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The NanoString GeoMx digital spatial profiling is a new multiplexed platform that quantifies the abundance of tumor‐ and immune‐related proteins in a spatially resolved manner. We performed DSP for the simultaneous assessment of 52 analytes within spatially resolved tissue compartments defined by pan‐cytokeratin expression. We compared protein targets between 94 African American/Black and 65 European American/White cases, tumor and stromal tissue compartments, estrogen receptor alpha (ER)‐positive and ER‐negative cases, and explored potential biomarkers of survival. Of 33 analytes with robust signal for analysis, results were highly replicable. For a subset of markers, correlative analyses between DSP analytes and traditional immunohistochemistry scores revealed moderate to very strong associations between the two platforms. Similarly, DSP analytes and gene expression scores were concordant for 21 of 25 markers with overlap between the two datasets. Several analytes varied by ER status, and across the 25 immune markers surveyed, 14 had a significant inverse association with ER expression. B7 homolog 3 (B7‐H3; encoded by CD276) was the only analyte to show a significant difference by race, being lower in both the tumor and stromal compartments in Black women. DSP markers that were associated with survival included CD8, CD25, CD56, CD127, EpCAM, ER, Ki‐67, and STING. We conclude that DSP is an efficient tool for screening tumor‐ and immune‐related markers in a simultaneous fashion and yields results that are concordant with established immune profiling assays. DSP immune analytes were inversely associated with ER expression, in agreement with a substantial body of previous work that documents higher immune infiltration in ER‐negative breast cancers. This technology revealed that scores of the B7‐H3 protein were significantly lower in breast cancers from Black women compared with White women, an intriguing finding that requires replication in independent and racially diverse female populations., We evaluated the NanoString GeoMx digital spatial profiling platform for highly multiplexed immune profiling in a population of Black and White women with invasive breast cancer. Using DSP for discovery and conventional immunohistochemistry and gene expression data for validation, we found the DSP technology to be efficient, reproducible, and to yield results that are concordant with established immune profiling assays.

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

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

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

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P, GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

Background The mechanistic target of rapamycin (mTOR) pathway promoted by positive energy imbalance and insulin-like growth factors can be a mechanism by which obesity influences breast cancer risk. We evaluated the associations of body fatness with the risk of breast cancer varied with phosphorylated (p)-mTOR protein expression, an indication of the pathway activation. Methods Women with newly diagnosed breast cancer (n = 715; 574 [80%] Black and 141 [20%] White) and non-cancer controls (n = 1983; 1280 [64%] Black and 713 [36%] White) were selected from the Women’s Circle of Health Study. Surgical tumor samples among the cases were immunostained for p-mTOR (Ser2448) and classified as p-mTOR-overexpressed, if the expression level ≥ 75th percentile, or p-mTOR-negative/low otherwise. Anthropometrics were measured by trained staff, and body composition was determined by bioelectrical impedance analysis. Odds ratios (ORs) of p-mTOR-overexpressed tumors and p-mTOR-negative/low tumors compared to controls were estimated using polytomous logistic regression. The differences in the associations by the p-mTOR expression status were assessed by tests for heterogeneity. Results Cases with p-mTOR-overexpressed tumors, but not cases with p-mTOR-negative/low tumors, compared to controls were more likely to have higher body mass index (BMI), percent body fat, and fat mass index (P-heterogeneity P-heterogeneity = 0.27 and 0.48, respectively). Conclusions Our findings suggest that in this population composed of predominately Black women, body fatness is associated with breast cancer differently for p-mTOR overexpression and p-mTOR negative/low expression. Whether mTOR plays a role in the obesity and breast cancer association warrants confirmation by prospective studies.

Prior studies suggest a strong genetic influence on breast cancer prognosis. Six genome-wide association studies (GWAS) on breast cancer prognosis have been published to date. However, none of the reported loci was replicated across studies and only two passed genome-wide significance (P < 5 x 10-8). In the Pathways Study, a prospective cohort of breast cancer survivors begun in Kaiser Permanente Northern California (KPNC) in 2006, we carried out a GWAS of overall survival (OS) in 3,973 patients. Trans-ethnic meta-GWAS identified an association with OS of a locus on chromosome 15 that almost reached genome-wide significance (P = 9.42 x 10-8). This locus spanned the UACA gene, a key regulator of tumor suppressor Par-4. We found that receipt of chemotherapy modified the effect of the UACA locus on OS (Pinteraction = 2.4 x 10-4). This observation led us to hypothesize that the UACA locus effect on OS may be specific to Par-4 dependent chemotherapies, which include anti-HER2 therapy and doxorubicin. We stratified patients into two groups, those who received Par-4 dependent chemotherapy agents versus other patients. In separate trans-ethnic meta-GWAS, the UACA locus was significantly associated with OS in patients taking Par-4 dependent chemotherapies (P = 1.27 x 10-9), while no association was observed in the other patients (P = 0.21). To evaluate whether the UACA gene may be responsible for this association, we performed a transcriptome-wide association study (TWAS) of OS in White patients taking Par-4 dependent chemotherapies. Higher UACA gene expression was significantly associated with OS (P = 4.68 x 10-7), the only gene reaching transcriptome-wide significance (P < 4.34 x 10-6). These results suggest that higher UACA expression may inhibit Par-4 induced apoptosis and lead to stronger chemoresistance and worse survival. We attempted to validate our findings in the independent KPNC Genetic Epidemiology Research on Aging (GERA) cohort. The GERA cohort included only 168 White patients with incident breast cancer after DNA collection who received Par-4 dependent chemotherapies. We found a non-significant association (hazard ratio (HR) = 1.46, P = 0.66) consistent with Pathways Study findings. However, the GERA cohort also included 1,983 prevalent breast cancer patients with biospecimen collection after diagnosis. In this group, the risk allele frequency in breast cancer survivors receiving Par-4 dependent chemotherapies was significantly lower than that in the White population (P = 5.50 x 10-3) while the risk allele frequency in the those not receiving these chemotherapies was similar to the population (P = 0.07). This is consistent with Pathways Study observations that the UACA locus risk allele significantly increased risk of mortality in patients taking Par-4 dependent chemotherapies. A higher mortality in breast cancer survivors carrying the risk allele would result in decreased risk allele frequency. We further validated our findings in Shanghai Breast Cancer Survival Study (SBCSS)and Shanghai Breast Cancer Study, which were conducted from 1996 to 2006 in urban Shanghai and recruited 5,575 breast cancer patients. In this independent Asian breast cancer population, the UACA locus was modestly associated with OS in the overall population (HR = 1.18, P = 0.012), and more significantly in 1,289 SBCSS patients who received anthracyclines (HR = 1.66, P = 1.55 x 10-4). This is the first human study suggesting the Par-4 pathway affects breast cancer patient survival with UACA a key modulator of treatment outcomes by anti-Her2 therapy and doxorubicin. Our findings suggest a path toward new predictive pharmacogenetic markers for personalized medicine targeting the Par-4 pathway for breast cancer treatment. Citation Format: Lawrence H Kushi, Qianqian Zhu, Emily Schultz, Jirong Long, Janise M Roh, Emily Valice, Cecile A Laurent, Li Yan, Isaac J Ergas, Warren Davis, Dilrini K Ranatunga, Marilyn L Kwan, Ping-Ping Bao, Wei Zheng, Xiao-Ou Shu, Christine B Ambrosone, Song Yao. Genome-wide association study identifies UACA as a modulator of breast cancer chemoresistance and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-05.

Background: In preclinical models of breast cancer (BC), chronic stress enhances tumor growth and metastasis through β-adrenergic signaling as part of the “fight or flight” stress response pathway. These effects involve norepinephrine-mediated sympathetic regulation of cancer-related immunity. In a novel discovery, adrenergic stress in tumor-bearing mouse models of BC was associated with symptoms of intense cold discomfort, reduced CD8+ T cells, and higher immunosuppressive myeloid derived suppressor cells (MDSC) and regulatory T cells. BC survivors often experience heightened sympathetic activation and anecdotally report symptoms of feeling overly cold. Based on preclinical findings, symptoms of cold discomfort reported by BC survivors are hypothesized to identify those with reduced anti-cancer immunity and increased immunosuppression. Methods: Women with incident stage I to III BC were prospectively enrolled into the Women’s Health after Breast Cancer Study prior to BC treatment at Roswell Park Comprehensive Cancer Center. Participants provided blood samples and completed a survey assessing BC risk factors at the time of diagnosis and survivorship outcomes one-year post. Symptoms of being persistently and inappropriately cold as well as the occurrence of hot flashes and sweats were assessed using a Likert scale patterned on the validated Multidimensional Assessment of Fatigue Scale. A total of 424 women who had questionnaire data and plasma samples were included in the study. A panel of 27 Th1, Th2, Th9, and Th17 cytokines were assayed using a multiplex Luminex bead-based approach. Perceived symptoms of thermal discomfort were evaluated using logistic regression over cytokine tertiles (T1, T2, T3). Principal component analysis (PCA) was used to identify clusters of cytokines associated with symptoms of thermal discomfort. Cytokine composite scores were further refined based on their role with anti-tumor or pro-tumor activity. Multivariate models were adjusted for age, race, menopausal status, body mass index, stage, estrogen receptor status, grade, and treatment received. Results: Forty-six percent (195/424) of patients reported symptoms of feeling cold while 65% (275/424) experienced hot flashes and night sweats. There were no differences in patient or tumor characteristics between women who reported feeling cold versus those who did not, with women receiving chemotherapy more likely to report feeling cold (p = 0.01). Importantly, menopausal onset occurring after BC diagnosis or receipt of hormonal therapy were not associated with symptoms of feeling cold, but as expected were associated with experiencing hot flashes indicating that feeling cold is a distinct symptom from hot flashes. Higher pre-treatment levels of IL-6 was associated with 40-55% lower risk of feeling inappropriately cold 1-year post-diagnosis (T3 vs T1: OR=0.58, 95% CI: 0.34-1.00, p=0.01). PCA analysis identified a composite cytokine score at 1-year post diagnosis, which included the Th1 cytokines IL-12p70 and TNFα, IL-9 and IL-21 as cytokines involved in Th9 antitumor immunity, and the type 3 interferon IFN-λ2/IL-28α, which are all associated with increased CD8+ T cell activity. Increased scores were associated with reduced odds of feeling cold (T3 vs T1: OR=0.42, 95% CI: 0.23-0.77, p=0.02). Hot flashes in contrast were not associated with individual cytokine levels or composite scores. Conclusions: Symptoms of cold discomfort are less likely to be reported by BC survivors with a composite cytokine pattern associated with increased anti-tumor immunity. Further research is needed to determine if this symptom is associated with increased adrenergic stress and worse BC outcomes as observed in preclinical models. Citation Format: Shipra Gandhi, Maithreyi Sarma, Kristopher Attwood, Christine B. Ambrosone, Elizabeth A. Repasky, Chi-Chen Hong. Symptoms of cold discomfort are reduced in breast cancer patients with a composite cytokine pattern associated with increased anti-tumor immunity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-16.

PURPOSE: Fracture and osteoporosis are known side effects of aromatase inhibitors (AIs) for postmenopausal hormone receptor positive (HR+) breast cancer (BC) patients. How modifiable lifestyle factors impact fracture risk in these patients is relatively unknown. METHODS: We conducted a prospective cohort study to examine the association of lifestyle factors, focusing on physical activity, with risk of incident major osteoporotic fracture and osteoporosis in 2,152 HR+ BC patients diagnosed from 2006–2013 at Kaiser Permanente Northern California and who received AIs. Patients self-reported lifestyle factors at study entry and at six-month follow-up. Fracture and osteoporosis outcomes were prospectively ascertained by physician-adjudication and bone mineral density (BMD) values, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable proportional hazards regression. Models were adjusted for age, menopausal status, race/ethnicity, body mass index (BMI), AJCC stage, breast cancer treatment, prior osteoporosis, and prior major fracture. RESULTS: Over a median 6.1 years of follow-up after AI initiation, 165 women experienced an incident osteoporotic fracture and 243 women had osteoporosis. No associations were found between overall moderate-vigorous physical activity and fracture risk, although

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_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.)

Background: The disproportionate burden of more aggressive breast cancer subtypes among African American/Black women may stem from multilevel determinants. However, data are limited regarding the impacts of neighborhood social environmental characteristics among Black women. Methods: We evaluated the association between neighborhood-level socioeconomic status (nSES) and breast cancer subtypes in the Women's Circle of Health and Women's Circle of Health Follow-up Study, which included 1,220 Black women diagnosed from 2005 to 2017 with invasive breast cancer. nSES at diagnosis was measured using NCI's census tract-level SES index. We used multilevel multinomial logistic regression models to estimate the association of nSES with breast cancer subtypes [triple-negative breast cancer (TNBC), HER2-positive vs. luminal A], adjusting for individual-level SES, body mass index, and reproductive factors. We tested for interactions by neighborhood racial composition. Results: Compared with census tracts characterized as high nSES, the relative risk ratios (RRR) for TNBC were 1.81 [95% confidence interval (CI): 1.20–2.71] and 1.95 (95% CI: 1.27–2.99) for women residing in areas with intermediate and low nSES, respectively (Ptrend = 0.002). Neighborhood racial composition modified the association between nSES and TNBC; the highest relative risk of TNBC was among women residing in low nSES areas with low proportions of Black residents. Conclusions: Black women residing in socioeconomically disadvantaged neighborhoods may have an increased risk of TNBC, particularly in areas with lower proportions of Black residents. Impact: Places people live may influence breast tumor biology. A deeper understanding of multilevel pathways contributing to tumor biology is needed.

Background:Evidence suggests etiologic heterogeneity among breast cancer subtypes. Previous studies with six-marker IHC classification of intrinsic subtypes included small numbers of black women.Methods:Using centralized laboratory results for estrogen receptor (ER), progesterone receptor, HER2, proliferation marker, Ki-67, EGFR, and cytokeratin (CK)5/6, we estimated case-only and case–control ORs for established breast cancer risk factors among cases (n = 2,354) and controls (n = 2,932) in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. ORs were estimated by ER status and intrinsic subtype using adjusted logistic regression.Results:Case-only analyses by ER status showed etiologic heterogeneity by age at menarche, parity (vs. nulliparity), and age at first birth. In case–control analyses for intrinsic subtype, increased body mass index and waist-to-hip ratio (WHR) were associated with increased risk of luminal A subtype, whereas older age at menarche and parity, regardless of breastfeeding, were associated with reduced risk. For basal-like cancers, parity without breastfeeding and increasing WHR were associated with increased risk, whereas breastfeeding and age ≥25 years at first birth were associated with reduced risk among parous women. Basal-like and ER−/HER2+ subtypes had earlier age-at-incidence distribution relative to luminal subtypes.Conclusions:Breast cancer subtypes showed distinct etiologic profiles in the AMBER consortium, a study of more than 5,000 black women with centrally assessed tumor biospecimens.Impact:Among black women, high WHR and parity without breastfeeding are emerging as important intervention points to reduce the incidence of basal-like breast cancer.

There are differential risk relationships between parity and breast cancer according to estrogen receptor (ER) status, with an increased risk of ER− disease reduced by breastfeeding. This may be particularly relevant for understanding the higher incidence of ER− tumors in Black women, who are more likely to be parous and less likely to breastfeed than other U.S. groups. Potential mechanisms for these relationships may include effects of disordered breast involution on inflammatory milieu in the breast as well as epigenetic reprogramming in the mammary gland, which can affect cell fate decisions in progenitor cell pools. In normal breast tissue, parity has been associated with hypermethylation of FOXA1, a pioneer transcription factor that promotes the luminal phenotype in luminal progenitors, while repressing the basal phenotype. In breast tumors, relationships between FOXA1 methylation and parity were strongest among women who did not breastfeed. Here, we summarize the epidemiologic literature regarding parity, breastfeeding, and breast cancer subtypes, and review potential mechanisms whereby these factors may influence breast carcinogenesis, with a focus on effects on progenitor cell pools in the mammary gland.

PURPOSE: Limited epidemiologic data are available on the expression of adipokines leptin (LEP) and adiponectin (ADIPOQ) and adipokine receptors (LEPR, ADIPOR1, ADIPOR2) in the breast tumor microenvironment (TME). The associations of gene expression of these biomarkers with tumor clinicopathology is not well understood. METHODS: NanoString multiplexed assays were used to assess the gene expression levels of LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 within tumor tissues among 162 Black and 55 White women with newly diagnosed breast cancer. Multivariate mixed effects models were used to estimate associations of gene expression with breast tumor clinicopathology (overall and separately among Blacks). RESULTS: Black race was associated with lower gene expression of LEPR (P=0.002) and ADIPOR1 (P=0.01). Lower LEP, LEPR, and ADIPOQ gene expression were associated with higher tumor grade (P=0.0007, P

Breast cancer is the most common cancer diagnosed in women. It is associated with multiple symptoms in both patients and caregivers, such as stress, anxiety, depression, sleep disturbance, and fatigue. Stress appears to promote cancer progression via activation of the sympathetic nervous system releasing epinephrine and norepinephrine as well as activation of hypothalamic-pituitary-adrenal axis releasing cortisol. These stress hormones have been shown to promote the proliferation of cancer cells. This review focuses on stress-reducing strategies which may decrease cancer progression by abrogating these pathways, with a main focus on the β-adrenergic signaling pathway. Patients utilize both non-pharmacologic and pharmacologic strategies to reduce stress. Non-pharmacologic stress-reduction strategies include complementary and alternative medicine techniques, such as meditation, yoga, acupuncture, exercise, use of natural products, support groups and psychology counseling, herbal compounds, and multivitamins. Pharmacologic strategies include abrogating the β2-adrenergic receptor signaling pathway to antagonize epinephrine and norepinephrine action on tumor and immune cells. β-Blocker drugs may play a role in weakening the pro-migratory and pro-metastatic effects induced by stress hormones in cancer and strengthening the anti-tumor immune response. Preclinical models have shown that non-selective β1/2-blocker use is associated with a decrease in tumor growth and metastases and clinical studies have suggested their positive impact on decreasing breast cancer recurrence and mortality. Thus, non-pharmacological approaches, along with pharmacological therapies part of clinical trials are available to cancer patients to reduce stress, and have promise to break the cycle of cancer and stress.

PURPOSE: Understanding the contribution of tumor genome biology to racial disparities of triple-negative breast cancer (TNBC) is important for narrowing the cancer mortality gap between Black and White women. METHODS: We evaluated tumor somatic mutations using targeted sequencing of a customized panel of 151 genes and 15 copy number variations (CNVs) within a population of 133 TNBC patients, including 71 Black and 62 White women. RESULTS: The overall mutational burden between Black and White women with TNBC was not significantly different, with a median of 5 somatic changes per patient (point mutations and CNVs combined) for the customized panel (range 1–31 for Blacks vs. 1–26 for Whites; p=0.76). Of the 151 genes examined, none were mutated at a significantly higher frequency in Black than in White cases, whereas two genes were mutated at a higher frequency in White cases - PIK3CA and NCOR1. No significant difference in the frequency of CNVs was observed between Black and White women with TNBC in our study population. CONCLUSIONS: Of gene mutations and CNVs in TNBC tumors from Black and White women, only PIK3CA and NCOR1 had significantly different, although slight, frequencies by race. These results indicate that overall differences observed in the mutation spectra between Black and White women with breast cancer are likely due to the differential distributions of breast cancer subtypes by race.

Background The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. Methods Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. Results Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. Conclusions The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Background: Understanding the molecular influence of epidemiological risk factors can provide insights into breast cancer etiology and progression, and lead to better prevention efforts and treatment guidelines. The link between modifiable breast cancer risk factors and tumor genomic alterations remains unexplored. This study evaluated the association of tobacco use and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30) (1-3), and nine breast cancer driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) (4,5), in a subset of The Cancer Genome Atlas (TCGA). Method: Clinical and genomic data were retrieved from the TCGA database, and breast cancer risk factor information was collected from four TCGA sites; in all, 219 female breast cancer cases were included. Pre-diagnostic tobacco use was defined as never or ever; alcohol consumption was defined as drinkers or non-drinkers. Total SCNV was obtained by summing all segments with ≥|0.2|. TSMB was calculated by summing all significant mutations for each case. SBS signatures were computed using whole exome sequencing data. Analyses were conducted in all tumors (i.e., pooled) and by stratifying according to estrogen receptor (ER) status using multivariate regression, adjusting for co-variables. Results: Tobacco users had higher TSMB compared to non-users (p Conclusion: This study provides preliminary evidence that tobacco use and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. Future larger epidemiological studies are required to confirm these findings. References 1. Vineis P, et al. Mutational signatures associated with tobacco smoking in human cancer. Science. 2016;354(6312):618-22. 2. Alexandrov LB, et al. Clock-like mutational processes in human somatic cells. Nat Genet. 2015;47(12):1402-7. 3. Petljak M, Alexandrov LB. Understanding mutagenesis through delineation of mutational signatures in human cancer. Carcinogenesis. 2016;37(6):531-40. 4. Heng YJ, et al. The molecular basis of breast cancer pathologic phenotypes. J Pathol. 2017 Nov;241(3):375-91. 5. Ciriello G, et al. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell. 2015 Oct 10;163(2):506-19. Citation Format: Yujing J Heng, Susan E Hankinson, Jun Wang, Ludmil B Alexandrov, Christine B Ambrosone, Victor Piana de Andrade, Adam M Brufsky, Fergus J Couch, Tari A King, Francesmary Modugno, Celine M Vachon, A. Heather Eliassen, Rulla M Tamimi, Peter Kraft. Tobacco use, alcohol consumption, and breast cancer somatic genomic alterations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-07.

Background: Racial disparities in breast cancer outcome continues to be a major health care challenge. The reasons underlying this disparity are multifactorial with a recent focus on the tumor microenvironment. The characterization of infiltrating immune cell populations in the tumor microenvironment are lacking in Black breast cancer patients. To address this research gap, we employed immunohistochemical (IHC) staining and quantitative digital imaging to assess CD8+ T-cells in breast tumor samples from the Women’s Circle of Health Study (WCHS), a population-based case-control study of breast cancer in Black and White women. Our aim was to characterize and compare the density, localization and distribution of CD8+ T cells, and explore their prognostic value in each racial group. Methods: Tumor-infiltrating CD8+ lymphocytes were assessed by IHC staining of tissue microarray (TMA) cores from 736 breast cancer patients, including 597 Blacks and 139 Whites. The Aperio platform was used for quantitative image analysis of TMA cores. Racial differences in demographic and clinical characteristics were evaluated using the Mann-Whitney U and Fisher’s exact tests. Overall (OS) and breast cancer-specific (DSS) survival were summarized by race using the Kaplan-Meier method and compared using the log-rank test. The associations between demographic/clinical factors and CD8 expression were evaluated using a general linear model (GLM). Multivariable Cox regression models were used to evaluate associations between survival outcomes and both race and CD8 expression, while adjusting for age. Results: Black women had a higher percentage of high-grade tumors in addition to higher prevalence of ER-negative and triple negative tumors than white women. There was a statistically significant difference in OS (p=0.043), showing worse outcomes among Black patients. Black patients had significantly higher CD8+ expression compared to White patients, with mean values of 756.2/mm2 and 292.4/mm2 respectively (p Conclusions: We observed a stronger presence of CD8+ T cells in tumor microenvironment from Black breast patients, suggesting the existence of distinct tumor immune responses in this population. Our current data do not support that CD8+ T cells contribute to breast cancer survival disparities given the lack of prognostic significance of CD8 expression in this sample. CD8+ T cells may become less cytotoxic towards tumor cells as a result of immunosuppression or exhaustion; therefore, in-depth immuno-profiling of the versatile immune cell subsets and their qualities of breast tumor microenvironment in Black patients is warranted to understand their roles in breast cancer racial disparities. Citation Format: Yara Abdou, Song Yao, Kristopher Attwood, Gary Zirpoli, Wiam Bshara, Christine Ambrosone, Angela Omilian. Racial differences in infiltration of CD8+ T-cells in breast tumors of Black and White women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-02.

Background Compared to U.S. white women, African American women are more likely to die from ductal carcinoma in situ (DCIS). Elucidation of risk factors for DCIS in African American women may provide opportunities for risk reduction. Methods We used data from three epidemiologic studies in the African American Breast Cancer Epidemiology and Risk Consortium to study risk factors for estrogen receptor (ER) positive DCIS (488 cases; 13,830 controls). Results were compared to associations observed for ER+ invasive breast cancer (n = 2,099). Results First degree family history of breast cancer was associated with increased risk of ER+ DCIS [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.31, 2.17]. Oral contraceptive use within the past 10 years (vs. never) was also associated with increased risk (OR: 1.43, 95%CI: 1.03, 1.97), as was late age at first birth (≥25 years vs., Highlights • Few studies of risk factors for ductal carcinoma in situ (DCIS) have evaluated associations for African American women. • We analyzed data from the African American African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. • Family history of breast cancer, reproductive factors, and anthropometric factors were associated with risk of ER+ DCIS. • In general, risk factor associations for ER+ DCIS were similar to those for ER+ invasive breast cancer. • Our findings support a common etiology and pathogenesis between ER+ DICS and ER+ invasive cancer in African American women.

PURPOSE: The Women’s Circle of Health Follow-Up Study is an ongoing longitudinal study of African American/Black breast cancer survivors in New Jersey, specifically designed to evaluate the impact of obesity and related comorbidities on breast cancer survival and health-related quality-of-life in this understudied population. Here, we describe our recruitment and data collection methods, and compare characteristics of the overall cohort and the subcohort with follow-up data. METHODS: Newly diagnosed breast cancer cases have been recruited into the study since 2006. Pre-diagnosis data on relevant factors and a saliva sample are collected during an in-person interview within 12 months from diagnosis. In 2013, we began active follow up by recontacting participants annually, including two home visits at approximately 2 and 3 years post-diagnosis, during which blood samples are collected. Mortality outcomes (all-cause and breast cancer-specific mortality) are ascertained through linkage with New Jersey State Cancer Registry files. We expect to assemble a cohort of over 2,000 Black breast cancer survivors with at least 800 of them having detailed post-diagnosis data. RESULTS: Distribution of sociodemographic characteristics, body mass index, comorbidities, clinicopathologic characteristics, and treatment modalities were very similar between those in the full cohort and the subset with follow-up data and blood samples. Obesity (>50%), hypertension (>58%) and diabetes (22%) were common in this population. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: This ongoing longitudinal study represents a unique resource to better understand breast cancer outcomes, patient-reported symptoms, and health-related quality of life among Black breast cancer survivors.

Heart failure (HF) is a clinical syndrome characterized by typicalsymptoms and signscaused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Due to increasing incidence, prevalence and, most importantly mortality, HF is a healthcare burden worldwide, despite the improvement of treatment options and effectiveness. Acute and chronic cardiac injuries trigger the activation of neurohormonal, inflammatory, and mechanical pathways ultimately leading tofibrosis, which plays a key role in the development of cardiac dysfunction and HF. The use ofnanoparticlesfortargeted drug deliverywould greatly improve therapeutic options to identify, prevent and treatcardiac fibrosis. In this review we will highlight the mechanisms of cardiac fibrosis development to depict the pathophysiological features for passive and active targeting of acute and chronic cardiac fibrosis with nanoparticles. Then we will discuss how cardiomyocytes, immune and inflammatory cells, fibroblasts and extracellular matrix can be targeted with nanoparticles to prevent or restore cardiac dysfunction and to improve themolecular imagingof cardiac fibrosis.

Mammogram-detected breast cancers have a better prognosis than those identified through clinical breast exam (CBE) or through self-detection, primarily because tumors detected by mammography are more likely to be smaller and do not involve regional nodes. In a sample of 1,322 Black women, aged 40-75 years, diagnosed with breast cancer between 2002 and 2016, we evaluated factors associated with CBE and self-detection versus screening mammogram as the initial mode of breast cancer detection, using multivariable logistic regression models. Compared with screening mammogram, history of routine screening mammogram (OR 0.20, 95% CI: 0.07, 0.54) and performance of breast self-examination (BSE) (OR 0.31, 95% CI: 0.13, 0.74) before diagnosis were associated with lower odds of CBE as the initial mode of detection, while performance of CBEs before diagnosis (OR 11.04, 95% CI: 2.24, 54.55) was positively associated. Lower body mass index (2 vs. ≥35.0 kg/m2: OR 2.46, 95% CI: 1.52, 3.98), performance of BSEs before diagnosis (less than once per month: OR 4.08, 95% CI: 2.45, 6.78; at least monthly: OR 4.99, 95% CI: 3.13, 7.97), and larger tumor size (1.0-2.0 cm vs. 2.0 cm vs.

Young black women are at higher risk of triple‐negative breast cancer (TNBC); however, a majority of the genetic studies on cancer predisposition were carried out in White populations. The underrepresentation of minority racial/ethnic populations in cancer genetic studies may have led to disproportionate gaps in our knowledge of cancer predisposition genes in these populations. We surveyed the protein‐truncating mutations at the exome‐wide scale and in known breast cancer predisposition genes among 170 patients of multiple racial/ethnic groups with early‐onset (≤age 50) TNBC from two independent cohorts. Black patients, on average, had a higher number of truncating mutations than Whites at the exome‐wide level, but fewer truncating mutations in the panel of known breast cancer genes. White TNBC patients showed a strong enrichment of truncating variants in known breast cancer genes, whereas no such enrichment was found among Black patients. Our findings indicate likely more breast cancer disposition genes yet to be discovered in minority racial/ethnic groups, and the current multigene panels may result in unequal benefits from cancer genetic testing.

COX and ALOX genes are involved in inflammatory processes and that may be related to breast cancer risk differentially between White and Black women. We evaluated distributions of genetic variants involved in COX2 and ALOX-related pathways and examined their associations with breast cancer risk among 1,275 White and 1,299 Black cases and controls who participated in the Women’s Circle of Health Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. Our results showed differential associations of certain genetic variants with breast cancer according to menopausal and ER status in either White or Black women. In White women, an increased risk of breast cancer was observed for COX2-rs689470 (OR: 2.02, P = 0.01) in the dominant model, and was strongest among postmenopausal women (OR: 2.72, P = 0.02) and for estrogen receptor positive (ER+) breast cancers (OR: 2.60, P = 0.001). A reduced risk was observed for ALOX5-rs7099874 (OR: 0.75, P = 0.01) in the dominant model, and was stronger among postmenopausal women (OR: 0.68, P = 0.03) and for ER+ cancer (OR: 0.66, P = 0.001). Four SNPs (rs3840880, rs1126667, rs434473, rs1042357) in the ALOX12 gene were found in high LD (r2 >0.98) in White women and were similarly associated with reduced risk of breast cancer, with a stronger association among postmenopausal women and for ER− cancer. Among Black women, increased risk was observed for ALOX5-rs1369214 (OR: 1.44, P = 0.003) in the recessive model and was stronger among premenopausal women (OR: 1.57, P = 0.03) and for ER+ cancer (OR: 1.53, P = 0.003). Our study suggests that genetic variants of COX2 and ALOX genes are associated with breast cancer, and that these associations and genotype distributions differ in subgroups defined by menopausal and ER status between White and Black women. Findings may provide insights into the etiology of breast cancer and areas for further research into reasons for breast cancer differences between races.

Importance Obesity disproportionately affects Black women, who also have a higher risk of death after a breast cancer diagnosis compared with women of other racial/ethnic groups. However, few studies have evaluated the association of measures of adiposity with mortality among Black breast cancer survivors. Objective To assess the association of measures of adiposity with survival after a breast cancer diagnosis among Black women. Design, Setting, and Participants This prospective population-based cohort study comprised 1891 women with stage 0 to IV breast cancer who self-identified as African American or Black and were ages 20 to 75 years. The New Jersey State Cancer Registry was used to identify women living in 10 counties in New Jersey who were recruited from March 1, 2006, to February 29, 2020, and followed up until September 2, 2020. Exposures Measures of adiposity, including body mass index, body fat distribution (waist circumference and waist-to-hip ratio), and body composition (percent body fat and fat mass index), were collected during in-person interviews at approximately 10 months after breast cancer diagnosis. Main Outcomes and Measures All-cause and breast cancer–specific mortality. Results Among 1891 women, the mean (SD) age at breast cancer diagnosis was 54.5 (10.8) years. During a median follow-up of 5.9 years (range, 0.5-14.8 years), 286 deaths were identified; of those, 175 deaths (61.2%) were associated with breast cancer. A total of 1060 women (56.1%) had obesity, and 1291 women (68.3%) had central obesity. Higher adiposity, particularly higher waist-to-hip ratio, was associated with worse survival. Women in the highest quartile of waist-to-hip ratio had a 61% increased risk of dying from any cause (hazard ratio [HR], 1.61; 95% CI, 1.12-2.33) and a 68% increased risk of breast cancer death (HR, 1.68; 95% CI, 1.04-2.71) compared with women in the lowest quartile. The risks of all-cause and breast cancer–specific death were similarly high among women in the highest quartile for waist circumference (HR, 1.74 [95% CI, 1.26-2.41] and 1.64 [95% CI, 1.08-2.48], respectively), percent body fat (HR, 1.53 [95% CI, 1.09-2.15] and 1.81 [95% CI, 1.17-2.80]), and fat mass index (HR, 1.57 [95% CI, 1.11-2.22] and 1.74 [95% CI, 1.10-2.75]); however, the risk was less substantial for body mass index (HR, 1.26 [95% CI, 0.89-1.79] and 1.33 [95% CI, 0.84-2.10]). In analyses stratified by estrogen receptor status, menopausal status, and age, a higher waist-to-hip ratio was associated with a higher risk of all-cause death among women who had estrogen receptor–negative tumors (HR, 2.24; 95% CI, 1.14-4.41), women who were postmenopausal (HR, 2.15; 95% CI, 1.28-3.61), and women who were 60 years or older at diagnosis (HR per 0.10-U increase, 1.76; 95% CI, 1.37-2.26). Conclusions and Relevance In this population-based cohort study, central obesity and higher adiposity were associated with higher all-cause and breast cancer–specific mortality among Black breast cancer survivors. Simple measures of body fat distribution and body composition were found to be useful tools for identifying Black women with a higher risk of death after a breast cancer diagnosis.

Background: To address a critical gap for application of cancer chronotherapy of when would be the best time(s) for treating an individual cancer patient, we conducted a pilot study to characterize diurnal variations of gene expression in oral mucosal tissue, which is vulnerable to damage from cancer therapies. Methods: We conducted RNA-seq assay on individual oral mucosal samples collected from 11 healthy volunteers every 4 hours (6 time points). Using a cosine-based method, we estimated the individual and average values of peak-time and amplitude for each gene. Correlations between gene expression peak-times and age was examined, adjusting for individual’s sleep timing. Results: Among candidate gene pathways that are relevant to treatment response, 7 of 16 genes ('PER3, CIART, TEF, PER1, PER2, CRY2, ARNTL') involved in circadian regulation and 1 of 118 genes ('WEE1') involved in cell cycle regulation achieved p-value ≤ 0.1 and relative amplitude>0.1. The average peak times were approximately 10:15 for PER3, CIART and TEF, 10:45 for PER1, 13:00 for WEE1, PER2 and CRY2, and 19:30 for ARNTL. Ranges in peak times across individuals differed by gene (e.g., 8 hours for PER1; 16.7 hours for WEE1). Older people had later peak times for PER1 (r = 0.77, p = 0.03) and PER3 (r = 0.69, p-value = 0.06). Conclusion: In oral mucosa, expression of some genes relevant to treatment response displayed diurnal variation. These genes may be candidates for development of biomarkers for optimizing individual timing of cancer therapy using non-invasively collected oral mucosa.

IMPORTANCE: The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes in US Black women compared with non-Hispanic White women with breast cancer is poorly described. OBJECTIVE: To determine whether US Black and non-Hispanic White women with breast cancer have a different prevalence of PVs in 12 cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Participants were Black and non-Hispanic White women diagnosed with breast cancer, unselected for family history or age at diagnosis. Data were collected from June 1993 to June 2020; data analysis was performed between September 2020 and February 2021. MAIN OUTCOMES AND MEASURES: Prevalence of germline PVs in 12 established breast cancer susceptibility genes. RESULTS: Among 3946 Black women (mean [SD] age at diagnosis, 56.5 [12.02] y) and 25 287 non-Hispanic White women (mean [SD] age at diagnosis, 62.7 [11.14] y) with breast cancer, there was no statistically significant difference by race in the combined prevalence of PVs in the 12 breast cancer susceptibility genes evaluated (5.65% in Black vs 5.06% in non-Hispanic White women; P = .12). The prevalence of PVs in CHEK2 was higher in non-Hispanic White than Black patients (1.29% vs 0.38%; P

Background Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment, constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women. Methods Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast tumor microenvironment from 1315 patients from the Women’s Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in 3 independent cohorts. Results We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence but also the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+ and B-cell response, and further, a more exhausted CD8+ T-cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor–positive patients. Among hormone receptor–negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival. Conclusions Our findings of a distinct exhausted CD8+ T-cell signature in Black breast cancer patients indicate an immunobiological basis for their more aggressive disease and a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Cardiovascular diseases represent the first cause of morbidity in Western countries, and chronic heart failure features a significant health care burden in developed countries. Efforts in the attempt of finding new possible strategies for the treatment of CHF yielded several approaches based on the use of stem cells. The discovery of direct cardiac reprogramming has unveiled a new approach to heart regeneration, allowing, at least in principle, the conversion of one differentiated cell type into another without proceeding through a pluripotent intermediate. First developed for cancer treatment, nanotechnology-based approaches have opened new perspectives in many fields of medical research, including cardiovascular research. Nanotechnology could allow the delivery of molecules with specific biological activity at a sustained and controlled rate in heart tissue, in a cell-specific manner. Potentially, all the mediators and structural molecules involved in the fibrotic process could be selectively targeted by nanocarriers, but to date, only few experiences have been made in cardiac research. This review highlights the most prominent concepts that characterize both the field of cardiac reprogramming and a nanomedicine-based approach to cardiovascular diseases, hypothesizing a possible synergy between these two very promising fields of research in the treatment of heart failure.

PURPOSE: Circulating anti-Müllerian hormone (AMH) levels are positively associated with time to menopause and breast cancer risk. We examined breast cancer associations with single nucleotide polymorphisms (SNPs) in the AMH gene or its receptor genes, ACVR1 and AMHR2, among African American women. METHODS: In the AMBER consortium, we tested 65 candidate SNPs, and 1,130 total variants, in or near AMH, ACVR1, and AMHR2 and breast cancer risk. Overall, 3,649 cases and 4,230 controls contributed to analyses. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were calculated using multivariable logistic regression. RESULTS: After correction for multiple comparisons (false discovery rate of 5%), there were no statistically significant associations with breast cancer risk. Without correction for multiple testing, four candidate SNPs in ACVR1 and one near AMH were associated with breast cancer risk. In ACVR1, rs13395576[C] was associated with lower breast cancer risk overall (OR=0.84; 95% CI: 0.72, 0.97) and for ER+ disease (OR=0.75; CI: 0.62, 0.89)(p

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

Background African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome. Methods We examined the association of CD8+ cytotoxic T cells with clinical-pathological variables in the Women’s Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8+ T cells were scored for each patient tumor sample with digital image analysis. Results Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8+ T cell density (median 87.6/mm2 vs. 53.1/mm2; p + T cell density was significantly higher in younger patients and patients with high-grade and ER/PR-negative tumors. No significant associations were observed between CD8+ T cell density and overall survival or breast cancer-specific survival in the overall population, or when Black patients were analyzed as a separate group. However, when stratified by subtype, Black women with triple-negative breast cancer and high CD8+ T cell density showed a trend towards better overall survival in comparison with patients with low CD8+ T cell density (HR = 0.51; 95% CI 0.25–1.04). Conclusions Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups.

Variability in toxicity and response to the same dose of medication may occur among cancer patients and contribute to the unpredictability of clinical outcomes. In addition to the potential importance of clinical factors in determining drug effects, inherited differences in drug metabolism are likely to have a profound effect on treatment outcomes. Pharmacogenetics, the study of the contribution of genetic variation to the interindividual differences, may allow for the individualization of therapy and improved prediction of pharmacodynamic events, including host toxicity and treatment efficacy. The taxanes paclitaxel and docetaxel have an important role in the treatment of early-stage breast cancer as well as metastatic disease. Although methotrexate has been widely used to treat many cancers, including leukemia, lymphomas, and breast cancer, as well as some autoimmune diseases, there has been limited research to evaluate the effects of genetic variability on treatment outcomes.

Loss of immunoreactivity in tissue sections has been shown to occur when slide sections are stored at room temperature for prolonged periods of time. We conducted a systematic investigation to determine the extent of staining loss in various storage conditions to determine an optimal storage method. We investigated 6 antibodies that are commonly used for breast cancer subtyping in research studies with immunohistochemistry (ER, PR, HER2, CK5/6, EGFR, and Ki67) in formalin-fixed paraffin-embedded breast tissue microarrays consisting of 148 patients. Tissue microarrays were sectioned at various time points: fresh, 1 week, 1 month, 6 months, and 12 months before staining. Slides sectioned at each time point were stored in 5 storage conditions: desiccator, paraffin dipped, 4°C, -20°C, and -80°C. Immunohistochemistry scores were assessed over time with McNemar Test and Bowker Test of Symmetry. Desiccator storage was the only storage condition that did not show any loss in immunoreactivity for any antibody or time point in our study. Paraffin coated slides were the most difficult storage method operationally and also showed the most loss in immunoreactivity. Storing sections in a desiccator was the most effective method for minimizing immunoreactivity loss. Cold storage at 4°C is an intermediate option that is not as protective as a desiccator, but offers the advantage of being accessible to virtually all research labs.

Background The molecular mechanisms underlying the association between increased adiposity and aggressive breast cancer phenotypes remain unclear, but likely involve the adipokines, leptin (LEP) and adiponectin (ADIPOQ), and their receptors (LEPR, ADIPOR1, ADIPOR2). Methods We used immunohistochemistry (IHC) to assess LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 expression in breast tumor tissue microarrays among a sample of 720 women recently diagnosed with breast cancer (540 of whom self-identified as Black). We scored IHC expression quantitatively, using digital pathology analysis. We abstracted data on tumor grade, tumor size, tumor stage, lymph node status, Ki67, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from pathology records, and used ER, PR, and HER2 expression data to classify breast cancer subtype. We used multivariable mixed effects models to estimate associations of IHC expression with tumor clinicopathology, in the overall sample and separately among Blacks. Results Larger proportions of Black than White women were overweight or obese and had more aggressive tumor features. Older age, Black race, postmenopausal status, and higher body mass index were associated with higher LEPR IHC expression. In multivariable models, lower LEPR IHC expression was associated with ER-negative status and triple-negative subtype (P Conclusions Lower LEPR IHC expression within the breast tumor microenvironment might contribute mechanistically to inter-individual variation in aggressive breast cancer clinicopathology, particularly ER-negative status and triple-negative subtype.

Background: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA). Methods: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status. Results: Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER− tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P < 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER− disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction. Conclusions: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. Impact: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.

BACKGROUND: Building upon our earlier findings of significant associations between hair dye and relaxer use with increased breast cancer risk, we evaluated associations of select characteristics of use with breast tumor clinicopathology. METHODS: Using multivariable-adjusted models we examined the associations of interest in a case-only study of 2,998 women with breast cancer, overall and stratified by race and estrogen receptor (ER) status, addressing multiple comparisons using Bonferroni correction. RESULTS: Compared to salon application of permanent hair dye, home kit and combination application (both salon and home kit application) were associated with increased odds of poorly differentiated tumors in the overall sample. This association was consistent among Black (home kit: OR 2.22, 95% CI: 1.21–5.00; combination: OR 2.46, 95% CI: 1.21–5.00), but not White women, and among ER+ (home kit: OR 1.47, 95% CI: 0.82–2.63; combination: OR 2.98, 95% CI: 1.62–5.49) but not ER− cases. Combination application of relaxers was associated with increased odds of tumors >2.0 cm vs.

PURPOSE: In postmenopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor positive (ER+) and negative (ER-) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 postmenopausal women from the Nurses’ Health Study (NHS) and NHSII. METHODS: Differential gene expression was analyzed separately in ER+ and ER- disease both comparing overweight (BMI ≥25 to

Breast cancer is a heterogeneous disease, characterized by molecularly and phenotypically distinct tumor subtypes, linked to disparate clinical outcomes. American women of African ancestry (AA) are more likely than those of European ancestry (EA) to be diagnosed with aggressive, estrogen receptor negative (ER−) or triple negative breast cancer, and to die of this disease. However, the underlying causes of AA predisposition to ER−/triple negative breast cancer are still largely unknown. In this study, we performed high-throughput whole-genome miRNA expression profiling in breast tissue samples from both AA and EA women. A number of differentially expressed miRNAs, i.e., DEmiRs defined as >2-fold change in expression and false discovery rate

Background MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. Methods Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. Results A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26–1.65; p = 3.15 × 10−7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16–1.44 (p = 4.18 × 10–6) and OR = 1.33, 95% CI = 1.17–1.51 (p = 1.6 × 10–5), respectively). Conclusion Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.

PURPOSE: Self-reported weight, height and body mass index (BMI) are commonly used in cancer epidemiology studies, but information on the validity of self-reports among cancer survivors is lacking. This study aimed to evaluate the validity of these self-reported measures among African American (AA) breast cancer survivors, known to have a high obesity prevalence. METHODS: We compared the self-reported and measured values among 243 participants from the Women’s Circle of Health Follow-Up Study (WCHFS), a population-based longitudinal study of AA breast cancer survivors. Multivariable-adjusted linear regressions were used to identify factors associated with reporting errors. We also examined the associations of self-reported and measured BMI with obesity-related health outcomes using multivariable logistic regressions, with hypertension as an example, to evaluate the impact of misreporting. RESULTS: We found that self-reported and measured values were highly correlated among all and when stratified by participants’ characteristics (intraclass correlation coefficients ≥0.99, 0.84 and 0.96 for weight, height and BMI, respectively). The agreement between BMI categories (normal, overweight and obese) based on self-reported and measured data was excellent (kappa=0.81). Women who were older, never smoked, had higher grade tumors or greater BMI tended to have over-estimated BMI calculated from self-reported weight and height. The BMI-hypertension association was similar using self-reported (OR per 5 kg/m(2) increase: 1.63; 95% CI: 1.27–2.10) and measured BMI (1.58; 95% CI: 1.23–2.03). CONCLUSIONS: Self-reported weight, height and BMI were reasonably accurate in the WCHFS. IMPLICATIONS: Our study supports the use of these self-reported values among cancer survivors when direct measurements are not possible.

Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women. Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants. Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, and ER− cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79–0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER− disease. The only genes showing heterogeneity between ER− and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P ≤ 0.02). We also noted genes associated with autoimmune and atopic disorders. Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER− breast cancers. Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 27(3); 321–30. ©2018 AACR.

Background: The prevalence of frailty at population-level is expected to increase in Europe, changing the focus of Public Health. Here, we report on the activities of the A3 Action Group, focusing on managing frailty and supporting healthy ageing at community level. Methods: A three-phased search strategy was used to select papers published between January 2016 and May 2018. In the third phase, the first manuscript draft was sent to all A3-Action Group members who were invited to suggest additional contributions to be included in the narrative review process. Results: A total of 56 papers were included in this report. The A3 Action Group developed three multidimensional tools predicting short⁻medium term adverse outcomes. Multiple factors were highlighted by the group as useful for healthcare planning: malnutrition, polypharmacy, impairment of physical function and social isolation were targeted to mitigate frailty and its consequences. Studies focused on the management of frailty highlighted that tailored interventions can improve physical performance and reduce adverse outcomes. Conclusions: This review shows the importance of taking a multifaceted approach when addressing frailty at community level. From a Public Health perspective, it is vital to identify factors that contribute to successful health and social care interventions and to the health systems sustainability. info:eu-repo/semantics/publishedVersion

Plant-based diets are recommended for cancer survivors, but their relationship with breast cancer outcomes has not been examined. We evaluated whether long-term concordance with plant-based diets reduced the risk of recurrence and mortality among a prospective cohort of 3646 women diagnosed with breast cancer from 2005 to 2013. Participants completed food frequency questionnaires at diagnosis and 6-, 25-, and 72-month follow-up, from which we derived plant-based diet indices, including overall (PDI), healthful (hPDI), and unhealthful (uPDI). We observed 461 recurrences and 653 deaths over a median follow-up of 9.51 years. Using multivariable-adjusted Cox proportional hazards models, we estimated hazard ratios (HR) and 95% confidence intervals for breast cancer recurrence and all-cause, breast-cancer-specific, and non-breast-cancer mortality. Increased concordance with hPDI was associated with a reduced hazard of all-cause (HR 0.93, 95% CI: 0.83–1.05) and non-breast-cancer mortality (HR 0.83, 95% CI: 0.71–0.98), whereas increased concordance with uPDI was associated with increased hazards (HR 1.07, 95% CI: 0.96–1.2 and HR 1.20, 95% CI: 1.02–1.41, respectively). No associations with recurrence or breast-cancer-specific mortality were observed. In conclusion, healthful vs. unhealthful plant-based dietary patterns had differing associations with mortality. To enhance overall survival, dietary recommendations for breast cancer patients should emphasize healthful plant foods.