Risk Of ER-negative Breast Cancer Research Articles

Ferritin and Serum Iron in a Causal Relationship with Estrogen Receptor-Negative Breast Cancer: a Two-Sample Mendelian Randomization Study.

The aim of this study was to explore the causal relationship between different serum iron statuses (ferritin, transferrin, transferrin saturation, and serum iron) and the occurrence of estrogen receptor (ER)-positive or ER-negative breast cancer. The summary data on serum iron status exposure were gathered from the IEU OpenGWAS Project, the UK Biobank, and other databases. Concurrently, the summary data for ER+ and ER- breast cancer are sourced from the Breast Cancer Association Consortium (BCAC). By examining the causal link between iron status and breast cancer, we deployed five distinct Mendelian randomization (MR) algorithms, namely MR-Egger, inverse variance weighted (IVW), weighted median, simple mode, and MR-PRESSO. To assess heterogeneity and horizontal pleiotropy, Cochran's Q and MR-Egger algorithms were applied, respectively. Elevated ferritin levels are associated with an increased risk of ER-negative breast cancer (OR(IVW) = 1.042, 95% CI (1.005, 1.081), p = 0.025; OR (weighted median) = 1.050, 95% CI (1.001, 1.102), p = 0.046; and OR (MR-PRESSO) = 1.042, 95% CI (1.005, 1.081), p = 0.039). Conversely, an increase in the serum iron level is linked to a reduced risk of ER-negative breast cancer (OR (IVW) = 0.791, 95% CI (0.649, 0.962), p = 0.019; and OR (MR-PRESSO) = 0.791, 95% CI (0.649, 0.962), p = 0.028). However, there is no evidence of a causal relationship between transferrin, transferrin saturation, and ER-negative breast cancer. For ER-positive breast cancer, none of the four different iron statuses demonstrated a causal relationship. Ferritin is positively correlated with ER-negative breast cancer, while serum iron is negatively associated with ER-negative breast cancer. However, there is no causal relationship between the four iron statuses and ER-positive breast cancer.

Abstract 3011: Psychosocial stress, social support, and incident breast cancer by estrogen receptor status

Abstract Introduction: Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. We investigated the relationship between stressful life events and incident breast cancer by ER status among postmenopausal women. We further evaluated whether this association is modified by social support. Methods: Our analysis included 76,951 postmenopausal women enrolled in the Women’s Health Initiative. Participants were followed for events for up to 26 years (median, 16.7). We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for associations between baseline self-reported stressful life events and incident breast cancer by ER status. Results: The mean age was 63 (SD 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared to women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs Quartile 1; HR=1.30; 95%CI 1.01-1.68; Ptrend=0.050). Additionally, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR=2.39; 95%CI 1.29-4.44; Pinteraction<0.001). Moreover, while the interaction was not statistically significant, we observed an elevated risk for ER-negative breast cancer among women in the highest quartile of stressful life events reporting lower social support. Conclusion: In this cohort of postmenopausal women, higher experiences of pre-diagnostic stressful life events were associated with increased risk of ER-negative breast cancer. Citation Format: Wayne R. Lawrence, Jasmine A. McDonald, Faustine Williams, Meredith S. Shiels, Neal D. Freedman, Ziqiang Lin, Jared W. Magnani. Psychosocial stress, social support, and incident breast cancer by estrogen receptor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3011.

Abstract 6470: Coffee and tea consumption, coffee-related metabolites, and breast cancer risk in US Women

Abstract Background: Coffee intake may protect against breast cancer; however, previous studies have been inconsistent and potential underlying mechanisms remain unclear. We aimed to 1) examine the association between total coffee, tea, and caffeine intake and breast cancer risk and 2) identify plasma metabolites associated with coffee intake and examine these metabolites in relation to breast cancer risk. Methods: Data on breast cancer risk factors were collected from questionnaires administered biennially and at the time of blood collections (Nurses’ Health study, NHS, distant collection: 1989-1990, recent collection: 2000-2002; NHSII, 1996-1999). We evaluated the association between total coffee (caffeinated and decaffeinated), tea consumption and caffeine intake and breast cancer risk in the full cohort using Cox regression models. Leveraging dietary and metabolomic data, we identified and validated plasma metabolites associated with coffee intake in 2,033 women from the NHSII breast cancer sub-study. We then evaluated the prospective association of all prior (PMID: 32788283) and new coffee-related metabolites with breast cancer risk in a nested case-control study using conditional logistic regression models. Results: We documented 10,060 cases of invasive breast cancer during 3,901,211 person-years of follow-up. In pooled, multivariable-adjusted models, compared to never consumers (0 cups/d), women consuming ≥6 cups/d of total coffee were at lower risk of invasive breast cancer (HR, 0.91; 95% CI, 0.82, 1.00; P-trend<0.01). Stratified analysis showed a significant effect modification by BMI (P-interaction=0.03). Compared to never consumers, drinking ≥6 cups of coffee per day was inversely associated with risk of invasive breast cancer among lean women (HR, 0.83; 95% CI, 0.72, 0.97) but not among overweight or obese women. Moreover, a lower risk of ER-negative breast cancer was observed with total coffee (HR ≥6 cups/d vs. 0 cups/day 0.75; 95% CI, 0.59, 0.95; P-trend=0.01) and decaffeinated coffee consumption (HR ≥4 cups/d vs. o cups/day 0.66; 95% CI, 0.45, 0.95; P-trend=0.01). Among the 31 studied metabolites, no single metabolite was associated with breast cancer risk. Associations were generally consistent between ER-positive and ER-negative breast cancer, although trigonelline seemed to be suggestively stronger for ER-negative (OR, 95% CI, 0.87, 0.75-1.01; P-value=0.061). Furthermore, 1,7-dimethyluric acid, some cholesterol esters (C18:1 CE, C18:2 CE and C20:4 CE) and trigonelline, all positively associated with coffee, were indicative of an inverse association with breast cancer risk among lean women. Conclusions: Coffee consumption was associated with lower breast cancer risk, particularly among lean women and ER-negative breast cancer. Some metabolites that might explain some of the observed inverse associations. Nonetheless, these results merit further exploration. Citation Format: Andrea Romanos-Nanclares, Oana A. Zeleznik, Mingyang Song, Walter C. Willett, Rulla M. Tamimi, Wendy Y. Chen, Michelle D. Holmes, Jae Hee Kang, A. Heather Eliassen. Coffee and tea consumption, coffee-related metabolites, and breast cancer risk in US Women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6470.

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.

A Mendelian randomization study of the effect of tea intake on breast cancer.

The relationship between tea consumption and the risk of breast cancer is inconsistent in previous observational studies and is still in dispute. We intended to detect the causal association between tea consumption and breast cancer risk using two-sample Mendelian randomization (MR) analysis. The summary statistics of tea consumption was obtained from the UK Biobank Consortium with 349,376 individuals and breast cancer information was obtained from the Breast Cancer Association Consortium (BCAC) (122,977 cases and 105,974 non-cases). Sensitivity analyses of evaluating the influence of outliers and pleiotropy effects were performed by a variety of MR methods under different model assumptions. After potentially excluding pleiotropic single nucleotide polymorphisms (SNPs) using the MR Pleiotropy RESidual Sum and Outlier method, the odds ratio (OR) for per extra daily cup of tea intake for overall, estrogen receptor (ER)-positive, and ER-negative breast cancer risk was 1.029 [95% confidence interval (CI) = 0.983-1.077, P = 0.2086], 1.050 (95% CI = 0.994-1.109, P = 0.078), and 1.081 (95% CI = 0.990-1.103, P = 0.6513), respectively. The results were consistent with a sensitivity analysis that excluded SNPs associated with other phenotypes, manifesting that the findings were convincing and robust. Moreover, in the multivariable MR analysis, the null associations for breast cancer risk remained after adjusting for smoking and alcohol consumption separately or together. Our MR results based on genetic data did not support a causal relationship between tea consumption and breast cancer risk.

Targeting the mTOR Pathway for the Prevention of ER-Negative Breast Cancer.

Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787.

Association between Breast Cancer Polygenic Risk Score and Chemotherapy-Induced Febrile Neutropenia: Null Results

Simple SummaryThe most common complication of chemotherapy for cancer patients is febrile neutropenia (FN). This is an abnormally low blood neutrophil count coupled with a fever that leaves patients susceptible to fatal infections. Genetic variants for breast cancer risk linked to chemotherapy-induced toxicity have been previously explored. We study the association between a validated 313 genetic marker-based breast cancer polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever, and febrile neutropenia (FNc) in Asian breast cancer patients treated with chemotherapy. PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were 9% less likely to develop neutropenia, and 13% less likely to develop FNc. However, the associations were not statistically significant. No dose-dependent trend was observed for the estrogen receptor- (ER-) positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). Breast cancer PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.Background: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients. Methods: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls. Results: PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79–1.06]; FNc: 0.87 [0.73–1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

Two distinct mechanisms underlie estrogen-receptor-negative breast cancer susceptibility at the 2p23.2 locus.

Genome wide-association studies (GWAS) have established over 400 breast cancer risk loci defined by common single nucleotide polymorphisms (SNPs), including several associated with estrogen-receptor (ER)-negative disease. Most of these loci have not been studied systematically and the mechanistic underpinnings of risk are largely unknown. Here we explored the landscape of genomic features at an ER-negative breast cancer susceptibility locus at chromosome 2p23.2 and assessed the functionality of 81 SNPs with strong evidence of association from previous fine mapping. Five candidateregulatory regions containing risk-associated SNPs were identified. Regulatory Region 1 in the first intron of WDR43 contains SNP rs4407214, which showed allele-specific interaction with the transcription factor USF1 in in vitro assays. CRISPR-mediated disruption of Regulatory Region 1 led to expression changes in the neighboring PLB1 gene, suggesting that the region acts as a distal enhancer. Regulatory Regions 2, 4, and 5 did not provide sufficient evidence for functionality in in silico and experimental analyses. Two SNPs (rs11680458 and rs1131880) in Regulatory Region 3, mapping to the seed region for miRNA-recognition sites in the 3' untranslated region of WDR43, showed allele-specific effects of ectopic expression of miR-376 on WDR43 expression levels. Taken together, our data suggest that risk of ER-negative breast cancer associated with the 2p23.2 locus is likely driven by a combinatorial effect on the regulation of WDR43 and PLB1.

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies

Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n=37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend>0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR=0.90, 95% CI: 0.83, 0.98 comparing≥60 g/d with<1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing≥25 g/d with<1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR=0.98, 95% CI: 0.97, 0.99 per 350mg/d). Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.

Serum iron status and the risk of breast cancer in the European population: a two-sample Mendelian randomisation study

BackgroundPrevious observational studies have provided conflicting results on the association between serum iron status and the risk of breast cancer. Considering the relevance of this relationship to breast cancer prevention, its elucidation is warranted.ObjectWe used a two-sample Mendelian randomisation (MR) study to explore the causal relationship between serum iron status and the risk of breast cancer.MethodTo select single nucleotide polymorphisms (SNPs) that could be used as instrumental variables for iron status, we used the Genetics of Iron Status consortium, which includes 11 discovery and 8 replication cohorts, encompassing 48,972 individuals of European descent. Moreover, we used the OncoArray network to select SNPs that could be considered instrumental variables for the outcome of interest (breast cancer); this dataset included 122,977 individuals of European descent with breast cancer and 105,974 peers without breast cancer. Both conservative (SNPs associated with overall iron status markers) and liberal (SNPs associated with the levels of at least one iron status marker) approaches were used as part of the MR analysis. For the former, we used an inverse-variance weighted (IVW) method, whereas for the latter, we used the IVW, MR-Egger regression, weighted median and simple mode methods.ResultsWhen the conservative approach was used, iron status showed no significant association with the risk of breast cancer or any of its subtypes. However, when the liberal approach was used, transferrin levels were found to be positively associated with the risk of ER-negative breast cancer based on the simple mode method (OR for MR, 1.225; 95% CI, 1.064, 1.410; P = 0.030). Nevertheless, the levels of the other iron status markers showed no association with the risk of breast cancer or its subtypes (P > 0.05).ConclusionIn our MR study, the liberal approach suggested that changes in the concentration of transferrin could increase the risk of ER-negative breast cancer, although the levels of other iron status markers had no effect on the risk of breast cancer or its subtypes. This should be verified in future studies.

Abstract 837: Healthful and unhealthful plant-based diets and risk of breast cancer in U.S. women: Results from the Nurses' Health Studies

Abstract Purpose: Plant-based diets have been associated with lower risk of various diseases, including type 2 diabetes, cardiovascular disease and other cardiometabolic risk factors and are recommended for both health and environmental benefits. However, the association between plant-based diet quality and breast cancer remains unclear. Therefore, we examined the associations of plant-based diet quality with risk of total and subtypes of breast cancer. Methods: We followed 74,516 women from the Nurses' Health Study (NHS, 1984-2016), and 93,915 women from the Nurses' Health Study II (NHSII, 1991-2017), without cancer at baseline. Incident invasive breast cancer cases were confirmed with medical records, and subtypes were determined by tissue microarray data and pathology reports. We assessed an overall plant-based diet index (PDI) from dietary data collected using repeated semi-quantitative food-frequency questionnaires (FFQ), by assigning positive scores to plant foods and reverse scores to animal foods. We also investigated a healthful PDI (hPDI) where healthy plant foods (whole grains, fruits/vegetables, nuts/legumes, oils, tea/coffee) received positive scores, while less healthy plant foods (juices/sweetened beverages, refined grains, potatoes/fries, sweets) and animal foods received reverse scores. We also assessed an unhealthful PDI (uPDI), assigning positive scores to less healthy plant foods, and reverse scores to healthy plant foods and animal foods. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were calculated with Cox proportional hazards models using data pooled across cohorts, adjusting for breast cancer risk factors. Results: Over 4,193,915 person-years of follow-up, we documented 11,281 incident invasive breast cancer cases. Women with greater adherence to PDI were at modestly lower risk of breast cancer [HR Q5vsQ1 0.92; 95% CI 0.86, 0.99; p trend=0.02]. Furthermore, greater adherence to a hPDI was associated with a decreased risk of overall breast cancer [HR Q5vsQ1 0.90; 95% CI 0.85, 0.96, p trend=&amp;lt;0.001]. We observed significant heterogeneity by estrogen receptor (ER) status (p=0.01), with the strongest inverse association between hPDI and breast cancer observed with ER-negative tumors [HR Q5vsQ1 0.75; 95% CI 0.64, 0.89; p trend=&amp;lt;0.001]. Moreover, higher uPDI was positively associated with a higher risk of ER-negative breast cancer [HR Q5vsQ1 1.21; 95% CI 1.02, 1.44; p trend=0.02] (p for heterogeneity=0.03). Conclusions: This study provides evidence that adherence to a plant-based dietary pattern and, specifically, its healthful version, may reduce the risk of breast cancer, especially those that are more likely to be aggressive tumors. In contrast, a low-quality plant-based diet may be associated with an increased risk of ER-negative breast cancer. Citation Format: Andrea Romanos-Nanclares, Walter C. Willett, Bernard Rosner, Laura C. Collins, Frank B. Hu, Estefania Toledo, A. Heather Eliassen. Healthful and unhealthful plant-based diets and risk of breast cancer in U.S. women: Results from the Nurses' Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 837.

Lipids, Anthropometric Measures, Smoking and Physical Activity Mediate the Causal Pathway From Education to Breast Cancer in Women: A Mendelian Randomization Study.

PurposeWe aimed to investigate whether obtaining a higher level of education was causally associated with lower breast cancer risk and to identify the causal mechanism linking them.MethodsThe main data analysis used publicly available summary-level data from 2 large genome-wide association study consortia. Mendelian randomization (MR) analysis used 65 genetic variants derived from the Social Science Genetic Association Consortium as instrumental variables for years of schooling. The outcomes from the Breast Cancer Association Consortium (BCAC) were the overall breast cancer risk (122,977 cases/105,974 controls in women) and the two subtypes: estrogen receptor (ER)-positive breast cancer and ER-negative breast cancer. Fixed and random effects inverse variance weighted methods were used to estimate the causal effects, along with other additional MR methods for sensitivity analyses.ResultsResults showed that each additional standard deviation of 4.2 years of education was causally associated with a 27% lower risk of ER-negative breast cancer (odds ratio, 0.73; 95% confidence interval, 0.64–0.84; p-value < 0.001). This finding was consistent with the results of the sensitivity analyses. Physical activities can help improve the protective effect of education against breast cancer, with relatively large mediation proportions. Education increases the risk of ER-positive breast cancer due to alterations in high-density lipoprotein level, triglyceride level, height, waist-to-hip ratio, body mass index, and smoking status, with relative medium mediation proportions. Other mediators including low-density lipoprotein, hip circumference, number of cigarettes smoked per day, time spent performing light physical activity, and performing vigorous physical activity for > 10 minutes explain a small part of the causal effect of education on the risk of developing breast cancer, and their mediation proportion is approximately 1%.ConclusionA low level of education is a causal risk factor in the development of breast cancer as it is associated with poor lipid profile, obesity, smoking, and types of physical activity.

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer

To determine whether genetically predicted circulating levels of cytokines are associated with risk of overall breast cancer (BC), estrogen receptor (ER)-positive and ER-negative BC, we conducted two-sample MR analyses using data from the most comprehensive genome-wide association studies (GWAS) on cytokines in 8293 Finnish participants and the largest BC GWAS from the Breast Cancer Association Consortium (BCAC) with totally 122,977 BC cases and 105,974 healthy controls. We systematically screened 41 cytokines (of which 24 cytokines have available instruments) and identified that genetically predicted circulating levels (1-SD increase) of MCP1 (OR: 1.08; 95% CIs: 1.03–1.12; P value: 3.55 × 10−4), MIP1b (OR: 1.02; 95% CIs: 1.01–1.04; P value: 2.70 × 10−3) and IL13 (OR: 1.06; 95% CIs: 1.03–1.10; P value: 3.33 × 10−4) were significantly associated with increased risk of overall BC, as well as ER-positive BC. In addition, higher levels of MIP1b and IL13 were also significantly associated with increased risk of ER-negative BC. These findings suggest the crucial role of cytokines in BC carcinogenesis and potential of targeting specific inflammatory cytokines for BC prevention.

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study

Soy-based dietary supplements have been promoted as natural alternatives to menopausal hormone therapy, but their potential effect on breast cancer development is controversial. We examined the relation between the consumption of soy supplements and the risk of breast cancer, overall and by tumor hormone receptor status, among women aged >50 y. In total, 76,442 women from the Etude Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort, born between 1925 and 1950, were followed from 2000 to 2011 (11.2 y on average, starting at a mean age of 59.5 y; 3608 incident breast cancers), with soy supplement use assessed every 2-3 y. HRs of breast cancer were estimated with the use of multivariable Cox models. Compared with never using soy supplements, the HRs associated with current use of soy supplements were 0.92 (95% CI: 0.76, 1.11) for all, 0.78 (95% CI: 0.60, 0.99) for estrogen receptor (ER)-positive, and 2.01 (95% CI: 1.41, 2.86) for ER-negative breast cancers. There was no association between past use of soy supplements and breast cancer. HRs for current use were 1.36 (95% CI: 0.95, 1.93) and 0.82 (95% CI: 0.65, 1.02) among women with and without a family history of breast cancer, respectively (P-interaction=0.03) and 1.06 (95% CI: 0.87, 1.30) ≥5y after menopause compared with 0.50 (95% CI: 0.31, 0.81) in premenopause or ≤5y postmenopause (P-interaction=0.04). In this cohort of women aged >50 y, we report opposing associations of soy supplements with ER-positive and ER-negative breast cancer risk. Our results also caution against the use of these supplements in women with a family history of breast cancer. Whether the risk profile of soy supplements could be more favorable among premenopausal or recently postmenopausal women deserves further investigation.

A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study

BackgroundIntakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting. Materials and methodsWe assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours. ResultsA high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4–Q1) 1.37; 95% confidence interval (CI), 1.14–1.64; P for trend=0.0001, q value=0.004] as well as a high desaturation index (DI16) (16:1n–7/16:0) [OR (Q4–Q1), 1.28; 95% C, 1.07–1.54; P for trend=0.002, q value=0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3–T1)=2.01; 95% CI, 1.03–3.90; P for trend=0.047], whereas no association was found for ER-positive tumours (P-heterogeneity=0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor. ConclusionThese findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

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.

Abstract 1288: Telomere length genetic risk score is associated with breast cancer risk

Abstract Background: Genome-wide association studies (GWAS) have identified associations of telomere maintenance genes with breast cancer risk. This, coupled with the recognized role of telomere dysfunction as a cancer hallmark, has motivated the need for further study of telomeres and breast cancer. Further, the meta-GWAS discovery of seven single nucleotide polymorphisms (SNPs) associated with telomere length (TL) enables the use of an aggregated genetic risk score (GRS) for TL. We hypothesized that a higher GRS (representing shorter TL) would be associated with increased risk of breast cancer, and that a strengthened association may exist between higher TL GRS and aggressive breast cancer risk. Methods: In a race/ethnically diverse sample of invasive breast cancer cases (N=1,108) and non-cases (N=20,023) from the Women’s Health Initiative, we derived an unweighted TL GRS using seven previously identified TL-associated SNPs. Women were postmenopausal and the average age at enrollment was 63.9 years. We tested TL GRS associations with overall breast cancer risk and for estrogen receptor (ER), progesterone receptor (PR), and her2/neu (HER2) status-specific breast cancer risk using Cox proportional hazards models adjusted for age and race/ethnicity (in the entire sample) and age in strata of European American (EA; N=9,796), African American (AA; N=7,504), and Hispanic American (HA; N=3,229) women. We also considered reproductive risk factors, family history of breast cancer, hormone therapy, tumor characteristics, BMI, physical activity, smoking, alcohol, and US region as potential confounders. Results: We observed a small but statistically significant association between higher TL GRS (shorter TL) and reduced risk of overall breast cancer in the entire sample (HR=0.96, 95% CI: 0.93-1.00). Results of race/ethnicity-stratified analyses for TL GRS and overall breast cancer risk were not significant. The TL GRS was independently associated with decreased risk of ER-negative, PR-positive, and HER2-positive breast cancer risk in the entire sample (HR=0.82, 95% CI: 0.71-0.94, HR=0.94, 95% CI: 0.89-0.99, and HR=0.88, 95% CI: 0.79-0.99, respectively). Similarly, the TL GRS was associated with a reduced risk of ER-negative breast cancer in AA (HR=0.79, 95% CI: 0.64-0.97) and independently with PR-positive and HER2-positive breast cancer risk in HA (HR=0.85, 95% CI: 0.75-0.97 and HR=0.79, 95% CI: 0.58-0.99, respectively). Adjustment for other covariates did not influence hazards. Conclusions: Our results suggest that higher TL GRS is associated with reduced risk of overall breast cancer and with the development of specific breast cancer subtypes, such as ER negativity and/or PR and HER2 positivity. While our focus on GWAS-implicated SNPs may not encompass the full spectrum of genes involved in TL, further studies into the potential mechanism for shorter TL and reduced breast cancer risk are needed. Citation Format: Laurie Grieshober, Jean Wactawski-Wende, Rachael Hageman Blair, Lina Mu, Leah Preus, Jing Nie, Jiali Han, Jaymie R. Meliker, Thomas Rohan, Heather M. Ochs-Balcom. Telomere length genetic risk score is associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1288. doi:10.1158/1538-7445.AM2017-1288

Sex hormone measurements using mass spectrometry and sensitive extraction radioimmunoassay and risk of estrogen receptor negative and positive breast cancer: Case control study in UK Collaborative Cancer Trial of Ovarian Cancer Screening (UKCTOCS)

IntroductionAssociations of endogenous sex hormone levels and all as well as estrogen-receptor (ER)-positive breast cancers are well described. However, studies investigating their association with ER-negative tumours are limited and none use accurate assays such as mass spectrometry. MethodsWithin the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a nested case-control study was undertaken of postmenopausal-women who developed ER-negative (n=92) or ER-positive (n=205) breast cancer after sample donation and 297 (1:1) age-matched controls. Androgens (testosterone and androstenedione) were measured using mass spectrometry and estradiol by extraction radioimmunoassay (RIA). Bioavailable estradiol and testosterone were calculated using the total hormone level and the sex hormone-binding globulin concentration. Subjects were classified according to the quartile range among controls. Logistic regression was used to estimate odds-ratio (OR) and 95% confidence-intervals (CI) of the associations between two factors and breast cancer risk. A separate analysis was done by stratifying the women based on whether they provided their samples less than or more than 2years before diagnosis. ResultsEstradiol and free estradiol were significantly higher prior to diagnosis of ER-negative breast cancer compared with controls while androgens and SHBG did not show any difference. Estradiol, free estradiol, free testosterone and SHBG were significantly higher before ER-positive breast cancer diagnosis compared with controls. Women had a twofold increased ER-negative breast cancer risk if estradiol and free estradiol were in the top quartile but not androgens (testosterone and androstenedione) or SHBG. These associations remained significant only when samples closer (median 1.1y before) to diagnosis were analyzed rather than farther from diagnosis (median 2.9y before). Women had a 2.34 (95% CI: 1.21–4.61, p=0.001), 2.21 (95% CI: 1.14–4.38, p=0.001), 2 (95% CI: 1.05–3.89, p=0.005) fold increased ER-positive breast cancer risk if estradiol, free estradiol and free testosterone respectively were in the top quartile. These associations remained significant regardless of whether the samples were collected less than or more than 2years prior to diagnosis. ConclusionIn postmenopausal women increased estrogens but not androgens are associated with ER-negative breast cancer. Previously reported associations of estradiol and free testosterone with ER-positive breast cancer are confirmed. The use of mass spectrometry and sensitive RIA add validity to these findings.

Gene-based analysis of the fibroblast growth factor receptor signaling pathway in relation to breast cancer in African American women: the AMBER consortium.

We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific estrogen receptor (ER) subtypes. Tagging single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 3237 SNPs in 3663 breast cancer cases (including 1983 ER-positive, and 1098 ER-negative) and 4687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint (AdaJoint) test to determine the association of each gene in the FGFR signaling pathway with overall breast cancer and ER subtypes. The FGF1 gene was significantly associated with risk of ER-negative breast cancer (P = 0.001). The FGFR2 gene was associated with risk of overall breast cancer (P = 0.002) and ER-positive breast cancer (P = 0.002). The FGF1 gene affects risk of ER-negative breast cancer in African American women. We confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes.