Elevated Breast Cancer Risk Research Articles

Short-term follow-up of contrast-enhanced mammography lesions after negative breast MRI in women with elevated breast cancer risk

PurposeTo determine the outcome of enhancing lesions detected on contrast-enhanced mammography (CEM) that had no correlate on magnetic resonance imaging (MRI) and underwent short-term follow-up CEM. MethodsIn this retrospective single-center study, we identified patients with elevated breast cancer risk who had a CEM between 2014 and 2021 showing indeterminate enhancement on recombined images (BI-RADS 0, 3, 4) that had no correlate on subsequent MRI (performed within one month), and therefore underwent short-term follow-up CEM (performed within eight months). Medical records and imaging studies were reviewed to collect data on patient and lesion characteristics, and outcomes. Cancer incidence with 95% confidence interval (CI) was calculated. ResultsThis study included 71 women (median age 49 years) with 81 enhancing CEM lesions who underwent short-term follow-up CEM (median 6.2 months) after MRI reported no correlate. Of 81 lesions (median size = 0.7 cm), 73 (90%) were non-mass enhancement and 8 (10%) were enhancing masses. No sonographic correlate was identified for 75 lesions that had a same-day targeted ultrasound. Two cancers (2.5%, 95% CI 0.3–8.6) were diagnosed during the short-term follow-up period, one at 6-months (invasive ductal carcinoma) and one at 12-months (ductal carcinoma in situ). The remaining 79 lesions were benign at 6-month follow-up CEM and at one-year mammographic follow-up. ConclusionsFollow-up CEM of MRI-occult lesions is prudent and may be reasonable to perform at one-year given the low incidence of cancer detected at six-months (one of 81) in our small study sample.

Genetic counseling and testing for females at elevated risk for breast cancer: Protocol for the randomized controlled trial of the Know Your Risk intervention

BackgroundGenetic counseling and testing have an important role in the care of patients at elevated risk for breast cancer. However, conventional pre- and post-test genetic counseling is labor and time intensive, less accessible for patients living outside major urban centers, and impractical on a large scale. A patient-driven approach to genetic counseling and testing may increase access, improve patients' experiences, affect efficiency of clinical practice, and help meet workforce demand. The objective of this 2-arm randomized controlled trial is to determine the efficacy of Know Your Risk (KYR), a genetic counseling patient preference intervention. MethodsFemales (n = 1000) at elevated risk (>20% lifetime) for breast cancer will be randomized to the KYR intervention or conventional genetic counseling. The study will provide comprehensive assessment of breast cancer risk by multigene panel testing and validated polygenic risk score. Primary outcome is adherence to National Comprehensive Cancer Network guidelines for a clinical encounter every 6–12 months and an annual mammogram (breast MRI if recommended) determined by medical record review. Secondary outcomes include adherence to other recommended cancer screening tests determined by medical record review and changes in breast cancer knowledge, perception of risk, post-test/counseling distress, and satisfaction with counseling by completion of three surveys during the study. Study aims will be evaluated for non-inferiority of the KYR intervention compared to conventional genetic counseling. ConclusionIf efficacious, the KYR intervention has the potential to improve patients' experience and may change how genetic counseling is delivered, inform best practices, and reduce workforce burden.Trial Registration: ClinicalTrials.govNCT05325151

The importance of SOCS1 - 1478 CA/del polymorphism and expression in breast cancer: a case-control study in the north of Iran.

This project aimed to evaluate the relationship between the suppressor of cytokine signaling-1 (SOCS1) - 1478 CA > del genetic variation and breast cancer susceptibility. Moreover, we investigated the SOCS1 mRNA expression level in cancerous tissues. A total of 100 patients with breast cancer and 120 healthy individuals were selected. Genomic DNA was extracted from blood. SOCS1 genotyping and relative gene expression were performed using ARMS-PCR (Amplification-Refractory Mutation System-Polymerase Chain Reaction) and real-time PCR, respectively. In breast cancer patients, the prevalence of genotype frequencies of SOCS1 (- 1478 CA > del) CA/CA, CA/del, and del/del was 52, 31, and 17%, respectively. Among controls, the distribution of CA/CA, CA/del, and del/del was 63, 15, and 22%, respectively. The chi-square test reported that a significant difference was observed in the genotypic distribution of SOCS1 (- 1478 CA > del) polymorphism between cases and controls (χ2 = 8.08, P = 0.01). In addition, the presence of the CA/del genotype was associated with an elevated risk of breast cancer (in the codominant model: OR 2.51; 95% CI 1.27-4.96, P = 0.007 and in the over dominant model: OR 2.54; 95% CI 1.32-4.90, P = 0.005). However, there was no significant difference in allelic distributions between the groups (P > 0.05). There was no significant difference in the breast cancer risk associated with the dominant and recessive genetic models when the reference was CA/CA and CA/CA + CA/del genotype, respectively (P = 0.09 and P = 0.38). Moreover, the expression of SOCS1 decreased in cancerous tissues as compared to the adjacent non-cancerous tissues (P < 0.0001). In conclusion, a functional SOCS1 promoter polymorphism (- 1478 CA > del) may affect breast cancer susceptibility.

Safety of lactational exposure to venlafaxine on the rat mammary gland development and carcinogenesis in F1 female offspring

The chronic use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (SNRIs) may result in human gynecomastia, mammoplasia, galactorrhea, and elevated breast cancer risk. As antidepressants are frequently used for postpartum depression (PPD) treatment, this study investigated the adverse effects of lactational exposure to venlafaxine (VENL, a selective SNRI) on mammary gland development and carcinogenesis in F1 female offspring. Thus, lactating Wistar rats (F0) received VENL by oral gavage at daily doses of 3.85, 7.7, or 15.4 mg/kg (N = 9, each group) from lactational day (LD 1) until the weaning of the offspring (LD 21). F1 female offspring were euthanized for mammary gland, and ovary histological analyses on the post-natal day (PND) 22 and 30 (1 pup/litter/period, N = 9, each group). At PND 22, other females (2 pups/litter, N = 18, each group) received a single dose of carcinogen N-methyl-N-nitrosourea (MNU, 50 mg/kg) intraperitoneally (i.p.) for tumor susceptibility assay until PND 250. Tumor incidence and latency were recorded and representative tumor samples were collected for histopathology. The results indicate that lactational exposure to VENL did not alter the development of the mammary gland (epithelial ductal tree or the mean number of terminal end buds), or the ovary (weight and primary, secondary, tertiary, and Graafian follicles) in prepubertal F1 female offspring. In addition, VENL exposure did not influence tumor incidence or tumor latency in adult female offspring that received MNU. Thus, the findings of this animal study indicated that lactational VENL exposure, a period similar to human PPD, did not exert an adverse effect on the mammary gland development at the prepubertal phase or on chemically induced mammary tumorigenesis in adult F1 female rats.

Implementation of a Novel Patient Decision Aid for Women with Elevated Breast Cancer Risk Who Are Considering MRI Screening: A Pilot Study.

To determine the feasibility and acceptability of using a patient decision aid (DA) for women with elevated breast cancer risk who are considering MRI screening. This pilot study employed a mixed methods design to develop, modify, and test an interactive DA. The DA was administered among a consecutive patient sample with an estimated Tyrer-Cuzick v.8 lifetime breast cancer risk of 20% or greater and without a pathologic genetic mutation. The decisional conflict scale was used to measure decisional conflict. Post-intervention provider and patient feedback evaluated shared decision-making, feasibility, and acceptability. Twenty-four patients participated, with a median age of 44 years. Prior to DA use, sixteen patients (67%) were unsure whether to add MRI to their screening, six patients elected MRI (25%), and two patients declined MRI (8%). Following DA use, thirteen of sixteen of the initially undecided participants (81%) established a preference, with eleven electing to add MRI screening. Of participants with an initial preference, all maintained the same decision following use of the DA. Prior to the DA, the median decisional conflict score among participants was 25% (range 0-60%) compared with 0% (range 0-25%) after the DA. Healthcare providers reported that the DA was useful and easily incorporated into clinical workflow. This pilot study shows that there may be a benefit to DA utilization in the high-risk breast cancer clinic to guide shared decision-making in establishing a screening preference. The findings warrant further research to test the use of the DA in a larger, multi-site trial.

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European...

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

The role of polygenic risk scores in breast cancer risk perception and decision-making.

Polygenic risk scores (PRS) have the potential to improve the accuracy of clinical risk assessments, yet questions about their clinical validity and readiness for clinical implementation persist. Understanding how individuals integrate and act on the information provided by PRS is critical for their effective integration into routine clinical care, yet few studies have examined how individuals respond to the receipt of polygenic risk information. We conducted an embedded Ethical, Legal, and Social Implications (ELSI) study to examine if and how unaffected participants in a US population breast cancer screening trial understood and utilized PRS, as part of a multifactorial risk score combining traditional risk factors with a genetic risk assessment, to make screening and risk-reduction decisions. Semi-structured qualitative interviews were conducted with 24 trial participants who were designated at elevated risk for breast cancer due to their combined risk score. Interviews were analyzed using a grounded theory approach. Participants understood PRS conceptually and accepted it as one of many risk factors to consider, yet the value and meaning they ascribed to this risk estimate varied. Most participants reported financial and insurance barriers to enhanced screening with MRI and were not interested in taking risk-reducing medications. These findings contribute to our understanding of how PRS may be best translated from research to clinical care. Furthermore, they illuminate ethical concerns about identifying risk and making recommendations based on polygenic risk in a population screening context where many may have trouble accessing appropriate care.

Breast cancer risk associated with missense variants in BRCA2.

10501 Background: Greater than 90% of missense variants in BRCA2 are classified as variants of uncertain significance (VUS). In addition, among the few known missense pathogenic variants (PVs) in BRCA2, breast cancer risk has been reported to be lower compared to pathogenic truncating variants (PTVs) (Li et al., 2022) . Herein, we aim to reclassify several missense variants in BRCA2 and investigate the associated breast cancer risk. Methods: A total of 450 BRCA2 missense variants in the C-terminal DNA binding domain (DBD) were evaluated for functional effect utilizing a previously validated homology-directed DNA double-strand repair (HDR) assay. The results of the functional evaluation along with clinical, structural, and in-silico data were applied to the rules-based ACMG/AMP criteria for variant classification to identify pathogenic/likely pathogenic (P/LP) variants and benign/likely benign (B/LB) variants. A pooled case-control analysis was performed comparing the frequency of reclassified P/LP missense variants among 82,372 women with breast cancer within the Ambry Genetics database as cases and 174,167 unaffected women within gnomAD, CARRIERS, and BRIDGES datasets as controls to evaluate associated breast cancer risk. Separate case-control analysis and comparisons with BRCA2 DBD PTVs, exon 11 PTVs, and known missense PV standards in ENIGMA were also performed. Results: From the 450 missense variants in the DBD, 137 (30.4%) were noted to be functionally deleterious and 313 (69.6%) were functionally neutral by the HDR assay. Incorporation of the functional and other data into an ACMG/AMP model led to the reclassification of 439 (97.6%) variants, with 131 as P/LP and 308 as B/LB variants. In a pooled case-control analysis, reclassified BRCA2 missense P/LP variants were associated with clinically significant increased risks of breast cancer (Odds Ratio (OR):5.6, 95%CI:3.9–8.0), whereas B/LB missense variants were not (OR:1.1, 95%CI:1.1–1.2). Similarly elevated risks of breast cancer were observed for BRCA2 PTVs in the DBD (OR:6.8, 95%CI:5.1–9.0) and missense PV standards in ENIGMA (OR:7.8, 95%CI:4.1–14.7). However, PTVs in exon 11 of BRCA2 were associated with a lower risk of breast cancer (OR:4.4, 95%CI:3.8–4.9) compared to PTVs in DBD, confirming the ovarian cancer cluster region effect in BRCA2. Conclusions: The study demonstrates that the HDR functional assay in conjunction with other clinical and genomic data can be a powerful tool that can aid in the reclassification of &gt; 95% of missense variants in BRCA2. In addition, missense PVs in DBD were noted to have a similarly elevated risk of breast cancer as PTVs. The reclassification of the BRCA2 missense VUS and identification of associated breast cancer risk in this study will significantly influence breast cancer risk assessment and management strategies among carriers of these missense variants.

Willingness of women at increased genetic and non-genetic risk of breast cancer to participate in intervention trials to prevent cancer.

e24190 Background: The factors that influence willingness to participate (WTP) in breast cancer (BC) prevention trials are not well understood. WTP in BC prevention trials was examined in patients at increased risk of BC considering intervention and participant characteristics. Methods: Women self-identifying as being at increased risk for BC were recruited to a cross-sectional study of WTP in BC prevention trials. 78% (87 of 112) of participants completed ≥50% of a 29 item Likert Scale questionnaire about WTP in BC prevention trials that varied in intervention type and intensity, duration, time commitment, study procedures, and side effects of medications. Responses were dichotomized into “more willing” (“a lot” and “moderately”) versus “less willing” (“some,” “a little,” and “not at all”). A chi-square test was used to determine if responses differed between participants based on intervention and participant characteristics. Results: General WTP in BC ‘prevention’ studies was high at 79% “more willing”, including 67% and 72%, respectively, for unspecified physical activity and diet behavior change interventions. WTP differed significantly for diet-based behavior change interventions by type and duration; WTP was significantly lower for 12- versus 3-month interventions for both eliminating foods (28% versus 53% “more willing”, p = 0.0007) and for engaging in intermittent fasting (30% versus 45% “more willing”, p = 0.042). For physical activity, WTP decreased with duration of the intervention with 28% fewer WTP for one hour of low intensity exercise/day when compared to 30 minutes (p &lt; 0.0001). For medications, less than half of participants (46%) expressed being “more willing” to participate, and WTP decreased significantly when possible side effects were presented (81% “less willing”) with 95% “less willing” for medications with a rare risk of serious side effects. WTP was influenced by BC risk gene mutation status, with higher proportions among gene carriers compared to non-gene carriers (59% versus 21% “more willing,” p = 0.0013), including WTP in medication chemoprevention studies (38% versus 8% “more willing,” p = 0.002). Conclusions: WTP in BC prevention trials of behavior change is high among patients at elevated risk of BC but for all women was found to be significantly negatively influenced by greater time commitment and duration of intervention beyond a few months. WTP in studies of medication is lower compared to behavior change, and very low for medications with any side effects. Overall, WTP is greater in women with known genetic risk. This study suggests that WTP may be influenced by how patients perceive their level of risk. These results also suggest that despite interest in behavior change prevention, patients may not fully recognize the relationship between sustained behavior change and potential for prevention benefit.

0816 Actigraphy-Measured Sleep Timing and Risk of Breast Cancer in the UK Biobank

Abstract Introduction Shift work leading to circadian disruption is associated with increased breast cancer risk, but it remains unclear whether typical sleep timing variation in the general population that may cause less extreme disruption is also associated with increased risk. Prior studies relied on sleep timing assessed using self-report, but research using actigraphy is limited. Our goal was to characterize the association between sleep timing and breast cancer risk using actigraphy-based measures. Methods Our sample included 43,109 women without a history of breast cancer in the UK Biobank cohort who wore Axivity-AX3 accelerometers over 7 days. We estimated sleep midpoints, the median of sleep onset and waking. Social jetlag was estimated as the absolute difference in average weekend and weekday sleep midpoints. We used multivariable Cox models to estimate hazards ratios (HRs) and 95% confidence intervals (CI), adjusting for age, body mass index, participant characteristics, socioeconomic status, physical activity, menopause, parity, and oral contraceptive use. We conducted a sensitivity analysis excluding shift workers to control for potential strong confounding from shift work. Results Over 6.2 years of follow-up, there were 683 incident breast cancer cases. Earlier and later sleep midpoints were not associated with breast cancer (Early, &amp;lt; 4:00AM HR:1.08 [95%CI: 0.89-1.32]; Later, ≥5:00AM HR:1.24 [0.86-1.81]; vs. Reference 4:00-4:59 AM). Per-hour increases in social jetlag were suggestively associated with greater breast cancer risk (HR:1.09 [0.96-1.24]), but significantly higher risk was only noted at the highest levels of social jetlag comparing ≥2 hours to &amp;lt; 1 hour (HR:1.58 [1.13-2.20]). Results were unchanged when excluding shift workers. Conclusion Higher levels of social jetlag among UK women appeared to be associated with elevated breast cancer risk, possibly due to circadian disruption. While our results suggest that minimizing variation between weekday and weekend sleep timing may be related to lower breast cancer risk, replication of our findings in future studies using actigraphy-based measures and larger case numbers is needed. Support (if any) Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

Hyperglycemia and O-GlcNAc transferase activity drive a cancer stem cell pathway in triple-negative breast cancer

BackgroundEnhanced glucose metabolism is a feature of most tumors, but downstream functional effects of aberrant glucose flux are difficult to mechanistically determine. Metabolic diseases including obesity and diabetes have a hyperglycemia component and are correlated with elevated pre-menopausal cancer risk for triple-negative breast cancer (TNBC). However, determining pathways for hyperglycemic disease-coupled cancer risk remains a major unmet need. One aspect of cellular sugar utilization is the addition of the glucose-derived protein modification O-GlcNAc (O-linked N-acetylglucosamine) via the single human enzyme that catalyzes this process, O-GlcNAc transferase (OGT). The data in this report implicate roles of OGT and O-GlcNAc within a pathway leading to cancer stem-like cell (CSC) expansion. CSCs are the minor fraction of tumor cells recognized as a source of tumors as well as fueling metastatic recurrence. The objective of this study was to identify a novel pathway for glucose-driven expansion of CSC as a potential molecular link between hyperglycemic conditions and CSC tumor risk factors.MethodsWe used chemical biology tools to track how a metabolite of glucose, GlcNAc, became linked to the transcriptional regulatory protein tet-methylcytosine dioxygenase 1 (TET1) as an O-GlcNAc post-translational modification in three TNBC cell lines. Using biochemical approaches, genetic models, diet-induced obese animals, and chemical biology labeling, we evaluated the impact of hyperglycemia on CSC pathways driven by OGT in TNBC model systems.ResultsWe showed that OGT levels were higher in TNBC cell lines compared to non-tumor breast cells, matching patient data. Our data identified that hyperglycemia drove O-GlcNAcylation of the protein TET1 via OGT-catalyzed activity. Suppression of pathway proteins by inhibition, RNA silencing, and overexpression confirmed a mechanism for glucose-driven CSC expansion via TET1-O-GlcNAc. Furthermore, activation of the pathway led to higher levels of OGT production via feed-forward regulation in hyperglycemic conditions. We showed that diet-induced obesity led to elevated tumor OGT expression and O-GlcNAc levels in mice compared to lean littermates, suggesting relevance of this pathway in an animal model of the hyperglycemic TNBC microenvironment.ConclusionsTaken together, our data revealed a mechanism whereby hyperglycemic conditions activated a CSC pathway in TNBC models. This pathway can be potentially targeted to reduce hyperglycemia-driven breast cancer risk, for instance in metabolic diseases. Because pre-menopausal TNBC risk and mortality are correlated with metabolic diseases, our results could lead to new directions including OGT inhibition for mitigating hyperglycemia as a risk factor for TNBC tumorigenesis and progression.

Night work and breast cancer risk in a cohort of female healthcare employees in Stockholm, Sweden

ObjectivesNight work has been classified as probably carcinogenic to humans by the International Agency for Research on Cancer, but epidemiological evidence was considered limited due to variability in findings and...

Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition.

Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Concentrations of C-peptide-a marker for insulin secretion-were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2 , or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2 , or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14-2.19) and WC (OR = 1.51, 95% CI = 1.09-2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94-1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. These findings suggest that being overweight or obese and metabolically unhealthy raises risk of postmenopausal breast cancer while overweight or obese women with normal insulin levels are not at higher risk. Additional research should consider the combined utility of anthropometric measures with metabolic parameters in predicting breast cancer risk.

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&amp;lt;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.

Parental occupational exposure to chemicals and risk of breast cancer in female offspring

ObjectivesParental exposure to chemicals at work has been hypothesized to be a potential predisposing factor for breast cancer in next generations. The objective of the present nationwide nested case-control study was to contribute with evidence to this area. MethodsWomen with primary breast cancer were identified using the Danish Cancer Registry and they were required to have information on either maternal or paternal employment history, which resulted in the inclusion of 5587 cases. For each case, 20 female cancer free controls were matched on year of birth using the Danish Civil Registration System. Employment history was linked to job exposure matrices to assess specific occupational chemical exposures. ResultsFor maternal exposures, we observed an association between ever exposure to diesel exhaust (OR = 1.13, 95% CI: 1.01–1.27) and exposure to bitumen fumes in the perinatal period (OR = 1.51, 95% CI: 1.00–2.26) and breast cancer in female offspring. Highest cumulative exposure to benzo(a)pyrene, diesel exhaust, gasoline and bitumen fumes was further indicated to increase the risk. Results further indicated a stronger association between diesel exhaust (OR = 1.23, 95% CI: 1.01–1.50) and benzo(a)pyrene exposure (OR = 1.23, 95% CI: 0.96–1.57) and estrogen receptor negative tumors than tumors with ER expression, while bitumen fumes seemed to elevate the risk of both hormonal subtypes. For paternal exposures, the main results did not indicate any associations with breast cancer in female offspring. ConclusionsOur study suggests an elevated breast cancer risk in daughters of women occupational exposed to some occupational pollutants, including diesel exhaust, benzo(a)pyrene and bitumen fumes. These findings need to be confirmed in future large-scale studies before any firm conclusions can be reached.

EPR23-082: Patient Awareness of Elevated Breast Cancer Risk After Routine Screening Mammogram and Risk Notification

EPR23-082: Patient Awareness of Elevated Breast Cancer Risk After Routine Screening Mammogram and Risk Notification

Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis.

Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.

Atrial fibrillation and breast cancer-Vicious twins? A systematic review and meta-analysis.

Epidemiological studies suggest a bidirectional association between atrial fibrillation and breast cancer. This study aimed to conduct a meta-analysis to elucidate the prevalence of atrial fibrillation among breast cancer patients, and the bidirectional association between atrial fibrillation and breast cancer. PubMed, the Cochrane Library, and Embase were searched to identify studies reporting the prevalence, incidence, and bidirectional association between atrial fibrillation and breast cancer. The study was registered with PROSPERO (CRD42022313251). Levels of evidence and recommendations were assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Twenty-three studies (17 retrospective cohort studies, 5 case-control studies and 1 cross-sectional study) involving 8,537,551 participants were included. Among patients with breast cancer, the prevalence of atrial fibrillation was 3% (11 studies; 95% CI: 0.6 to 7.1%) and the incidence was 2.7% (6 studies; 95% CI: 1.1 to 4.9%). Breast cancer was associated with increased risk of atrial fibrillation (5 studies; hazard ratio [HR]: 1.43, 95% CI: 1.12 to 1.82, I2 = 98%). Atrial fibrillation was also significantly associated elevated risk of breast cancer (5 studies HR: 1.18, 95% CI: 1.14 to 1.22, I2 = 0%). Grade assessment shown low certainty of the evidence for the risk of atrial fibrillation and moderate certainty of the evidence for the risk of breast cancer. Atrial fibrillation is not uncommon in patients with breast cancer and vice versa. There is a bidirectional association between atrial fibrillation (low certainty) and breast cancer (moderate certainty).

Abstract P6-02-04: Use of breast surveillance between women with pathogenic variants and variants of uncertain significance in breast cancer susceptibility genes

Abstract Background: Surveillance is a fundamental tool in the early detection and secondary prevention of many cancers. For women at increased genetic risk of breast cancer, mammography and breast magnetic resonance imaging (MRI) serve as the standard screening modalities. Use of surveillance mammography and MRI has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely pathogenic variants (P/LP). To address this gap, we examined the use of breast cancer surveillance and breast surgery in women who underwent multiple gene sequencing in a multicenter cohort of patients. We also expanded the surveillance literature by assessing correlates of breast MRI and mammography among women with VUS and investigating how rates of imaging changed over time after genetic testing. Methods: Using data from two cancer settings, we calculated use of risk reducing mastectomy (RRM) and surveillance for all women at genetically elevated risk of breast cancer, regardless of their personal history of breast cancer, with VUS or P/LP variants in a breast cancer susceptibility gene of high penetrance (BRCA1, BRCA2, PALB2, PTEN, TP53) and moderate penetrance (ATM, CDH1, CHEK2, NBN, NF1, STK11). The primary outcome was longitudinal use of surveillance mammography and breast MRI for women during the 13-month span after genetic testing, and each subsequent 13-month period up to 6 years afterwards. Results: Of 889 women, those with and without personal history of breast cancer were similar with regards to race/ethnicity, marital status, and high- or average-risk status. However, women with a personal history of breast cancer were on average older (54.1 vs 48.2 years), had longer follow-up time since genetic testing (3.4 vs 3.0 years), and were more likely to have VUS (62.5% vs 37.7%) compared to those without personal history of breast cancer. VUS carriers were less likely to undergo RRM compared to those with P/LP (HR=0.17, p=&amp;lt; 0.001) and high-risk women were more likely to undergo RRM than average-risk women (HR=3.91, p=0.005). Longitudinally, surveillance use among unaffected women decreased from 49.8% in the first year to 31.2% in the sixth year after genetic testing. In comparison, a greater proportion of women with a personal history of breast cancer underwent surveillance, which increased from 59.3% in the first year to 63.6% in the sixth year after genetic testing. Mammography rates did not differ between women with P/LP and VUS within the first 13 months after genetic testing and up to 4 years afterwards. Over the first four years after genetic testing, women with VUS were less likely to undergo annual MRIs compared to P/LP. This observation was true for women without a personal history of breast cancer (OR=0.34, p=0.003; OR=0.37, p=0.03; OR=0.19, p=0.004 for years 1, 2, and 3 respectively) as well as for women with a personal history of breast cancer (OR=0.31, p&amp;lt;=0.001; OR=0.33, p=0.002; OR=0.37, p=0.012; OR=0.3, p=0.14 for years 1, 2, 3, and 4 respectively). Conclusion: In this study of surveillance mammography and breast MRI use among women at elevated risk of breast cancer, we found that women with P/LP variants in breast cancer susceptibility genes are more likely to undergo annual breast MRI compared to those with VUS, whereas there was no difference between the groups in their use of annual surveillance mammography. This study is one of the first to examine maintenance of breast surveillance in a sample of women at elevated risk of breast cancer with non-negative genetic test results in BRCA1/2 as well as non-BRCA1/2 genes, while adjusting for personal and family history of cancer. In addition, we found that VUS, whether in high or moderate penetrance breast cancer susceptibility genes, was associated with lower use of annual breast MRI compared to P/LP variants, and equivalent use of annual mammography. These results add important evidence to dispel the myth of VUS-associated mismanagement of care. Citation Format: Sukh Makhnoon, Minxing Chen, Brooke Levin, Megan Ensinger, Kristin Mattie, Generosa Grana, Sanjay Shete, Banu K. Arun, Susan K. Peterson. Use of breast surveillance between women with pathogenic variants and variants of uncertain significance in breast cancer susceptibility genes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-04.