were collected during interviews, and tumor characteristics were abstracted from pathology reports. Case-control and case-case analyses were conducted using unconditional logistic regression., Results: Most risk factors were similarly associated with pure IDC and mixed IDC/DCIS. However, among postmenopausal women, risk of pure IDC was lower in women with body mass index (BMI) 25 to <30 [odds ratio (OR) 0.66; 95 % confidence interval (CI) 0.35-1.23] and BMI ≥ 30 (OR 0.33; 95 % CI 0.18-0.67) compared to women with BMI < 25, with no associations with mixed IDC/DCIS. In case-case analyses, women who breastfed up to 12 months (OR 0.55; 95 % CI 0.32-0.94) or longer (OR 0.47; 95 % CI 0.26-0.87) showed decreased odds of pure IDC than mixed IDC/DCIS compared to those who did not breastfeed., Conclusions: Associations with some breast cancer risk factors differed between mixed IDC/DCIS and pure IDC, potentially suggesting differential developmental pathways. These findings, if confirmed in a larger study, will provide a better understanding of the developmental patterns of breast cancer and the influence of modifiable risk factors, which in turn could lead to better preventive measures for pure IDC, which have worse disease prognosis compared to mixed IDC/DCIS.

Objectives: Prognostic risk factors influencing survival in patients with epithelial ovarian cancer (EOC) include tumor stage, grade, histologic subtype, debulking, and platinum status. Little is known about the impact of hormonal milieu and reproductive factors before cancer diagnosis on clinical outcome. We sought to evaluate whether oral contraceptive (OC) use carries any prognostic significance on overall survival (OS) in patients with EOC., Methods: Newly diagnosed patients with EOC, fallopian tube, and primary peritoneal cancers between 1982 and 1998 were prospectively evaluated with a comprehensive epidemiologic questionnaire. A retrospective chart review was performed to abstract clinicopathologic data, including OS. A Kaplan-Meier analysis was performed to compare survival across various exposures. A Cox regression model was used to compute adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs)., Results: We identified 387 newly diagnosed cancers with evaluable information in this cohort. Decreased risk of death was observed in women who reported prior use of OC (aHR, 0.79; 95% CI, 0.58-1.09), previous pregnancy (aHR, 0.77; 95% CI, 0.57-1.04), or a live birth (aHR, 0.81; 95% CI, 0.60-1.08) after adjusting for age at diagnosis, stage, and histologic subtype. Oral contraceptive use was associated with a crude reduced risk of death (HR, 0.55; 95% CI, 0.42-0.72), with reported median OS of 81 months in OC users versus 46 months in nonusers. Patients who reported a single live birth experienced the largest potential survival advantage (aHR, 0.61; 95% CI, 0.39-0.94). Oral contraceptive use and prior pregnancy were associated with improved survival across all strata., Conclusions: Oral contraceptive use may have lasting effects on epithelial ovarian tumor characteristics conferring favorable prognosis. Putative mechanisms that affect tumor biology include complex interactions between ovarian cells, host immune cells, and hormonal microenvironment during carcinogenesis. Future efforts should be directed to determine the role of reproductive factors in antitumor immunity.

Folate-mediated one-carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate-metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We conducted a comprehensive analysis of SNPs in eleven genes involved in one-carbon metabolism and risk of breast cancer in 1,275 European-American (EA) and 1,299 African-American (AA) women who participated in the Women's Circle of Health Study. Allele frequencies varied significantly between EA and AA populations. A number of these SNPs, specifically in genes including MTR, MTRR, SHMT1, TYMS and SLC19A1, were associated with overall breast cancer risk, as well as risk by estrogen receptor (ER) status, in either EA or AA women. Associations appeared to be modified by dietary folate intake. Although single-SNP associations were not statistically significant after correcting for multiple comparisons, polygenetic score analyses revealed significant associations with breast cancer risk. Per unit increase of the risk score was associated with a modest 19 to 50% increase in risk of breast cancer overall, ER positive or ER negative cancer (all p < 0.0005) in EAs or AAs. In summary, our data suggest that one-carbon metabolizing gene polymorphisms could play a role in breast cancer and that may differ between EA and AA women., (© 2015 UICC.)

Background: Menarche is a critical time point for diverging fates of mammary cells of origin. African American women have young age at menarche, which could be associated with their high rates of estrogen receptor-negative (ER-) breast cancer., Methods: In the AMBER Consortium, using harmonized data from 4426 African American women with breast cancer and 17 474 controls, we used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for ages at menarche and first live birth (FLB), and the interval between, in relation to ER+ and ER- breast cancer. All statistical tests were two-sided., Results: Risk of ER- breast cancer was reduced with later age at menarche among both parous and nulliparous women (≥15 vs <11 years OR = 0.62, 95% CI = 0.48 to 0.81 and OR = 0.56, 95% CI = 0.29 to 1.10, respectively), with no effect of age at FLB. For ER+ breast cancer, the inverse association was weaker among nulliparous women. While longer intervals between menarche and FLB were associated with increased risk of ER+ breast cancer in a dose-response fashion (OR for 20 year interval = 1.39, 95% CI = 1.08 to 1.79, P trend = .003), ER- risk was only increased for intervals up to 14 years and not beyond (P trend = .33)., Conclusions: While ER- breast cancer risk was markedly reduced in women with a late age at menarche, there was not a clear pattern of increased risk with longer interval between menarche and FLB, as was observed for ER+ breast cancer. These findings indicate that etiologic pathways involving adolescence and pregnancy may differ for ER- and ER+ breast cancer., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: We assessed the prevalence, patterns and predictors of dietary supplement use among participants of the databank and biorepository (DBBR) at a comprehensive cancer centre in western New York., Design: Archived epidemiological questionnaire data were obtained from the DBBR at Roswell Park Cancer Institute. Descriptive statistics and logistic regression explored the prevalence, patterns and predictors of lifetime use of four common supplements (multivitamins, vitamin C, vitamin E and calcium) and use of multivitamins, sixteen single vitamins/minerals and eighteen herbal/specialty supplements within the previous 10 years., Setting: Western New York, USA., Subjects: DBBR participants (n 8096) enrolled between December 2003 and July 2012 were included in these analyses: 66.9 % (n 5418) with cancer, 65.6 % (n 5309) women, mean age for patients v. cancer-free controls 59.9 (SD 12.6) years and 50.7 (SD 15.4) years, respectively., Results: Overall, 54.4 % of DBBR participants reported lifetime use of one or more supplements and 63.1 % reported use of one or more supplements within the previous 10 years (excluding multivitamins). Multivitamin use was high in this sample (lifetime: 64.1 %; 10 years: 71.3 %; current: 51.8 %). Supplementation was higher among cancer-free controls than cancer patients. Vitamin C, calcium and fish oil were the most common single vitamin, mineral and specialty product, respectively., Conclusions: A consistently high and increasing proportion of dietary supplement use over time remains clear. Supplementation is prevalent among cancer patients and may even be higher than predicted in cancer-free individuals. Further studies should assess the safety and efficacy of specific supplements in reducing disease risk.

African American (AA) women are more likely than European American (EA) women to be diagnosed with breast cancer at younger ages and to develop poor prognosis tumors. However, these racial differences are largely unexplained. Folate and other methyl-group nutrients may be related to breast carcinogenesis, but few studies have examined these associations in AA populations. We examined the associations of dietary intake of these nutrients with breast cancer risk overall, by menopausal and estrogen receptor (ER) status among 1,582 AA (749 cases) and 1,434 EA (744 cases) women using data from a case-control study, the Women's Circle of Health Study. Unconditional multivariable logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the association of each nutrient and breast cancer risk. In AA women, inverse associations were observed for natural food folate intake among premenopausal women (fourth vs. first quartile: OR = 0.57, 95% CI, 0.33-1.00; p for trend = 0.06) and for ER-positive tumors (fourth vs. first quartile: OR = 0.58, 95% CI, 0.36-0.93; p for trend = 0.03), whereas in EA women, a positive association was observed for intake of synthetic folate (fourth vs. first quartile: OR = 1.53, 95% CI, 1.06-2.21; p for trend = 0.03). Our findings suggest that natural food folate intake is inversely associated with breast cancer risk and that this association may vary by race, menopausal status or ER status. The finding of an increased risk observed among EA women with the highest intake of synthetic folate from fortified foods warrants further investigation., (© 2013 UICC.)

Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell-mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P-trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER-positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER-positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER-negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status., (© 2013 UICC.)

Purpose: It has long been held that parity reduces risk of breast cancer. However, accumulating evidence indicates that the effects of parity, as well as breastfeeding, may vary according to estrogen receptor (ER) status. We evaluated these associations in a case-control study among African-American women in New York City and New Jersey., Methods: In the Women's Circle of Health Study, including 786 African-American women with breast cancer and 1,015 controls, data on reproductive histories were collected from in-person interviews, with tumor characteristics abstracted from pathology reports. We calculated number of live births and months breastfeeding for each child, and examined each in relation to breast cancer by ER status, and for triple-negative (TN) breast cancer., Results: Although associations were not statistically significant, having children was associated with reduced risk of ER+ breast cancer [odds ratio (OR) 0.82, 95 % confidence interval (CI) 0.58-1.16], but increased risk of ER- tumors, with associations most pronounced for TN breast cancer (OR 1.81, 95 % CI 0.93-3.51). Breastfeeding gave no additional benefit for ER+ cancer, but reduced the risk of ER- disease associated with parity., Conclusions: Accumulating data from a number of studies, as well as our own in African-American women, indicate that the effects of parity and breastfeeding differ by ER status. African-American women are more likely to have children and not to breastfeed, and to have ER- and TN breast cancer. It is possible that breastfeeding in this population could reduce risk of more aggressive breast cancers.

Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44-21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy.

It has been observed previously that compared with women of European ancestry (EA), those of African ancestry (AA) are more likely to develop estrogen receptor (ER)-negative breast cancer, although the mechanisms have not been elucidated. We tested the associations between breast cancer risk and a targeted set of 20 genes known to be involved in estrogen synthesis, metabolism, and response and potential gene-environment interactions using data and samples from 1307 EA (658 cases) and 1365 AA (621 cases) participants from the Women's Circle of Health Study (WCHS). Multivariable logistic regression found evidence of associations with single-nucleotide polymorphisms (SNPs) in the ESR1 gene in EA women (rs1801132, odds ratio (OR)=1.47, 95% CI=1.20-1.80, P=0.0002; rs2046210, OR=1.24, 95% CI=1.04-1.47, P=0.02; and rs3020314, OR=1.43, 95% CI=1.19-1.70, P=0.00009), but not in AA women. The only other gene associated with breast cancer risk was CYP1A2 in AA women (rs2470893, OR=1.42, 95% CI=1.00-2.02, P=0.05), but not in EA women. When stratified by ER status, ESR1 rs1801132, rs2046210, and rs3020314 showed stronger associations in ER-positive than in ER-negative breast cancer in only EA women. Associations with the ESR1 SNPs in EA women also appeared to be stronger with longer endogenous estrogen exposure or hormonal replacement therapy use. Our results indicate that there may be differential genetic influences on breast cancer risk in EA compared with AA women and that these differences may be modified by tumor subtype and estrogen exposures. Future studies with a larger sample size may determine the full contribution of estrogen-related genes to racial/ethnic differences in breast cancer., (© 2014 Society for Endocrinology.)

Limiting energy-dense foods, fast foods, and sugary drinks that promote weight gain is a cancer prevention recommendation, but no studies have evaluated intake in relation to breast cancer risk in African American (AA) women. In a case-control study with 1692 AA women (803 cases and 889 controls) and 1456 European American (EA) women (755 cases and 701 controls), odds ratios (OR) and 95% confidence intervals (CI) for risk were computed, stratifying for menopausal and estrogen receptor (ER) status. Among postmenopausal EA women, breast cancer risk was associated with frequent consumption of energy-dense foods (OR = 2.95; 95% CI: 1.66-5.22), fast foods (OR = 2.35; 95% CI: 1.38-4.00), and sugary drinks (OR = 2.05; 95% CI: 1.13-3.70). Elevated risk of ER+ tumors in EA women was associated with energy-dense (OR = 1.75; 95% CI: 1.14-2.69) and fast foods (OR = 1.84; 95% CI: 1.22-2.77). Among AA women, frequent fast food consumption was related to premenopausal breast cancer risk (OR = 1.97; 95% CI: 1.13-3.43), and with ER+ tumors. Energy adjustment attenuated risk estimates in AA women, while strengthening them among EA women. Frequent consumption of energy-dense and fast foods that have poor nutritive value appeared to increase breast cancer risk in AA and EA women, with differences by menopausal status and ER status.

Purpose: Research on the role of red meat and poultry consumption in breast carcinogenesis is inconclusive, but the evidence in African-American (AA) women is lacking. The association between consuming meat and breast cancer risk was examined in the Women's Circle of Health Study involving 803 AA cases, 889 AA controls, 755 Caucasian cases, and 701 Caucasian controls., Methods: Dietary information was collected using a Food Frequency Questionnaire. Odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models adjusting for potential covariates., Results: Comparing the fourth versus the first quartiles, among Caucasian women, processed meat (OR = 1.48; 95 % CI 1.07-2.04), unprocessed red meat (OR = 1.40; 95 % CI 1.01-1.94), and poultry intakes (OR = 1.42; 95 % CI 1.01-1.99) increased breast cancer risk. Risk associated with poultry intake was more dominant in premenopausal women (OR = 2.33; 95 % CI 1.44-3.77) and for women with ER- tumors (OR = 2.55; 95 % CI 1.29-5.03) in the Caucasian group. Associations in AA women were mostly null except for a significant increased risk trend with processed meat consumption for ER+ tumors (OR = 1.36; 95 % CI 0.94-1.97, p trend = 0.04)., Conclusions: Overall, associations between breast cancer risk and consumption of red meat and poultry were of different magnitude in AA and Caucasian women, with further differences noted by menopausal and hormone receptor status in Caucasian women. This is the first study to examine racial differences in meat and breast cancer risk and represents some of the first evidence in AA women.