Breast Cancer Risk Research Articles

Impacts of Matrix Metalloproteinase-2 Promoter Genotypes on Breast Cancer Risk.

Matrix metalloproteinase-2 (MMP-2) has been implicated in the pathogenesis of breast cancer (BC). However, there is limited research on the role of MMP-2 genotypes in BC risk. This study aimed to investigate the associations between two MMP-2 promoter polymorphisms, rs243865 and rs2285053, and BC risk. MMP-2 genotypes were analyzed using PCR-based RFLP methodology in a cohort comprising 1,232 BC cases and 1,232 controls. Genotypic frequencies of MMP-2 rs243865 and rs2285053 in controls were consistent with Hardy-Weinberg equilibrium (p=0.3702 and 0.2036, respectively). There were no significant differences in the distribution of rs243865 and rs2285053 genotypes between BC cases and controls (p for trend=0.1602 and 0.2170, respectively). Variant genotypes at rs243865 and rs2285053 appeared to confer a protective effect, although not statistically significant (all p>0.05). Similarly, the variant T allele at rs243865 and rs2285053 showed a non-significant trend towards decreased BC risk (OR=0.84 and 0.89, 95%CI=0.69-1.02 and 0.78-1.02, p=0.0811 and 0.1043, respectively). There was no interaction observed between MMP-2 rs243865 or rs2285053 genotypes and age. Stratified analysis did not reveal significant associations between MMP-2 rs243865 or rs2285053 genotypes and triple-negative breast cancer (TNBC) (p=0.6458 and 0.8745, respectively). Among both TNBC and non-TNBC cases, none of the variant genotypes at rs243865 or rs2285053 showed significant associations with TNBC (all p>0.05). MMP-2 rs243865 and rs2285053 genotypes appear to have a minimal impact on individual susceptibility to BC or TNBC.

Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.

Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear. We analyzed a prospective cohort of 66,308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs). In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.83, 1.49-2.26) and males (2.03, 1.51-2.73) as well as early-onset breast cancer in females (3.06, 2.20-4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12, 2.14) and 1.69 (1.11, 2.57) in the highest genetic risk category and 1.03 (0.64, 1.67) and 0.81 (0.36, 1.85) in the lowest. Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

Rare germline genetic variation in PAX8 transcription factor binding sites and susceptibility to epithelial ovarian cancer.

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.

Factors Contributing to Bleeding in Breast Cancer Wounds: A Literature Review

Aims: In Indonesia, breast cancer ranks first in the number of new cases; there is a significant increase in the number of cases every year. Complications of breast cancer include bleeding that affects quality of life, psychology, activity limitations, anemia, increased treatment time, economic burden, and the threat of death. Breast cancer is often found in advanced stages, increasing the risk of bleeding. The literature review analyzes research articles that discuss factors associated with breast cancer wound bleeding. Methods: Inclusion criteria include articles discussing breast cancer bleeding, cancer in general, cancer wounds, themes relevant to research, research can be a quantitative, qualitative, mixed method, meta-analysis, in English and Indonesian, from 2013 to 2023, full text. Keywords in the database are "risk factors," bleeding, breast cancer, and malignant wound. Literature searches use journal databases, namely Pubmed and ScienceDirect. This research uses the author's literature review method to analyze, evaluate, and criticize published research results. Results: Fifteen articles met the inclusion criteria, most of them retrospective, examining factors of anticoagulation therapy on breast cancer bleeding, articles examining bleeding factors in several types of cancer, and five articles examining factors of post-operative breast cancer bleeding. Conclusion: Breast cancer wound bleeding factors are chemotherapy, radiation, comorbidities, malignant fungating wounds, BMI≥40, dressings, thrombocytopenia, reconstructive surgery, advanced stage, infection, and therapy (anticoagulants, anti-inflammatory pain relief, NSAIDs). Suggestions for further research are analyzing various bleeding factors, examining which factors are most related to bleeding, and looking at the pattern of relationships between several factors in bleeding.

Barriers and facilitators to breast cancer screening among high-risk women: a qualitative study.

Women with greater than 20-25% lifetime breast cancer risk are recommended to have breast cancer screening with annual mammogram and supplemental breast MRI. However, few women follow these screening recommendations. The objective of this study was to identify barriers and facilitators of screening among women at high risk for breast cancer, guided by the Health Services Utilization Model (HSUM). Unaffected high-risk women (N=63) completed semi-structured qualitative interviews exploring their experiences with breast cancer screening. Interviews were audio recorded, transcribed verbatim, and analyzed using a combined deductive and inductive approach. Most participants (84%) had received a screening mammogram; fewer (33%) had received a screening breast MRI. Only 14% had received neither screening. In line with the HSUM, qualitative analysis identified predisposing factors, enabling factors, and need factors associated with receipt of breast cancer screening. Enabling factors - including financial burden, logistic barriers, social support, and care coordination - were most frequently discussed. Predisposing factors included knowledge, health beliefs, and self-advocacy. Need factors included healthcare provider recommendation, family history of breast cancer, and personal medical history. Although HSUM themes were consistent for both mammography and breast MRI, participants did highlight several important differences in barriers and facilitators between the two screening modalities. Barriers and enabling factors associated with supplemental screening for high-risk women represent possible intervention targets. Future research is needed to develop and test multilevel interventions targeting these factors, with the ultimate goal of increasing access to supplemental screening for high-risk women.

Systematic assessment of HER2 status in ductal carcinoma in situ of the breast: a perspective on the potential clinical relevance

In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients.

Global burden of breast cancer and attributable risk factors in 204 countries and territories, from 1990 to 2021: results from the Global Burden of Disease Study 2021

Background and objectiveBreast cancer is a leading cause of morbidity and mortality among women worldwide. This study aimed to assess the global burden of breast cancer and identify attributable risk factors across 204 countries and territories from 1990 to 2021.MethodsUsing data from the Global Burden of Disease Study 2021, we analyzed the incidence, mortality, disability-adjusted life years (DALYs), and risk factors associated with breast cancer. We obtained and analyzed the age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs rate from 1990 to 2021. We assessed geographical variations and the impact of the Socio-demographic Index (SDI) using regression analysis and stratification by SDI quintiles. Additionally, we estimated the risk factors attributable to breast cancer deaths and DALYs using the comparative risk assessment framework of the GBD study.ResultsGlobally, breast cancer incident cases increased from 875,657 in 1990 to 2,121,564 in 2021. The ASIR rose from 16.42 to 26.88 per 100,000 (95% CI: 1.54–1.60). High SDI regions showed the highest ASIR (66.89 per 100,000 in 2021), while Low SDI regions had the lowest (6.99 per 100,000 in 2021). The global ASDR decreased from 10.42 to 8.54 per 100,000, and the age-standardized DALYs rate decreased from 313.36 to 261.5 per 100,000 between 1990 and 2021. However, these improvements were not uniform across SDI regions. Risk factors included high body-mass index, alcohol use, tobacco, and high fasting plasma glucose, with variations across SDI regions.ConclusionThe global burden of breast cancer has increased significantly from 1990 to 2021, with disparities observed across SDI regions. While high SDI areas show improvements in mortality and DALYs, lower SDI regions face increasing burdens. Targeted interventions addressing modifiable risk factors and improving healthcare access in less developed regions are crucial for reducing the global impact of breast cancer.

Breast Cancer Screening Using Mammography, Digital Breast Tomosynthesis, and Magnetic Resonance Imaging by Breast Density

Information on long-term benefits and harms of screening with digital breast tomosynthesis (DBT) with or without supplemental breast magnetic resonance imaging (MRI) is needed for clinical and policy discussions, particularly for patients with dense breasts. To project long-term population-based outcomes for breast cancer mammography screening strategies (DBT or digital mammography) with or without supplemental MRI by breast density. Collaborative modeling using 3 Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models informed by US Breast Cancer Surveillance Consortium data. Simulated women born in 1980 with average breast cancer risk were included. Modeling analyses were conducted from January 2020 to December 2023. Annual or biennial mammography screening with or without supplemental MRI by breast density starting at ages 40, 45, or 50 years through age 74 years. Lifetime breast cancer deaths averted, false-positive recall and false-positive biopsy recommendations per 1000 simulated women followed-up from age 40 years to death summarized as means and ranges across models. Biennial DBT screening for all simulated women started at age 50 vs 40 years averted 7.4 vs 8.5 breast cancer deaths, respectively, and led to 884 vs 1392 false-positive recalls and 151 vs 221 false-positive biopsy recommendations, respectively. Biennial digital mammography had similar deaths averted and slightly more false-positive test results than DBT screening. Adding MRI for women with extremely dense breasts to biennial DBT screening for women aged 50 to 74 years increased deaths averted (7.6 vs 7.4), false-positive recalls (919 vs 884), and false-positive biopsy recommendations (180 vs 151). Extending supplemental MRI to women with heterogeneously or extremely dense breasts further increased deaths averted (8.0 vs 7.4), false-positive recalls (1088 vs 884), and false-positive biopsy recommendations (343 vs 151). The same strategy for women aged 40 to 74 years averted 9.5 deaths but led to 1850 false-positive recalls and 628 false-positive biopsy recommendations. Annual screening modestly increased estimated deaths averted but markedly increased estimated false-positive results. In this model-based comparative effectiveness analysis, supplemental MRI for women with dense breasts added to DBT screening led to greater benefits and increased harms. The balance of this trade-off for supplemental MRI use was more favorable when MRI was targeted to women with extremely dense breasts who comprise approximately 10% of the population.

Carcinogenic industrial air pollution and postmenopausal breast cancer risk in the National Institutes of Health AARP Diet and Health Study

BackgroundChemicals emitted from industrial facilities include known or suspected mammary carcinogens and endocrine disruptors, but epidemiologic studies are limited. We evaluated associations between air emissions of multiple carcinogenic chemicals and postmenopausal breast cancer risk in a large prospective U.S. cohort. MethodsWe used the U.S. Environmental Protection Agency’s Toxics Release Inventory to estimate historical airborne emissions (1987–1995) of 19 known and probable carcinogens for participants enrolled (1995–1996) in the NIH-AARP Diet and Health Study. Among 170,402 women, 15,124 breast cancers were diagnosed through 2018. We constructed inverse distance- and wind-weighted average emissions metrics within 1, 2, 5, and 10 km of the enrollment address for each chemical. We estimated multivariable adjusted HRs and 95 % CIs for categories (quartiles, tertiles, medians) of each chemical in association with breast cancer overall and separately by type (invasive, ductal carcinoma in situ) and estrogen receptor (ER) status. ResultsWe observed an association between benzene emissions and breast cancer risk that was strongest at 1 km (HRQ4 vs. non-exposed = 2.06, 95 %CI: 1.34–3.17; p-trend = 0.001). The magnitude of the association weakened with increasing distance (2 km HRQ4 vs. non-exposed = 1.17, 95 %CI=0.92–1.49; p-trend = 0.19; 5 km HRQ4 vs. non-exposed = 1.05, 95 %CI=0.94–1.16; p-trend = 0.37; 10 km HRQ4 vs. non-exposed = 0.95, 95 %CI=0.89–1.02; p-trend = 0.19) and appeared to be most relevant for invasive rather than intraductal disease. Overall risk was also elevated for vinyl chloride at 5 km (HR≥median vs. non-exposed = 1.20, 95 %CI=1.01–1.43; p-trend = 0.04), but not 2 km or 10 km. We observed suggestive associations for asbestos, trichloroethylene, and styrene in different subgroup analyses, but risk patterns were not clear across distances. Associations with other chemicals were generally null, with limited evidence of heterogeneity by disease type or ER status. ConclusionsAn increased risk of breast cancer associated with relatively high levels of industrial benzene emissions warrants additional study, particularly among participants with diverse sociodemographic characteristics that live in areas with higher density of industrial facilities.

Tumor grade and progesterone receptor status in predicting benefit of chemotherapy in high genomic risk breast cancer

ABSTRACT Background Not all eligible breast cancer (BC) patients could afford the expensive test of 21-gene recurrence score (RS) assay. This study aimed to identify clinicopathological factors associated with high-risk RS and examine whether these factors correlate with the benefit of chemotherapy. Research design and methods Patients diagnosed with early-stage BC, node-negative, and estrogen receptor-positive disease were identified from the Surveillance, Epidemiology, and End Results Oncotype DX database. Result We included 74,605 patients. Those with higher grade (p < 0.001) and progesterone receptor-negative (PR Neg) (p < 0.001) had the highest odds of a high-risk RS. Among them, 3.2%, 10.1%, 39.1%, 18.6%, 41.6%, and 80.1% had high-risk RS tumors in PR-positive (PR Pos)/well-differentiated (G1), PR Pos/moderately differentiated (G2), PR Pos/poorly and/or undifferentiated (G3), PR Neg/G1, PR Neg/G2, and PR Neg/G3 groups, respectively. Receipt of chemotherapy was associated with improved breast cancer-specific survival (p = 0.010) and overall survival (p < 0.001) in high-risk RS cohort. However, there were no survival benefits from chemotherapy in patients with PR Neg/G3 disease and other groups after stratification by grade and PR status (all p ≥ 0.05). Conclusion Our study aids in refining patient selection for the RS testing, which is crucial given its economic implications. However, 21-gene RS remains pivotal for treatment decision-making.

Female patients with hepatitis B may exhibit a reduced risk of breast cancer: A review of NHANES data.

Hepatic viral infections and breast cancer (BC) constitute major global health challenges, yet the interconnection between these hepatic infections and BC continues to be ambiguous. Conducting a comprehensive evaluation of the link between hepatitis virus infection and the incidence of BC and leveraging data from the National Health and Nutrition Examination Survey covering the period from 1999 to March 2022, we utilized logistic regression and subgroup analysis, among other methodologies, to execute a cross-sectional investigation. The univariate logistic regression analysis elucidates that individuals classified as non-Hispanic White exhibit a markedly higher incidence of BC at 2.620 (95% confidence interval [CI], 1.117-7.676; P = .045); moreover, advanced age at 1.063 (95% CI, 1.036-1.093; P < .001), elevated educational attainment at 1.962 (95% CI, 1.17-3.366; P = .012), and higher income levels at 2.835 (95% CI, 1.303-7.439; P = .017) emerge as significant predisposing factors for BC. In contrast, a greater number of live births significantly diminishes the risk of BC, reducing the incidence to 81.1% with each additional birth. Pertaining to hepatitis and vaccination status, our analysis distinctly demonstrates that only hepatitis B at 0.110 (95% CI, 0.018-0.353; P = .002) bears a significant inverse relationship with BC risk, suggesting a protective effect. The multivariate logistic regression analysis further reveals a negative association between hepatitis B infection and BC incidence, whereas hepatitis B vaccination shows a positive correlation with the disease incidence. After adjusting for all covariates, model 3 delineates odds ratios (95% CI) as follows: 0.14 (0.02-0.50; P = .009) and 1.92 (0.99-3.62; P = .046). Our investigation uncovers that within the general populace, there exists an inverse correlation between hepatitis B infection and BC incidence; in addition, the administration of the hepatitis B virus vaccine is potentially positively associated with the prevalence of BC.

Long-term exposure to air pollution at residential and workplace addresses and breast cancer risk: A case-control study nested in the French E3N-Générations cohort from 1990 to 2011

BackgroundAn increasing evidence links air pollution to breast cancer (BC) risk. Yet, pollutant exposure estimates at the workplace location in pollution exposure assessment have not been considered. ObjectivesThis study investigates the association between particulate matters (PM2·5, PM10) and nitrogen dioxide (NO2) atmospheric concentrations (1990–2011), at the women’s residential and workplace locations, and BC risk. MethodsThis case-control study of 2419 BC cases and 2984 controls, was nested in the French prospective E3N cohort. The annual mean PM2·5, PM10 and NO2 concentrations were estimated using a Land Use Regression model (50 m x 50 m resolution) and assigned to the women’s geocoded residential and workplace locations, from cohort recruitment to their index date (date of case diagnosis). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using multivariate logistic regression models. ResultsAn increased BC risk was observed for a 10 µg/m3 increase of the 1990–2011 average PM2·5 concentration estimates (OR=1·28; CI 1·00, 1·63). An increased risk was suggested for a 10 µg/m3 increase for PM10 (OR=1·09; CI 0·92, 1·30) and NO2 (OR=1·05; CI 0·97, 1·13). No effect modification by menopausal status, nor difference by hormone receptor status were observed. DiscussionThis study is the first to estimate BC risk and long-term air pollutant exposure from both, residential and workplace location histories. Results suggest that residential PM2·5, PM10 and NO2 concentrations are strongly correlated with workplace ones, indicating that residential data may serve as proxy for overall exposure. Future studies should consider exposure during commuting.

Elucidating the mechanism of plasticizers inducing breast cancer through network toxicology and molecular docking analysis

ObjectiveThe objective of this study was to elucidate the molecular mechanisms underlying the potential contribution of commonly utilized plasticizers, including Diethyl phthalate (DEP), Dimethyl phthalate (DMP), and Dioctyl phthalate (DOP), to the pathogenesis of breast cancer. This study aimed to highlight the complex interactions between these environmental chemicals and key molecular pathways implicated in tumorigenesis. MethodsWe employed network toxicology and molecular docking techniques to analyze the interactions between plasticizers and key proteins implicated in breast cancer. Utilizing databases such as the TCGA, we performed an expression analysis of selected key genes in breast cancer tissue compared to normal controls. Enrichment analysis was conducted to identify the biological pathways associated with these genes. ResultsEnrichment analysis highlighted the association of these plasticizer-targeted genes with pathways integral to adenocarcinoma development, suggesting a broad impact of plasticizers on hormone-dependent and other forms of cancers. Subsequent expression analysis using data from the TCGA breast cancer database indicated significant upregulation or downregulation of these genes in breast cancer tissues compared to normal controls, confirming their pivotal roles in tumor biology. Furthermore, the molecular docking analysis revealed that plasticizers, including DEP, DMP, and DOP, exhibit specific binding interactions with key proteins such as MAPK1, AKT1, SRC, ESR1, and ALB, which are crucial in the regulation of breast cancer pathogenesis. ConclusionThe study provides evidence that exposure to plasticizers may influence breast cancer pathogenesis through interactions with critical proteins and signaling pathways. By employing network pharmacology, protein interactions, and molecular docking, our findings highlight the potential risks posed by plasticizers. These results underscore the need for further epidemiological and clinical research to fully understand the implications of plasticizer exposure on breast cancer risk, thus informing future preventive and therapeutic strategies.

Women’s experiences of risk-stratified breast cancer screening in the MyPeBS trial: a qualitative comparative study across two European countries

Objective Risk-stratification should improve the benefits-to-harms ratio for breast screening, whereby higher-risk women receive additional screening and low-risk women are screened less. This study investigated the effects of healthcare context by comparing how women in England and France experienced risk-based breast screening. Methods and measures Fifty-two women were purposively sampled from participants who underwent risk-based screening in the MyPeBS trial. Women received objectively-derived 5-year breast cancer risk estimates (low = < 1%, average = 1–1.66%, high = ≥ 1.67 to <6%, very-high-risk = ≥ 6%). This determined future trial-related screening schedules and prevention options. Semi-structured interviews were transcribed for thematic framework analysis. Results Two overarching themes were produced: the importance of supported risk communication and accessibility of risk management. Overall, risk-based breast screening was viewed positively. However, trial procedures, especially in risk estimate provision, differed across sites. Women at increased risk were more reassured when appointments were with specialist healthcare professionals (HCP). When absent, this resulted in reduced satisfaction with risk communication and greater uncertainty about its personal relevance. Low-risk women’s views on extended mammogram schedules seemed linked to how health services are organised differently. Conclusions Context is an important consideration regarding acceptability of healthcare innovations such as risk-stratified screening: it should not be assumed that findings from one country apply universally.

Clinical Significance of Combined Density and Deep-Learning-Based Texture Analysis for Stratifying the Risk of Short-Term and Long-Term Breast Cancer in Screening.

Assessing a woman's risk of breast cancer is important for personalized screening. Mammographic density is a strong risk factor for breast cancer, but parenchymal texture patterns offer additional information which cannot be captured by density. We aimed to combine BI-RADS density score 4th Edition and a deep-learning-based texture score to stratify women in screening and compare rates among the combinations. This retrospective study cohort study included 216,564 women from a Danish populations-based screening program. Baseline mammograms were evaluated using BI-RADS density scores (1-4) and a deep-learning texture risk model, with scores categorized into four quartiles (1-4). The incidence rate ratio (IRR) for screen-detected, interval, and long-term cancer were adjusted for age, year of screening and screening clinic. Compared with subgroup B1-T1, the highest IRR for screen-detected cancer were within the T4 category (3.44 (95% CI: 2.43-4.82)-4.57 (95% CI: 3.66-5.76)). IRR for interval cancer was highest in the BI-RADS 4 category (95% CI: 5.36 (1.77-13.45)-16.94 (95% CI: 9.93-30.15)). IRR for long-term cancer increased both with increasing BI-RADS and increasing texture reaching 5.15 (4.31-6.16) for the combination of B4-T4 compared with B1-T1. Deep-learning-based texture analysis combined with BI-RADS density categories can reveal subgroups with increased rates beyond what density alone can ascertain, suggesting the potential of combining texture and density to improve risk stratification in breast cancer screening.

Polygenic Risk Score (PRS) Combined with NGS Panel Testing Increases Accuracy in Hereditary Breast Cancer Risk Estimation.

Breast cancer (BC) is the most prominent tumor type among women, accounting for 32% of newly diagnosed cancer cases. BC risk factors include inherited germline pathogenic gene variants and family history of disease. However, the etiology of the disease remains occult in most cases. Therefore, in the absence of high-risk factors, a polygenic basis has been suggested to contribute to susceptibility. This information is utilized to calculate the Polygenic Risk Score (PRS) which is indicative of BC risk. This study aimed to evaluate retrospectively the clinical usefulness of PRS integration in BC risk calculation, utilizing a group of patients who have already been diagnosed with BC. The study comprised 105 breast cancer patients with hereditary genetic analysis results obtained by NGS. The selection included all testing results: high-risk gene-positive, intermediate/low-risk gene-positive, and negative. PRS results were obtained from an external laboratory (Allelica). PRS-based BC risk was computed both with and without considering additional risk factors, including gene status and family history. A significantly different PRS percentile distribution consistent with higher BC risk was observed in our cohort compared to the general population. Higher PRS-based BC risks were detected in younger patients and in those with FH of cancers. Among patients with a pathogenic germline variant detected, reduced PRS values were observed, while the BC risk was mainly determined by a monogenic etiology. Upon comprehensive analysis encompassing FH, gene status, and PRS, it was determined that 41.90% (44/105) of the patients demonstrated an elevated susceptibility for BC. Moreover, 63.63% of the patients with FH of BC and without an inherited pathogenic genetic variant detected showed increased BC risk by incorporating the PRS result. Our results indicate a major utility of PRS calculation in women with FH in the absence of a monogenic etiology detected by NGS. By combining high-risk strategies, such as inherited disease analysis, with low-risk screening strategies, such as FH and PRS, breast cancer risk stratification can be improved. This would facilitate the development of more effective preventive measures and optimize the allocation of healthcare resources.

Impact of steroid hormone levels on estradiol-mediated regulation of cytochrome P450 2B6 compared to 1B1 in breast cancer cells.

Pharmacogenetic variants of the steroid hormone-metabolizing enzyme cytochrome P450 2B6 (CYP2B6) were reported to be associated with breast cancer (BC) risk and prognosis. CYP2B6 expression is inducible by estradiol (E2) but induction was demonstrated only under steroid hormone-deprived medium conditions. Physiological conditions, however, even under endocrinological BC treatment, do not correspond to complete steroid hormone depletion. The aim of this study was to investigate the E2-mediated CYP2B6 and CYP1B1 regulation under various steroid hormone conditions, including physiological concentrations, in human oestrogen receptor positive (T47D, MCF-7) and negative (MDA-MB-231) BC cell lines. We confirm that steroid-deprived pre-cultivation led to CYP2B6 upregulation in T47D, but not in MCF-7. However, when pre-cultivated with steroid-containing medium CYP2B6 was downregulated in T47D and MCF-7, while the addition of physiological E2 concentrations to steroid-deprived medium resulted in a downregulation in T47D. In contrast, CYP1B1 was never downregulated in any culture condition. Thus, we show that E2-mediated CYP2B6 regulation in BC cells depends on steroid hormone exposure in a cell line-specific manner. Our data indicates the importance of being careful with conclusions drawn from CYP2B6 induction findings in vitro, as we demonstrate potential influences of hormonal changes on CYP2B6 expression, which could impact steroid hormone homeostasis and, consequently, BC risk.

Polycystic ovary syndrome and risk of breast cancer in premenopausal and postmenopausal women: a nationwide population-based cohort study.

Although some reproductive and metabolic characteristics of polycystic ovary syndrome (PCOS) are known risk factors for breast cancer, the evidence regarding a potential association between PCOS and breast cancer is scarce. In this population-based cohort study including all 1,719,452 women born in Denmark between 1940 and 1993, we investigated the association between PCOS and breast cancer. PCOS diagnoses, cancer diagnoses, covariates, migrations, and vital status were all obtained from national population and health registers. Hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer overall and for histological subtypes separately were calculated based on adjusted cox proportional hazards models. During a median follow-up of 26years, 63,078 women were diagnosed with breast cancer. We found an increased risk of breast cancer overall among women with PCOS compared with women without PCOS (HR: 1.21, 95% CI 1.02-1.44). In analyses stratified for menopausal status, the increased risk was restricted to postmenopausal women (HR: 1.63, 95% CI 1.23-2.15). The results for ductal and lobular histological subtypes analyses separately resembled those observed for breast cancer overall. This is the first study to report an increased risk of breast cancer among women with a history of PCOS. The increased risk was seemingly confined to postmenopausal women. Our results therefore contribute to an increased knowledge of the etiology of breast cancer, but our findings should be further confirmed in other large cohort studies with an appropriately long follow-up period.

Association between remnant cholesterol and the risk of 4 site-specific cancers: evidence from a cross-sectional and Mendelian randomization study

BackgroundRecent studies have implicated remnant cholesterol (RC) in the etiology, progression, and prognosis of cancer. However, very few of them concentrated on the study of the precise relationship between serum RC levels and cancer risk, leaving this subject unexplored. Consequently, this study aims to investigate the association between serum RC levels and 4 site-specific cancers, employing a dual approach that combines observational and mendelian randomization (MR) analysis.MethodsBased on data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020, this study collected data from18,067 participants. To rule out confounders, this study utilized weighted multivariable logistic regression and assessed non-linear associations using restricted cubic spline (RCS) regression, followed by two-piecewise linear regression. Sensitivity analysis conducted in this study included subgroup analysis, multiple imputation, outlier removal, and propensity score matching. To strengthen causal inference, this study employed univariable and multivariable MR analysis. The robustness and reliability of the findings were estimated by the application of replication and meta-analysis.ResultsThe results of multivariable logistic regression analysis demonstrated a significant association between serum RC levels and breast cancer, showing that individuals in the higher logRC category had a higher risk of breast cancer compared to those in the lower category (Q3 vs. Q1: OR = 1.71, 95% CI: 1.01–2.88, P = 0.044). Weighted RCS revealed an inverted L-shape association between RC and the risk of breast cancer (P-nonlinear = 0.0386, P-overall = 0.010). Primary MR analysis provided evidence for an increased risk of breast (IVW: OR = 1.08, 95% CI: 1.03–1.12, P = 0.000951) and colorectal cancer (IVW: OR = 1.12, 95% CI: 1.00-1.24, P = 0.0476) associated with RC. However, the results of replication and meta-analysis did not support a significant causal association of RC with the risk of breast cancer (OR = 1.04, 95% CI: 0.95–1.13), lung cancer (OR = 0.95, 95% CI: 0.88–1.03), colorectal cancer (OR = 1.05, 95% CI: 0.92–1.19), and prostate cancer (OR = 1.01, 95% CI: 0.95–1.08).ConclusionAlthough a non-linear relationship was observed in the cross-sectional study between remnant cholesterol levels and breast cancer risk, MR analyses failed to provide any causal evidence.

A Large Cohort Study of Height and Mammographic Density in Relation to Breast Cancer Risk among Korean Women.

Height and mammographic breast density are well-known risk factors for breast cancer. This study aims to investigate the association between height and mammographic density with breast cancer risk in a large population-based cohort of Korean women. This retrospective cohort study included 4,851,115 women aged 40 and older who underwent screening mammography through the Korean National Cancer Screening Program (KNCSP) between 2009 and 2014 and were followed up until 2016. Multivariable Cox proportional hazard models were employed to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between height, mammographic density, and breast cancer risk. A taller stature was associated with an increased risk of breast cancer, with women in the highest quintile of height (Q5) having a 1.54-fold [95% CI: 1.49, 1.59] greater risk compared to those in the lowest quintile (Q1). When analyzing breast cancer risk based on height and mammographic density, women in the highest quintile for height (Q5) with extremely dense breasts had a 4.51-fold [95% CI: 4.24, 4.79] greater risk compared to those in the lowest quintile (Q1) with almost entirely fatty breasts (p trend < 0.001). This first study to simultaneously examine these two variables found that height and mammographic density were independently associated with breast cancer risk in this large cohort of Korean women. Height and mammographic density can help stratify risk in screening populations for breast cancer. Careful consideration of screening strategies may be beneficial for taller women with dense breasts.