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Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear., Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes., Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions., Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction., (© 2021. The Author(s).)

Background: Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of enhanced screening regimens. To this end, we examined associations of breast cancer risk factors by mode of detection in screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort., Methods: Among 77,206 women followed for a median of 14.8 years, 2711 screen-detected and 1281 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening., Results: Factors associated with higher risks of symptom-detected and screen-detected breast cancer included current combined hormone therapy (HT) use (HR 2.07, 95% CI 1.72-2.48 and 1.45, 1.27-1.65, respectively) and history of benign breast disease (1.85, 1.64-2.08 and 1.43, 1.31-1.55, respectively). Current estrogen-only HT use was associated with symptom-detected (1.40, 1.15-1.71) but not screen-detected (0.95, 0.83-1.09) breast cancer. Higher risk of screen-detected but not symptom-detected breast cancer was observed for obese vs. normal body mass index (1.22, 1.01-1.48 and 0.76, 0.56-1.01, respectively), per 3 h/day sitting time (1.10, 1.04-1.16 and 0.97, 0.89-1.06, respectively), and ≥ 2 drinks per day vs. nondrinker (1.40, 1.16-1.69 and 1.27, 0.97-1.66, respectively)., Conclusions: Differences in risk factors for symptom-detected vs. screen-detected breast cancer were observed and most notably, use of combined and estrogen-only HT and a history of benign breast disease were associated with increased risk of symptomatic detected breast cancer., Impact: If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype., Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype., Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( P > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m 2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking., Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype., Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care., (©2021 American Association for Cancer Research.)

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer., (© The Author(s) 2020. Published by Oxford University Press.)

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10 -8 , at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants., Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed., Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1 , RAD51C , and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM , CDH1 , and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657&#95;661del5 founder pathogenic variant in NBN , were not associated with an increased risk of breast cancer., Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose: Excess body fatness and physical activity independently influence the risk of several types of cancer. However, few studies have examined whether physical activity mitigates the excess risk associated with higher body mass index (BMI)., Methods: We examined the individual and joint associations between BMI (kg/m 2 ) and leisure-time moderate-to-vigorous physical activity (MVPA, MET-hours/week) with the risk of three established excess body fatness-related cancers (breast, colon, and endometrial) among 43,795 postmenopausal women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort (1992/1993-2015). Further exclusions for women without an intact uterus resulted in 31,805 women for endometrial cancer analyses. Multivariable Cox proportional hazards regression was used to calculate hazard ratio (HR) and 95% confidence intervals (CIs) with interaction terms to assess multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction., Results: BMI and MVPA were individually associated with breast and endometrial cancer risk, but only BMI was associated with colon cancer risk. In joint analyses, increasing levels of MVPA did not lower the risk of these cancers among obese women. For example, compared to the common referent (BMI 18.5- < 25 kg/m 2 , MVPA > 0- < 7.5 MET-hours/week), BMI ≥ 30 kg/m 2 was associated with a higher risk of breast cancer among women with low MVPA (> 0-< 7.5 MET-hours/week: HR = 1.42, 95% CI: 1.22 - 1.67) and high MVPA (≥ 15 MET-hours/week: HR = 1.53, 95% CI: 1.25 - 1.87; RERI = 0.20, 95% CI: -0.14, 0.54, multiplicative P interaction  = 0.64)., Conclusion: Our results do not support the hypothesis that leisure-time physical activity mitigates the excess risk associated with higher BMI for risk of breast, endometrial, or colon cancer among postmenopausal women.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk., Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry., Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10 -18 ); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10 -8 )., Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Background: There is limited evidence of a potential inverse association between coffee, particularly caffeinated coffee, consumption and postmenopausal breast cancer risk, and few studies have examined this association by tumor hormone receptor status. To provide further evidence, we examined total, caffeinated, and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence overall, and by tumor estrogen receptor (ER) and/or progesterone receptor (PR) subtype., Methods: Among 57,075 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort who were cancer free and reported coffee intake in 1999, we identified 2,980 women diagnosed with invasive breast cancer during follow-up through June 2015. Multivariable-adjusted Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI)., Results: Neither total, caffeinated, nor decaffeinated coffee consumption was associated with invasive breast cancer risk; HRs (95% CIs) comparing consumption of ≥2 cups per day with <1 cup per month were 0.99 (0.89-1.11), 0.96 (0.87-1.06), and 1.06 (0.95-1.19), respectively. Similarly, coffee consumption was not associated with risk of hormone receptor-positive (ER + or PR + ) or hormone receptor-negative (ER - and PR - ) breast tumors., Conclusions: These findings do not support an association between coffee consumption and invasive breast cancer risk among postmenopausal women., Impact: This large prospective study contributes to the limited evidence on coffee consumption and breast cancer risk, finding no association overall or by tumor receptor subtype., (©2020 American Association for Cancer Research.)

Background: Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk., Methods: Associations between weight change and risk of breast cancer were examined among women aged 50 years and older in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (interval 1 median = 5.2 years; interval 2 median = 4.0 years). Sustained weight loss was defined as no less than 2 kg lost in interval 1 that was not regained in interval 2. Among 180 885 women, 6930 invasive breast cancers were identified during follow-up., Results: Compared with women with stable weight (±2 kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5 kg lost: hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70 to 0.96; >4.5-<9 kg lost: HR = 0.75, 95% CI = 0.63 to 0.90; ≥9 kg lost: HR = 0.68, 95% CI = 0.50 to 0.93). Women who lost at least 9 kg and gained back some (but not all) of it were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight., Conclusions: These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged 50 years and older. Breast cancer prevention may be a strong weight-loss motivator for the two-thirds of American women who are overweight or obese., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer., (© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.)

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype 1-3 . To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10 -8 ), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

Purpose: Histopathologic grade provides an integrated measure of biologic features which affects cancer prognosis. In invasive ductal breast cancer (IDBC), the grade of the ductal carcinoma in situ (DCIS) and invasive components are usually concordant, suggesting grade is established early in tumorigenesis and may be linked to etiologic factors. In this study, we used prospectively collected data from postmenopausal women in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort to compare risk factor associations among low-grade and high-grade DCIS, as well as low-grade and high-grade IDBC., Methods: Among 73,825 cancer-free women at enrollment in the CPS-II Nutrition Cohort in 1992-1993 (mean age: 62.1 years), we verified 802 diagnosed with DCIS (C50 8500/2; n = 430 low-grade and 372 high-grade) and 3,125 with IDBC (C50 8500/3; n = 2,221 low-grade and 904 high-grade) through June 2013. Person-time contribution was conditional on screening mammograms self-reported on biennial surveys. Multivariable-adjusted joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI)., Results: A personal history of benign breast disease was more strongly associated with higher risk of low-grade DCIS (HR = 2.20, 95% CI 1.81-2.67; p for heterogeneity = 0.0004) than high-grade DCIS. Consumption of two or more alcoholic drinks/day was only associated with a higher risk of low-grade IDBC (HR = 1.58, 95% CI 1.33-1.88; p for heterogeneity = 0.005)., Conclusions: These results suggest heterogeneity by grade for breast cancer etiology. Identification of potential risk factor differences among low-grade and high-grade DCIS and IDBC may help to clarify associations, and ultimately, improve breast cancer risk prediction models.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Purpose: In a screened population, breast cancer-specific mortality is lower for screen-detected versus symptom-detected breast cancers; however, it is unclear whether this association varies by follow-up time and/or tumor characteristics. To further understand the prognostic utility of mode of detection, we examined its association with breast cancer-specific mortality, overall and by follow-up time, estrogen receptor status, tumor size, and grade., Methods: In the Cancer Prevention Study-II Nutrition Cohort, 3975 routinely screened women were diagnosed with invasive breast cancer (1992-2015). Among 2686 screen-detected and 1289 symptom-detected breast cancers, 206 and 209 breast cancer deaths, respectively, occurred up to 24 years post diagnosis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox proportional hazard regression models., Results: Controlling for prognostic factors, symptom detection was associated with higher risk of breast cancer-specific death up to 5 years after diagnosis (HR ≤5years  = 1.88, 95% CI 1.21-2.91) this association was attenuated in subsequent follow-up (HR >5years  = 1.26, 95% CI 0.98-1.63). Within tumor characteristic strata, there was a 1.3-2.7-fold higher risk of breast cancer death associated with symptom-detected cancers ≤ 5 years of follow-up, although associations were only significant for women with tumors < 2 cm (HR ≤5years  = 2.42, 95% CI 1.19-4.93) and for women with grade 1 or 2 tumors (HR ≤5years  = 2.72, 95% CI 1.33-5.57). In subsequent follow-up, associations were closer to the null., Conclusions: Screen detection is a powerful prognostic factor for short-term survival. Among women who survived at least 5 years after breast cancer diagnosis, other clinical factors may be more predictive of breast cancer survival.

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry., Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP)., Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 -8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 -7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 -7 , HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster., Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I 2 values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR = 1.01, 95% CI 0.76-1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR = 0.80, 95% CI 0.61-1.03) and NSHDS cohorts (continuous RR = 0.73, 95% CI 0.54-0.97). The inverse association was also evident in the meta-analysis (continuous RR = 0.84, 95% CI 0.69-1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis., (© 2018 UICC.)

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER + or PR + /HER2 - ), 1,368 luminal B-like (ER + or PR + /HER2 + ), 521 HER2-enriched (ER - /PR - /HER2 + ), and 1,152 triple-negative (ER - /PR - /HER2 - ) disease. Ever parous compared with never was associated with lower risk of luminal A-like (HR, 0.78; 95% CI, 0.73-0.83) and luminal B-like (HR, 0.74; 95% CI, 0.64-0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02-1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause ( P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer ( P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies. Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011-21. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin-like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was carried out using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (OR hom  = 3.05, 95%CI = 1.72-5.44, P hom  = 1.47 × 10 -4 ), MAST2-rs12124649 (OR hom  = 1.73, 95% CI =1.18-2.54, P hom  = 5.24 × 10 -3 ), and INSR-rs10500204 (OR hom  = 1.96, 95% CI = 1.44-2.67, P hom =1.68 × 10 -5 ) were associated with increased risk of BCIS; however, only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with the risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (OR hom  = 1.78, 95% CI = 1.30-2.44, P hom  = 3.23 × 10 -4 ). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further., (© 2017 UICC.)

Purpose: Nearly half of the 3.5 million female breast cancer survivors in the US are aged 65 years or older at diagnosis, yet little is known about associations of obesity and physical activity with breast cancer-specific mortality (BCSM) among older survivors., Methods: Between 1992 and 2013, 5254 women in the Cancer Prevention Study-II Nutrition Cohort were diagnosed with local or regional breast cancer among whom 1771 deaths (505 breast cancer deaths) occurred. Multivariable Cox proportional hazards regression models were used to examine associations of pre- and post-diagnosis body mass index (BMI) and moderate-vigorous physical activity (MET-hours/week) with mortality outcomes stratified by age at diagnosis (<65, ≥65 years)., Results: Among women ≥65 years of age at diagnosis (n = 4226), pre- and post-diagnosis BMI (per 5 kg/m 2 ) were associated with a higher risk of BCSM (pre-diagnosis, HR 1.27, 95% CI 1.14-1.41; post-diagnosis, HR 1.19, 95% CI 1.04, 1.36); neither pre- nor post-diagnosis physical activity was associated with BCSM. Among women <65 years of age at diagnosis (n = 1028), BMI at both time points were not significantly associated with BCSM; however, there was a significant inverse trend of post-diagnosis physical activity with BCSM (P-trend = 0.01). Among both age groups, BMI and physical activity, regardless of when assessed, were significantly associated with all-cause mortality., Conclusions: Higher BMI, pre- or post-diagnosis, was associated with a higher risk of BCSM in older patients, independent of comorbidities and stage at diagnosis. Weight management should be discussed even with women aged 65 years or older to lower rates of BCSM.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer., Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis., Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95)., Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases., (© The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association)

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (OR int  = 0.77, 95% CI: 0.67-0.88, p int  = 1.8 × 10 -4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (OR int =1.36, 95% CI: 1.16-1.59, p int  = 1.9 × 10 -5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (OR int  = 1.26, 95% CI: 1.12-1.43, p int =1.8 × 10 -4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (OR int  = 0.89, 95% CI: 0.83-0.95, p int  = 5.2 × 10 -4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed., (© 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status., Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident., Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Purpose: Due to the limited evidence on the role of diet and cause-specific mortality among breast cancer survivors, current nutrition guidelines for this population are consistent with those for cancer prevention. We evaluated whether diets consistent with the American Cancer Society recommendations for cancer prevention were associated with risk of death in breast cancer survivors., Methods: Participants reported information on diet and other factors at baseline in 1992-1993 and twice during follow-up. A nine-point score reflecting concordance with diet recommendations was calculated. Multivariable-adjusted relative risks (RR) and 95 % confidence intervals (CI) for diet score in relation to overall and cause-specific mortality were computed using Cox proportional hazards regression methods., Results: Among 4,452 women diagnosed with locally and regionally staged breast cancer after baseline and until 2011, 1,204 died during follow-up through 2012 (398 from breast cancer). Prediagnostic diet score was not associated with mortality from any cause. Postdiagnostic diet score was associated with neither breast cancer-specific mortality (RR 1.44, 95 % CI 0.90-2.30 for scores 6-9 vs 0-2) nor cardiovascular disease mortality (RR 0.81, 95 % CI 0.47-1.39), but compared to a score of 0-2, a score of 6-9 was associated with a borderline lower risk of other causes of death (RR 0.78, 95 % CI 0.56-1.07, p trend  = 0.03; per two-point increase in score RR 0.88, 95 % CI 0.79-0.99). Of diet score components, only limiting red and processed meat consumption was associated with statistically significantly lower risk of total, CVD, and other non-breast cancer mortality., Conclusions: Diets consistent with guidelines for cancer prevention were not associated with breast cancer-specific mortality. However, their association with other causes of mortality underscores the importance of consuming a healthy diet in this population.

Importance: An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention., Objective: To evaluate combined risk stratification utility of common low penetrant single nucleotide polymorphisms (SNPs) and epidemiologic risk factors., Design, Setting, and Participants: Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality., Exposures: Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors., Main Outcomes and Measures: Degree of stratification of absolute risk owing to nonmodifiable (SNPs, family history, height, and some components of menstrual and/or reproductive history) and modifiable factors (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], menopausal hormone therapy [MHT], alcohol, and smoking)., Results: The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population., Conclusions and Relevance: This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation.

Background: Dietary energy density (ED) is a measure of diet quality that estimates the amount of energy per unit of food (kilocalories per gram) consumed. Low-ED diets are generally high in fiber and fruits and vegetables and low in fat. Dietary ED has been positively associated with body mass index (BMI) and other risk factors for postmenopausal breast cancer., Objective: We evaluated the associations of total dietary ED and energy-dense (high-ED) foods with postmenopausal breast cancer incidence., Methods: Analyses included 56,795 postmenopausal women from the Cancer Prevention Study II Nutrition Cohort with no previous history of breast or other cancers and who provided information on diet, lifestyle, and medical history in 1999. Multivariable-adjusted breast cancer incidence rate ratios (RRs and 95% CIs) were estimated for quintiles of total dietary ED and for the consumption of high-ED foods in Cox proportional hazards regression models., Results: During a median follow-up of 11.7 y, 2509 invasive breast cancer cases were identified, including 1857 estrogen receptor-positive and 277 estrogen receptor-negative tumors. Median dietary ED was 1.5 kcal/g (IQR: 1.3-1.7 kcal/g). After adjusting for age, race, education, reproductive characteristics, and family history, high compared with low dietary ED was associated with a statistically significantly higher risk of breast cancer (RR for fifth quintile compared with first quintile: 1.20; 95% CI: 1.05, 1.36; P-trend = 0.03). The association between the amount of high-ED foods consumed and breast cancer risk was not statistically significant. We observed no differences by estrogen receptor status or effect modification by BMI, age, or physical activity., Conclusion: These results suggest a modest positive association between total dietary ED and risk of postmenopausal breast cancer., (© 2016 American Society for Nutrition.)

Unlabelled: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Background: Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts., Methods: During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model., Results: Alcohol consumption was positively associated with risk of ER+ and ER- breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing ≥ 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER- breast cancer (Ptrend ≤ 0.001; Pcommon-effects by ER status: 0.57). Associations were similar for alcohol intake from beer, wine and liquor. The associations with alcohol intake did not vary significantly by total (from foods and supplements) folate intake (Pinteraction ≥ 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER- breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status., Conclusions: Alcohol consumption was positively associated with risk of both ER+ and ER- breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

Current use of menopausal hormone therapy (MHT) has important implications for postmenopausal breast cancer risk, and observed associations might be modified by known breast cancer susceptibility loci. To provide the most comprehensive assessment of interactions of prospectively collected data on MHT and 17 confirmed susceptibility loci with invasive breast cancer risk, a nested case-control design among eight cohorts within the NCI Breast and Prostate Cancer Cohort Consortium was used. Based on data from 13,304 cases and 15,622 controls, multivariable-adjusted logistic regression analyses were used to estimate odds ratios (OR) and 95 % confidence intervals (CI). Effect modification of current and past use was evaluated on the multiplicative scale. P values <1.5 × 10(-3) were considered statistically significant. The strongest evidence of effect modification was observed for current MHT by 9q31-rs865686. Compared to never users of MHT with the rs865686 GG genotype, the association between current MHT use and breast cancer risk for the TT genotype (OR 1.79, 95 % CI 1.43-2.24; P interaction = 1.2 × 10(-4)) was less than expected on the multiplicative scale. There are no biological implications of the sub-multiplicative interaction between MHT and rs865686. Menopausal hormone therapy is unlikely to have a strong interaction with the common genetic variants associated with invasive breast cancer.

The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS (HRper-allele =0.70; 95% CI: 0.58-0.85; ptrend  = 2.84 × 10(-4) ; HRheterozygotes  = 0.71; 95% CI: 0.55-0.92; HRhomozygotes  = 0.48; 95% CI: 0.31-0.76; p2DF  = 1.45 × 10(-3) ). In silico, the C allele of LSP1-rs3817198 was predicted to increase expression of the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C). In the meta-analysis, TNRC9-rs3803662 was significantly associated with increased death hazard (HRMETA =1.09; 95% CI: 1.04-1.15; ptrend  = 6.6 × 10(-4) ; HRheterozygotes  = 0.96 95% CI: 0.90-1.03; HRhomozygotes  = 1.21; 95% CI: 1.09-1.35; p2DF =1.25 × 10(-4) ). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1-rs3817198 and TNRC9-rs3803662., (© 2015 UICC.)

Purpose: Several circulating carotenoids have been inversely associated with postmenopausal breast cancer risk in large cohort studies and a pooled analysis. Whether associations differ by tumor or participant characteristics remains unclear. We investigated the associations of plasma carotenoids with postmenopausal breast cancer risk overall and by estrogen receptor (ER) status, tumor stage, smoking status, and body mass index, in a case-control study nested in the Cancer Prevention Study II Nutrition Cohort., Methods: A total of 496 invasive breast cancer cases diagnosed between blood draw in 1998-2001 and June 30, 2007 and matched 1:1 with controls on race, birth date, and blood draw date were included. Multivariable-adjusted conditional and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Plasma α-carotene above the lowest quartile was associated with significant 40-43% lower risk of invasive breast cancer risk (fourth vs. first quartile OR 0.60, 95% CI 0.41-0.87, P-trend = 0.037) after adjustment for multiple covariates. This inverse association was strengthened after further adjustment for other plasma carotenoids and total fruit and vegetable intake (fourth vs. first quartile OR 0.50, 95% CI 0.29-0.85, P-trend = 0.041). Other plasma carotenoids or total carotenoids were not associated with breast cancer risk. The inverse association of α-carotene with breast cancer remained for ER+, but not for ER- tumors, although test for heterogeneity was not statistically significant (P-heterogeneity = 0.49)., Conclusions: These results suggest that higher plasma α-carotene is associated with lower risk of invasive breast cancer.

Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS., Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile., Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies., Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.

Introduction: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium., Methods: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect., Results: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease., Conclusions: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival., Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided., Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust., Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors., (© The Author 2015. Published by Oxford University Press.)

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

Background: Results from preclinical studies suggest that flavonoids, which are ubiquitous in plant-based diets, lower breast cancer risk. Epidemiologic studies of flavonoid intake and breast cancer risk, however, are limited, and few investigated associations with the more aggressive estrogen receptor (ER)-negative (ER-) tumors., Objective: We examined the associations between 7 subclasses of dietary flavonoids and invasive postmenopausal breast cancer risk overall and by ER status in a U.S. prospective cohort., Methods: In 1999-2000, 56,630 postmenopausal women completed detailed self-administered questionnaires, among whom 2116 invasive breast cancers were verified during a mean follow-up period of 8.5 y. Cox proportional hazards regression was used to calculate multivariable-adjusted HRs and 95% CIs., Results: Total flavonoid intake was not associated with breast cancer risk. However, there was a modest inverse association between flavone intake and overall breast cancer risk (fifth vs. first quintile HR: 0.88; 95% CI: 0.76, 1.01; P-trend = 0.04) and between flavan-3-ol intake and risk of ER- breast cancer (for an increment of 40 mg/d; HR: 0.81; 95% CI: 0.67, 0.97) but not for ER-positive (ER+) breast cancer risk., Conclusion: The inverse association of flavan-3-ol intake with ER- but not ER+ breast cancer is consistent with other studies that suggest a beneficial role of plant-based diets in ER- breast cancer risk., (© 2014 American Society for Nutrition.)

We studied the interplay between 39 breast cancer (BC) risk SNPs and established BC risk (body mass index, height, age at menarche, parity, age at menopause, smoking, alcohol and family history of BC) and prognostic factors (TNM stage, tumor grade, tumor size, age at diagnosis, estrogen receptor status and progesterone receptor status) as joint determinants of BC risk. We used a nested case-control design within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), with 16 285 BC cases and 19 376 controls. We performed stratified analyses for both the risk and prognostic factors, testing for heterogeneity for the risk factors, and case-case comparisons for differential associations of polymorphisms by subgroups of the prognostic factors. We analyzed multiplicative interactions between the SNPs and the risk factors. Finally, we also performed a meta-analysis of the interaction ORs from BPC3 and the Breast Cancer Association Consortium. After correction for multiple testing, no significant interaction between the SNPs and the established risk factors in the BPC3 study was found. The meta-analysis showed a suggestive interaction between smoking status and SLC4A7-rs4973768 (Pinteraction = 8.84 × 10(-4)) which, although not significant after considering multiple comparison, has a plausible biological explanation. In conclusion, in this study of up to almost 79 000 women we can conclusively exclude any novel major interactions between genome-wide association studies hits and the epidemiologic risk factors taken into consideration, but we propose a suggestive interaction between smoking status and SLC4A7-rs4973768 that if further replicated could help our understanding in the etiology of BC., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: High body mass index (BMI) is an established risk factor for postmenopausal breast cancer. However, less is known about associations with waist circumference. In particular, it is unclear whether a larger waist circumference is associated with risk more than would be expected based solely on its contribution to BMI., Methods: We examined the associations of BMI and waist circumference with risk of postmenopausal breast cancer, with and without mutual adjustment, in the Cancer Prevention Study-II Nutrition Cohort. Analyses included 28,965 postmenopausal women who reported weight and waist circumference on a questionnaire in 1997 and were not taking menopausal hormones., Results: During a median follow-up of 11.58 years, 1,088 invasive breast cancer cases were identified. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated from multivariable-adjusted Cox proportional hazard regression models. Without adjustment for BMI, a larger waist circumference was associated with higher risk of breast cancer (per 10 cm increase in waist circumference, HR = 1.13, 95 % CI 1.08-1.19). However, adjustment for BMI eliminated the association with waist circumference (per 10 cm HR = 1.00, 95 % CI 0.92-1.08). BMI was associated with risk unadjusted for waist circumference (per 1 kg/m(2) HR = 1.04, 95 % CI 1.03-1.05) and adjusted for waist circumference (per 1 kg/m(2) HR = 1.04, 95 % CI 1.02-1.06)., Conclusions: Our study of predominantly white women provides evidence that a larger waist circumference is associated with higher risk of postmenopausal breast cancer, but not beyond its contribution to BMI.

Epidemiologic evidence supports an inverse association between physical activity and postmenopausal breast cancer. Whether associations exist for moderate activities, such as walking, and whether associations differ by estrogen receptor (ER) status, body mass index (BMI, kg/m(2)), adult weight gain, or use of postmenopausal hormones (PMH) is unclear. The relation between time spent sitting and breast cancer also is unclear. Among 73,615 postmenopausal women in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, 4,760 women were diagnosed with breast cancer between 1992 and 2009. Extended Cox regression was used to estimate multivariable-adjusted relative risks (RR) of breast cancer in relation to total recreational physical activity, walking, and leisure-time sitting. Differences in associations by ER status, BMI, weight gain, and PMH use were also evaluated. The most active women (those reporting >42 MET-hours/week physical activity) experienced 25% lower risk of breast cancer than the least active [0-<7 MET-hours/week; 95% confidence interval (CI), 0.63-0.89; Ptrend = 0.01]. Forty-seven percent of women reported walking as their only recreational activity; among these women, a 14% lower risk was observed for ≥7 hours/week relative to ≤3 hours/week of walking (95% CI, 0.75-0.98). Associations did not differ by ER status, BMI, weight gain, or PMH use. Sitting time was not associated with risk. These results support an inverse association between physical activity and postmenopausal breast cancer that does not differ by ER status, BMI, weight gain, or PMH use. The finding of a lower risk associated with ≥7 hours/week of walking may be of public health interest.

Background: Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single-nucleotide polymorphisms (SNPs) in β-carotene 15,15'-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium., Methods: We used unconditional logistic regression to test four SNPs in BCMO1 for associations with breast cancer risk in 9,226 cases and 10,420 controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also tested weighted multi-SNP scores composed of the two SNPs with strong, confirmed associations with circulating carotenoid concentrations., Results: Neither the individual SNPs nor the weighted multi-SNP scores were associated with breast cancer risk [OR (95% confidence interval) comparing extreme quintiles of weighted multi-SNP scores = 1.04 (0.94-1.16) for β-carotene, 1.08 (0.98-1.20) for α-carotene, 1.04 (0.94-1.16) for β-cryptoxanthin, 0.95 (0.87-1.05) for lutein/zeaxanthin, and 0.92 (0.83-1.02) for retinol]. Furthermore, no associations were observed when stratifying by estrogen receptor status, but power was limited., Conclusions: Our results do not support an association between SNPs associated with circulating carotenoid concentrations and breast cancer risk., Impact: Future studies will need additional genetic surrogates and/or sample sizes at least three times larger to contribute evidence of a causal link between carotenoids and breast cancer.

Background: The relationship between active cigarette smoking and breast cancer risk remains controversial because of unresolved issues of confounding and dose response., Methods: To investigate these issues further, we analyzed data from 73 388 women in the American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort. Analyses were based on 3721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from multivariable-adjusted Cox proportional hazard regression models. P values were two-sided. We also conducted meta-analyses of our results with those published from 14 other cohort studies., Results: In CPS-II, incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR =1.13, 95% CI = 1.06 to 1.21) than in never smokers. Women who initiated smoking before menarche (HR = 1.61, 95% CI = 1.10 to 2.34) or after menarche but 11 or more years before first birth (HR = 1.45, 95% CI = 1.21 to 1.74) had higher risk (P trend = .03). No relationships were observed with other smoking parameters. Alcohol consumption did not confound associations with smoking status, although neither current nor former smoking were associated with risk among never drinkers (P interaction = .11). In meta-analyses, current (HR = 1.12, 95% CI = 1.08 to 1.16) and former smoking (HR = 1.09, 95% CI = 1.04 to 1.15) were weakly associated with risk; a stronger association (HR = 1.21, 95% CI = 1.14 to 1.28) was observed in women who initiated smoking before first birth., Conclusions: These results support the hypothesis that active smoking is associated with increased breast cancer risk for women who initiate smoking before first birth and suggest that smoking might play a role in breast cancer initiation.