Risk Factors For Breast Cancer Research Articles

Mammographic density in relation to breast cancer risk factors among Chinese women

Abstract Background Increased mammographic density (MD) is a known breast cancer (BC) risk factor, but its influencing factors are unclear in Asian populations. This study examined the links between known BC risk factors and quantitatively measured MD in 7,351 Chinese women with non-malignant mammographic findings. Methods VolparaDensity software quantified volumetric MD measures: total breast (TBV), absolute dense (ADV), percent dense (PDV= ADV/TBV), and non-dense volumes (NDV= TBV-ADV). Multivariable linear regression models assessed associations between these MD metrics and BC risk factors. Results The mean age of the population was 50.1 (SD=8.3) years. The mean ADV, NDV, and PDV were 58.4 (SD=32.1), 382.8 (SD=202.0) cm³ and 14.8 (SD=7.1) %, respectively. PDV was inversely associated with age, weight, body mass index (BMI), parity, breastfeeding duration, and postmenopausal status, but positively linked to height and age at menopause. NDV showed opposite associations. ADV had similar associations to PDV, except for height, weight, and BMI, which differed for women with the lowest NDV. PDV associations with age at menarche, age at first birth, and breastfeeding duration varied by BMI and menopausal status. Conclusions MD may influence the relationship between reproductive factors and BC risk, depending on MD measure, menopausal status, and BMI. Impact This study examines how quantitative MD measures relate to known BC risk factors in an East Asian population, factoring in menopausal status and BMI. The results underscore the complex role of MD and confounding factors in BC risk, highlighting the need for tailored insights for future research and screening.

A Machine Learning Approach for Breast Cancer Risk Prediction in Digital Mammography

Breast cancer is among the most prevalent cancers in the female population globally. Therefore, screening campaigns as well as approaches to identify patients at risk are particularly important for the early detection of suspect lesions. This study aims to propose a workflow for the automatic classification of patients based on one of the most relevant risk factors in breast cancer, which is represented by breast density. The proposed classification methodology takes advantage of the features automatically extracted from mammographic images, as digital mammography represents the major screening tool in women. Textural features were extracted from the breast parenchyma through a radiomics approach, and they were used to train different machine learning algorithms and neural network models to classify the breast density according to the standard Breast Imaging Reporting and Data System (BI-RADS) guidelines. Both binary and multiclass tasks have been carried out and compared in terms of performance metrics. Preliminary results show interesting classification accuracy (93.55% for the binary task and 82.14% for the multiclass task), which are promising compared to the current literature. As the proposed workflow relies on straightforward and computationally efficient algorithms, it could serve as a basis for a fast-track protocol for the screening of mammograms to reduce the radiologists’ workload.

Gestational breast cancer: distinctive molecular and clinico-epidemiological features

Gestational breast cancer (GBC), defined as breast cancer (BC) diagnosed during pregnancy or the first-year post-partum, accounts for 6–15% of BC cases in women aged 20–44 years. GBC has worse prognosis than non-GBC, but reasons behind are not clear. The GEICAM/2012–03 Study (Molecular Characterization of Gestational Breast Cancer) is a multicenter prospective/retrospective observational registry of patients diagnosed with GBC. From November 2014 to June 2015 seventy patients diagnosed with GBC were included in the study, 30 diagnosed during pregnancy and 40 after delivery. Our current study was aimed to explore differences in epidemiological, clinico-pathological and gene expression features of GBC tumors, from the GEICAM/2012–03 Study, compared to non-GBC tumors from patients of similar age (< 43 years) from six different GEICAM studies, used as non- GBC control population. As per the main objective, the study found multiple differences showing GBC tumors as a different biological entity. GBC showed a more aggressive biology, with higher Ki67 levels, higher incidence of breast and/or ovarian cancer family history, and germline deleterious BRCA1/2 mutations, and are enriched in basal-like intrinsic subtype. GBC patients showed a lower number of tumor infiltrating lymphocytes, while specific genetic signatures highlight differences in GBC´s distinctive transcriptome. Our study shows that GBC is potentially a clinically and molecularly different entity, with specific epidemiological, clinical, and histological features, as well as a distinctive altered immune state and genetic signature. Nevertheless, further studies are needed to better understand the biology of GBC and to identify new targets against which develop new, more effective, targeted therapies.

Design, Synthesis, and Antitumor Potential of New Thiazole--contained 5-Fluoro-2-Oxindole Derivatives as Sunitinib Analogues.

Indole is considered the most promising scaffold for anticancer drug design due to its high bioavailability, unique chemical properties, and broad spectrum of pharmacological action. Twelve novel thiazole-containing the 5-fluoro-1,3-dihydro-2H-indol-2-one derivatives as sunitinib analogs were designed and synthesized, and their anticancer activity was evaluated against the NCI-60 cancer cell lines. The thiazole-contained 5-fluoro-1,3-dihydro-2H-indol-2-one derivatives were synthesized using Knoevenagel condensation of 1,3-thiazole-5-carboxylic acid 1. Their anticancer activities were evaluated by NCI-60 one-dose screen assay. The molecular docking studies were performed using AutoDock tools and the AutoDock Vina programs. The ADMETlab 2.0 web server predicted the physicochemical properties of compounds. Among the synthesized new 5-fluoro-2-oxindole derivatives, compound 3g demonstrated high antitumor activity (GI>70%) against eight types of cancer: leukemia, breast cancer, ovarian cancer, lung cancer, melanoma, CNS cancer, renal cancer, and colon cancer. The most activity was observed against breast cancer (T-47D, GI=96.17%), lung cancer (HOP-92, GI=95.95%), ovarian cancer (NCI/ADR-RES, GI=95.13%), and CNS cancer (SNB-75, GI=89.91%). The molecular docking results of compound 3g demonstrated the possibility of inhibiting VEGF2 receptors as his potential anticancer mechanism. The physicochemical properties predicted for compounds 3f and 3g showed positive results. Compound 3g demonstrated high in vitro NCI-60 anticancer activity against nine cancer types and showed cell growth inhibition against leukemia, CNS, and breast cancer at 6 - 31% higher than Sunitinib, and may represent the basis for further modification of the thiazole-containing analogs of the anticancer drug Sunitinib.

Association Between the rs13306703 and rs8192288 Variants of the SOD3 Gene and Breast Cancer and an In Silico Analysis of the Variants’ Impact

Background/Objectives: This study investigated the association between the rs13306703 and rs8192288 variants of the superoxide dismutase 3 (SOD3) gene and breast cancer (BC) in the Mexican population, conducting both genetic and in silico analyses. Methods: 357 healthy women and 386 BC patients were studied using TaqMan assays, qPCR, and RFLP-PCR. Results: The TT genotype and a recessive pattern of these variants were risk factors for BC (p &lt; 0.05). Specifically, the TT genotype of rs13306703 was associated with metastatic lymph nodes, tumor progression (III–IV), luminal A, nonresponse to chemotherapy, and ki-67 ≥ 20% with diabetes mellitus (DM). Meanwhile, the GT genotype of rs8192288 was associated with menopause, luminal A, tumor progression (III–IV), ki-67 ≥ 20%, and a positive estrogen receptor with nonresponse to chemotherapy. Additionally, the TT genotype combined with DM was identified as a BC risk factor (p &lt; 0.05). The TT haplotype was also found to be a risk factor for BC. In silico analysis suggested that these variants might influence SOD3 regulation by affecting transcription factors and active enhancer sites. Conclusions: The rs13306703 and rs8192288 variants of the SOD3 gene were associated with an increased risk of BC and may alter SOD3 regulation through effects on transcription factors, active enhancers, and transcription start sites, with modified motifs in breast epithelium cells.

Breast cancer and its determinants in Ethiopia: a systematic review and meta-analysis.

Breast cancer is the leading cause of cancer morbidity and mortality among women. Still, there is a paucity of studies to know the magnitude of the problem in Ethiopia. Hence, this review was intended to pool the prevalence and identify the determinants of breast cancer in Ethiopia. A systematic review and meta-analysis was conducted. Databases like PubMed/MEDLINE, HINARI, Science Direct, and Google Scholar, as well as websites of organisationsI organizations,rewere searched between 25 February and 6 March 2023. All observational studies in Ethiopia that reported either the magnitude and/or determinants of breast cancer regardless of publication status were included. Two authors independently assessed and extracted the data. The Joanna Briggs Institute meta-analysis of statistics assessment and review instrument quality appraisal tool was used to assess the quality of the articles. Effect estimates were done by using the random-effects model. The meta-analysis results were displayed by using forest plots. Seventeen articles were reviewed with 24 435 total participants. The pooled proportion of breast cancer morbidity among patients with cancer was 20. 58% (95% CI 17.25%, 23.90%) in Ethiopia. Consuming packed foods (POR=2.12, 95% CI 1.41, 3.17), presence of high cholesterol (POR=4.08; 95% CI 2.75, 6.07), physical inactivity (POR=3.27; 95% CI 1.80, 5.94), high body mass index (BMI) (POR=2.27; 95% CI 0.85, 6.03), postmenopause (POR=2.25; 95% CI 1.63, 3.10), family history of cancer (POR=3.65; 95% CI 0.85, 15.71) and lack of breastfeeding (POR=2.76; 95% CI 0.90, 7.92) were the determinants of breast cancer. One of five patients with cancer is diagnosed with breast cancer in Ethiopia. Furthermore, more than a quarter of women with cancer suffer from breast cancer. Processed food consumption, high cholesterol in the body, lack of physical activity, high BMI, postmenopause, family history of cancer and lack of breastfeeding were the risk factors for breast cancer. The use of healthy food sources such as fruits and vegetables, and homegrown varieties of crops rather than seeking processed foods would help. CRD42023417733.

Interaction of base excision repair gene polymorphism and estrogen-DNA adducts in breast cancer risk among East Asian women.

In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. We conducted a case-control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women.

Epigenetic Ageing and Breast Cancer Risk: A Systematic Review

ABSTRACTBackgroundAge is one of the strongest risk factors for breast cancer. Measures of biological age based on DNA methylation have gained popularity for their strong association with risk of many diseases, including cancer, which may help to identify high‐risk subgroups for targeted prevention.MethodsWe carried out a systematic review of prospective studies that examined the association of methylation‐based markers of ageing with risk of invasive breast cancer in healthy (breast cancer‐free) women, published up to May 2023. The search of three databases (MEDLINE, EMBASE and Web of Science) identified 2913 individual abstracts eligible for screening. Risk of bias assessment was conducted using ROBINS‐E.ResultsTen prospective studies met the eligibility criteria, and these were heterogeneous in design and findings. The most frequently assessed epigenetic ageing measures were Horvath's first‐generation clock, PhenoAge and GrimAge. Four studies reported mainly positive associations, five null associations and one reported a negative association. These associations were generally weak and the results were not consistent across epigenetic ageing measures.ConclusionThe summarised evidence is insufficient to support a role for current epigenetic ageing measures to stratify breast cancer risk.PROSPERO Registration: This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023417559)

Association between Clinical Features and Risk Factors for Breast Cancer through a Cross-Sectional Study

Introduction: Breast cancer was responsible for 685,000 deaths worldwide in 2020. Approximately half of all breast cancers arise in women who have no identifiable risk factors other than their gender and age. Objectives: The goal of this study was to determine the association between clinical features and breast cancer risk factors. Methods: This cross-sectional study was conducted among 50 histologically confirmed breast cancer patients included by purposive sampling technique in the Surgery Department of Rangpur Medical College, Rangpur. Results: The presence of breast lump was significantly associated with the residence of patients (p value&lt;0.011). The significant association between nipple retraction and family history may indicate a hereditary predisposition that affects the course of the disease (p value&lt;0.031). Conclusion: This research provides insights into vital aspects of breast cancer within a particular demographic, under scoring the necessity for focused approaches to public health to address the discrepancies in breast cancer presentation and outcomes. J Bangladesh Coll Phys Surg 2024; 42: 321-328

Implementation of polygenic risk scores in secondary prevention of (breast) cancer

Abstract Utilizing polygenic risk scores to inform secondary prevention of breast cancer via population screening programs is one of the pioneering applications of genomics in public health applications. Over the last decade, polygenic risk scores for breast cancer have been developed and validated in various European populations (AUC ± 0.63, OR per Z unit ± 1.6, depending on the population). In some countries, the polygenic risk score has been integrated with decision modeling tools, such as CanRisk in the Netherlands, and low-level implementation into health and care systems has started. Implementation strategies vary, but generally consider initial implementation into high-risk populations, such as breast cancer families, in specialized clinical setting, such as academic medical centres, or specialized cancer clinics, referring relatives of patients to population screening based on comprehensive risk modelling, including polygenic risk scores. This route may be followed by other disease fields as well. The presentations outlines the current evidence and considerations on breast cancer genetic risk modelling, clinical pilot studies and the outline of step-wise implementation of such models to benefit secondary prevention programs. We start from the perspective of a single hospital, to the needed steps to upscale to national populations, both in diversity of these populations, as the throughput of genetic testing and counselling, until the harmonization and recalibration of various European healthcare models. We draw from examples of the Genotyping on all patients (GOALL), building cancer health platforms (CanHeal) and Genome of Europe (GoE) consortia.

The association between mammographic breast density, epicardial adipose tissue volume and coronary artery disease

Abstract Background Dysfunctional adipose tissue is strongly linked to cardiometabolic disease. Epicardial adipose tissue (EAT) which is measurable on cardiac computed tomography (CT) is well correlated with cardiovascular disease (CVD), however it is not reported clinically. Breast mammography mandates reporting of breast density (BD), which is also a marker of breast adipose tissue quantity with less dense breasts indicating greater adipose tissue volume. Given the widespread use of screening mammography, this presents an opportunity to employ BD as a possible surrogate for CVD risk. Purpose To evaluate the correlation between BD, EAT and coronary artery disease (CAD). Methods Single-centre, retrospective, cross-sectional study, including women who had both clinically indicated coronary computed tomography angiogram (CCTA) and mammography. Epicardial adipose tissue volume (EATv) was quantified using semi-automated software (QFAT 2.0). BD was visually assessed by standard 4-level Breast Imaging-Reporting and Data System (BI-RADS) grade with grade A-B representing low density, and C-D representing high density. CAD was categorised as presence/absence of any coronary artery plaque, and CAD severity was quantified using the Coronary Artery Disease Reporting and Data Systems (CAD-RADS) score, with CAD-RADS 1-2 representing mild disease, CAD-RADS 3 moderate disease and CAD-RADS 4 severe disease. CAD analyses were adjusted for modifiable (hypertension, dyslipidaemia, diabetes, body mass index) and non-modifiable (age, past smoking, family history, breast cancer) risk factors. Logistic regression was performed with results presented as Odds Ratio (OR) and [95% Confidence Intervals]. Results Among 153 patients (mean age 62±10), 103 (67.3%) had low BD (high breast adiposity). Compared with high BD, low BD patients were older, had greater rates of hypertension, had significantly higher mean EAT (106.6 ± 43.0 vs 81.0 ± 31.6ml, p&amp;lt;0.001) (Figure 1), and body mass index (30.5 ± 6.3 vs 26.4 ± 5.4kg/m², p&amp;lt;0.001). Adjusted for age and hypertension, EATv remained independently predictive of low BD (OR:1.02 [1.01-1.03], p=0.006). Low BD made up a higher proportion of mild (76.5%), moderate (73.9%) and severe (80.0%) disease. Low BD was strongly associated with presence of CAD (prevalence 75% vs 48%, OR 3.21 [1.58-6.53], p=0.001) independent of EATv (p=0.25), and independent of modifiable (OR: 2.69 [1.24-5.92], p=0.012) and non-modifiable (OR: 2.42 [1.04-5.85], p=0.047) risk factors (Figure 2). Conclusions Low breast density is associated with higher EATv and independently associated with CAD presence beyond EATv and other risk factors. Consequently, mammographic breast density may act as an early risk identification tool for CAD in women.

Piperine: an emerging biofactor with anticancer efficacy and therapeutic potential.

Anticancer drug discovery needs serious attention to overcome the high mortality rate caused by cancer. There are still many obstacles to treating this disease, such as the high cost of chemotherapeutic drugs, the resulting side effects from the drug, and the occurrence of multidrug resistance. Herbaceous plants are a reservoir of natural compounds that can be anticancer drugs with novel mechanisms of action. Piperine, a bioactive compound derived from Piper species, is gaining attention due to its unique dual role in directly inhibiting tumor growth and enhancing the bioavailability of chemotherapeutic drugs. Unlike conventional treatments, Piperine exhibits a novel mechanism of action by modulating multiple signaling pathways, including apoptosis and autophagy, with low toxicity. Additionally, Piperine acts as a bioenhancer by improving the absorption and effectiveness of other anticancer agents, reducing the required dosage, and minimizing side effects. Therefore, this review aims to visualize a summary of Piperine sources, phytochemistry, chemical structure-anticancer activity relationship, anticancer activities of semi-synthetic derivatives, pharmacokinetic and bioavailability, in vitro and in vivo preclinical studies, mechanism of antitumor action, human clinical trials, toxicity, side effects, and safety of Piperine. References were collected from the Pubmed/MedLine database (https://pubmed.ncbi.nlm.nih.gov/) with the following keywords: "Piperine anticancer," "Piperine derivatives," "Piperine antitumor mechanism" and "Piperine pharmacokinetic and bioavailability," after filter process by inclusion and exclusion criteria, 101 were selected from 444 articles. From 2013 to 2023, there were numerous studies regarding preclinical studies of Piperine of various cell lines, including breast cancer, prostate cancer, lung cancer, melanoma, cervical cancer, gastric cancer, osteosarcoma, colon cancer, hepatocellular carcinoma, ovarian cancer, leukemia, colorectal cancer, and hypopharyngeal carcinoma. In vivo, the anticancer study has also been conducted on some animal models, such as Ehrlich carcinoma-bearing mice, Ehrlich ascites carcinoma cells-bearing Balbc mice, hepatocellular carcinoma-bearing Wistar rat, A375SM cells-bearing mice, A375P cells-bearing mice, SNU-16 cells-bearing BalbC mice, and HGC-27-bearing baby mice. Treatment with this compound leads to cell proliferation inhibition and induction of apoptosis. Piperine has been used for clinical trials of diseases, but no cancer patient report exists. Various semi-synthetic derivatives of Piperine show efficacy as an anticancer drug across multiple cell lines. Piperine shows promise for use in cancer clinical trials, either as a standalone treatment or as a bioenhancer. Its bioenhancer properties may enhance the efficacy of existing chemotherapeutic agents, providing a valuable foundation for developing new anticancer therapies.

Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice

Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.

Automated breast density assessment for full-field digital mammography and digital breast tomosynthesis.

Mammographic density is a strong risk factor for breast cancer (BC) and is reported clinically as part of Breast Imaging Reporting and Data System (BI-RADS) results issued by radiologists. Automated assessment of density is needed that can be used for both full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) as both types of exams are acquired in standard clinical practice. We trained a deep learning model to automate the estimation of BI-RADS density from a prospective Washington University (WashU) clinic-based cohort of 9,714 women, entering into the cohort in 2013 with follow-up through, October 31, 2020. The cohort included 27% non-Hispanic Black women. The trained algorithm was assessed in an external validation cohort that included 18,360 women screened at Emory from January 1, 2013 and followed through December 31, 2020 that included 42% non-Hispanic Black women. Our model-estimated BI-RADS density demonstrated substantial agreement with the density as assessed by radiologist. In the external validation, the agreement with radiologists for category B 81% and C 77% for FFDM and B 83% and C 74% for DBT show important distinction for separation of women with dense breast. We obtained a Cohen's κ of 0.72 (95% CI, 0.71, 0.73) in FFDM and 0.71 (95% CI 0.69, 0.73) in DBT. We provided a consistent and fully automated BI-RADS estimation for both FFDM and DBT using a deep learning model. The software can be easily implemented anywhere for clinical use and risk prediction.

Knowledge and Misinformation About Breast Cancer Risk Factors, Symptoms, and Prevention Among Healthy and Affected Women: A Study on 2375 Italian Participants

Background: Breast cancer is the most common cancer among women worldwide and remains the leading cause of death among Italian women. Despite increased breast cancer awareness and improved diagnostic techniques, mortality rates remain high globally. In Italy, despite the availability of screening programs by the National Health System (NHS) for all Italian women aged 50–69 every two years, the participation rate remains relatively low. The low uptake of screening may be attributed to a lack of general cancer knowledge among women, including awareness of risk factors, symptoms, and prevention measures. This study investigates the knowledge and misinformation in a population of Italian women regarding breast cancer risk factors, symptoms, and prevention. Methods: From March 2021 to January 2022, we conducted a survey targeting the female population in Italy, with a total of 2375 participants willingly participating in the study. To investigate factors linked to variations in attitudes toward breast cancer, the participants were categorized into two groups: the general population (Group A, n = 2235) and women who have had or currently have breast cancer (Group B, n = 140). Statistically significant differences were identified between these two groups. Results: The findings revealed considerable confusion regarding both the symptoms and causes associated with cancer, as well as prevention measures. This confusion was particularly prominent among women in the general population and those with lower levels of education. Conclusions: Given these insights, it remains crucial to promote accurate health information concerning risk factors, symptoms, and prevention strategies related to this devastating disease, emphasizing the ongoing importance of disseminating correct health information.

PALB2 analysis in the diagnostic process of breast cancer: An Italian monocentric experience.

The clinical utility of germline BRCA1 and BRCA2 testing is well established in patients with family history suggestive for hereditary breast and ovarian cancer syndrome. Recently, germline PALB2 pathogenic variants were also associated with an increased risk of breast and other cancers and, in the Italian population, it has been described in few studies without a systematic germline analysis of BRCA1, BRCA2 and PALB2. In this study, we described ASST Sette Laghi cancer genetic counselling services' experience in the analysis of 402 patients with suspected breast and ovarian cancer syndrome, by using BRCA1, BRCA2 and PALB2 germline genetic test. The frequency of PALB2 pathogenic variants was 1.2% compared to 3.5% and 3.2% for BRCA1 and BRCA2, respectively, whereas class 3 variants were detected in 0.3% and 0.5% of the BRCA1 and BRCA2 investigated patients, respectively. PALB2 pathogenic variants were identified in patients with a strong family history for breast cancer. Moreover, PALB2 variants were significantly associated with a younger age of breast cancer onset (mean age, 40.25 years) compared to wild-type patients (mean age 51.2 years, p-value = 0.0331). Similar to BRCA-associated breast cancer, the majority of PALB2 breast cancers were identified at an advanced clinical stage. Pedigree analysis revealed a family history of breast and ovarian cancer syndrome in all PALB2 pathogenic variants carriers (early breast cancer onset, bilateral breast cancer and ovarian cancer). In conclusion, the germline analysis of BRCA1, BRCA2 and PALB2 should be included in breast cancer clinical practice as a not negligible number of PALB2 carriers could be identified and referred to specific surveillance protocols.

Roles of miR-20a-5p in breast cancer based on the clinical and multi-omic (CAMO) cohort and in vitro studies

MicroRNAs are involved in breast cancer development and progression, holding potential as biomarkers and therapeutic targets or tools. The roles of miR-20a-5p, a member of the oncogenic miR-17-92 cluster, remain poorly understood in the context of breast cancer. In this study, we elucidate the role of miR-20a-5p in breast cancer by examining its associations with breast cancer risk factors and clinicopathological features, and its functional roles in vitro. Tissue microarrays from 313 CAMO cohort breast cancer surgical specimens were constructed, in situ hybridization was performed and miR-20a-5p expression was semiquantitatively scored in tumor stromal fibroblasts, and in the cytoplasm and nuclei of cancer cells. In vitro analysis of the effect of miR-20a-5p transfection on proliferation, migration and invasion was performed in three breast cancer cell lines. High stromal miR-20a-5p was associated with higher Ki67 expression, and higher odds of relapse, compared to low expression. Compared to postmenopausal women, women who were premenopausal at diagnosis had higher odds of high stromal and cytoplasmic miR-20a-5p expression. Cytoplasmic miR-20a-5p was significantly associated with tumor grade. In tumors with high cytoplasmic miR-20a-5p expression compared to low expression, there was a tendency towards having a basal-like subtype and high Ki67. In contrast, high nuclear miR-20a-5p in cancer cells was associated with smaller tumor size and lower odds of lymph node metastasis, compared to low nuclear expression. Transfection with miR-20a-5p in breast cancer cell lines led to increased migration and invasion in vitro. While the majority of our results point towards an oncogenic role, some of our findings indicate that the associations of miR-20a-5p with breast cancer related risk factors and outcomes may vary based on tissue- and subcellular location. Larger studies are needed to validate our findings and further investigate the clinical utility of miR-20a-5p.

Young Black Women's Breast Cancer Knowledge and Beliefs: A Sequential Explanatory Mixed MethodsStudy.

Black women under the age of 50 have a 111% higher breast cancer mortality rate than their White counterparts. The breast cancer mortality disparities among young Black women may be due in part to the fact that they are more likely to be diagnosed with late-stage, invasive breast cancer tumors. Psychosocial factors, such as lack of perceived risk for breast cancer, lack of awareness of breast cancer risk factors, and ambiguity about breast cancer screening guidelines are areas that are under investigated among young Black women. The purpose of this study was to identify young Black women's cancer beliefs and level of breast cancer risk knowledge. A sequential explanatory mixed methods study was conducted using quantitative data from the Health Information Trends Survey 6 (HINTS 6) (n = 25) and qualitative data from interviews with young Black female college students (n = 13). The results of the quantitative data analysis were used to guide the development of the qualitative interview guide. Data regarding participants' cancer beliefs, cancer risk factor knowledge, perceived cancer risk, and ambiguity about cancer screening behaviors were analyzed. The findings indicated young Black women have low perceived risk of developing cancer. Most participants were not aware of cancer recommendations that were targeted towards women under the age of 40. In addition, knowledge about lifestyle behavior risk factors for breast cancer was relatively low. Our findings underscore the importance of developing, disseminating, and implementing breast cancer education interventions that are targeted towards young Black women.

Two founder variants account for over 90% of pathogenic BRCA alleles in theOrkney and Shetland Isles in Scotland.

For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK populations. Here, we report a BRCA2 splice acceptor variant, c.517-2A>G, found in breast and ovarian cancer families from Shetland. We investigated the frequency and origin of this variant in a population-based research cohort of people of Shetland ancestry, VIKING I. The variant segregates with female breast and ovarian cancer in diagnosed cases and is classified as pathogenic. Exome sequence data from 2108 VIKING I participants with three or more Shetlandic grandparents was used to estimate the population prevalence of c.517-2A>G in Shetlanders. Nine VIKING I research volunteers carry this variant, on a shared haplotype (carrier frequency 0.4%). This frequency is ~130-fold higher than in UK Biobank, where the small group of carriers has a different haplotype. Records of birth, marriage and death indicate genealogical linkage of VIKING I carriers to a founder from the Isle of Whalsay, Shetland, similar to our observations for the BRCA1 founder variant c.5207T>C from Westray, Orkney. In total, 93.5% of pathogenic BRCA variant carriers in Northern Isles exomes are accounted for by these two drifted variants. We thus provide the scientific evidence of an opportunity for screening people of Orcadian and Shetlandic origins for each drifted pathogenic variant, particularly women with Westray or Whalsay ancestry.

Mammographic density and breast cancer risk among Black American women.

High mammographic density is a well-established risk factor for breast cancer; however, data from Black women are limited. It is largely unknown how mammographic density is associated with breast cancer subtypes among Black women. We examined the association between percent mammographic density (PMD) and breast cancer risk among participants in the Black Women's Health Study. Digital screening mammograms were available for 363 cases and 5541 non-cases. Cumulus software was used to assess PMD. We used inverse probability of sampling weights and Cox proportional hazards models, adjusted for age and body mass index, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and by age at mammography and estrogen receptor (ER) status of the breast tumors. Multivariable models included additional breast cancer risk factors. Tests of statistical significance were 2-sided. In simple models, women in the highest quartile of PMD had 53% increased odds of breast cancer compared to those in the lowest quartile (HR 1.53; 95% CI: 1.11, 2.11). HRs were 1.37 (95% CI: 0.83, 2.24) among women <55 years of age and 1.68 (95% CI: 1.10, 2.56) among women aged ≥55 years. HRs were 1.49 (95% CI: 1.02, 2.16) for ER+ cancer and 1.45 (95% CI: 0.73, 2.87) for ER- cancer. Associations were largely unchanged in multivariable models. In this study of U.S. Black women, higher PMD was associated with ER+ and ER- breast cancer risk. Findings from this study reinforce the importance of breast density as a risk factor for breast cancer in Black women.