Breast Cancer Mortality Research Articles

Trends in breast cancer mortality attributable to metabolic risks in Chinese women from 1990 to 2019: an age-period-cohort analysis.

Metabolic risks (MRs) are the primary determinants of breast cancer (BC) mortality among women. This study aimed to examine the changing trends in BC mortality associated with MRs and explore how they related to age, time period, and birth cohorts in Chinese women aged 25 and above. Data were sourced from the Global Burden of Disease Study 2019 (GBD2019). The BC mortality trajectories and patterns attributable to MRs were assessed using Joinpoint regression. The age-period-cohort (APC) model was employed to evaluate cohort and time period effects. The age-standardized mortality rate (ASMR) of BC mortality linked to MRs displayed an escalating trend from 1990 to 2019, demonstrating an average annual percentage change (AAPC) of 1.79% (95% CI: 1.69~1.87). AAPCs attributable to high fasting plasma glucose (HFPG) and high body mass index (HBMI) were 0.41% (95% CI: 0.32~0.53) and 2.75% (95% CI: 2.68~2.82), respectively. APC analysis revealed that BC mortality due to HBMI in women aged 50 and above showed a rise with age and mortality associated with HFPG consistently demonstrated a positive correlation with age. The impact of HBMI on BC mortality significantly outweighed that of HFPG. The risk of BC mortality linked to HBMI has steadily increased since 2005, while HFPG demonstrated a trend of initial increase followed by a decrease in the period effect. Regarding the cohort effect, the relative risk of mortality was greater in the birth cohort of women after the 1960s of MRs on BC mortality, whereas those born after 1980 displayed a slight decline in the relative risk (RR) associated with BC mortality due to HBMI. This study suggests that middle-aged and elderly women should be considered as a priority population, and control of HBMI and HFPG should be used as a primary tool to control metabolic risk factors and effectively reduce BC mortality.

Exploring research progress in studying serum exosomal miRNA-21 as a molecular diagnostic marker for breast cancer.

Breast cancer is one of the most prevalent malignancies affecting women globally and poses a significant public health challenge. Early clinical detection plays a pivotal role in providing optimal treatment opportunities and favorable prognoses, crucial for reducing breast cancer mortality and enhancing patients' quality of life. Therefore, the timely identification and diagnosis of breast cancer are imperative. Conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3), serve as reliable methods for actively monitoring disease progression and have become a routine auxiliary diagnostic approach in clinical settings. However, these biomarkers exhibit limitations in sensitivity and specificity, particularly in the early screening and diagnosis of tumors, often yielding results inconsistent with clinical manifestations. In recent years, research has increasingly focused on exosomes released by tumor cells as potential new biomarkers for early stage breast cancer screening. Exosomes carry various components, including tumor-derived proteins, nucleic acids, and lipids. This paper delves into the specific utilization of serum exosomal microRNA-21 (miR-21) as a biomarker for early detection and diagnosis of breast cancer, evaluating its efficacy within this framework.

Breast Cancer classification via Deep Learning approaches

Breast cancer is the most common type of cancer in women worldwide. In 2023, there were 2.296.840 (23,8% of all women with cancer) new diagnoses. Early diagnosis is a key factor in reducing the mortality rate of breast cancer. One of the screening methods used to prevent breast cancer is breast ultrasound. In this paper, a new model is proposed that starts from a resnet101 and increases the classification capacity of a normal resnet101. Experimental studies show how deep learning models can successfully classify breast ultrasound images. The proposed model achieves 91% accuracy with convergence in less than 30 epochs. This study shows that deep learning models are effective in classifying ultrasound images and could be used by a radiologist to increase the accuracy of diagnoses.

Feature Selection using Extra Trees for Breast Cancer Prediction

Breast cancer is a disease that seriously threatens women's health. It is considering a common death cause in women. Machine learning has made significant progress in recent years to improve the effectiveness of early diagnosis of various diseases. Accurate predication and detection help decrease the death rate of breast cancer. This paper aims to predict breast cancer using several machine-learning techniques. The idea is to lower the number of features in the Wisconsin Breast Cancer Dataset (WCDB) and use it for prediction. The study used the extra trees method for feature selection and Random forest, Logistic regression, and Support Vector Machine (SVM) for testing the dataset. According to the results, SVM achieved the best performance among the other models with 98% accuracy. The proposed method in this study proved its effectiveness in breast cancer prediction.

Abstract LB312: Subtype- and race-specific differences in immune landscape of breast cancer

Abstract Tumor mass comprises of not just the tumor cells but a variety of stromal cells. Immune cells residing within the tumor microenvironment modulate the growth and behavior of the tumor cells through a bi-directional crosstalk and affect the outcomes of cancer therapies. Breast cancer (BC) is a highly heterogeneous disease having four major molecular subtypes. Triple-negative breast cancer (TNBC) is the most aggressive subtype and has limited available therapeutic options. Further, it disproportionately affects African American (AA) women, with nearly two times higher incidence as compared to Caucasian American (CA) women. It is associated with an earlier onset and overall higher mortality of BC. Here, we investigated the differences in the immune landscape between TNBC and non-TNBC subtypes and examined if there existed any race-specific patterns. A total of 81 breast cancer samples with a distribution of 55 non-TNBC (28 CA and 27 AA) and 26 TNBC (12 CA and 14 AA) were selected after histopathologic analysis. Tissues were analysis using the NanoString nCounter® pancancer immune panel to determine tissue-specific immune cell populations. We observed a significantly higher presence of tumor-infiltrating lymphocytes in TNBC compared to non-TNBC, with a higher immune score for CD45+ (total lymphocytes), T-cells, B-cells and tumor-associated macrophages. Specifically, among the T-cell population, Treg cells, Th1 cells, and CD8+ cells were higher in TNBC samples. The pathway prediction indicated 'primary immunodeficiency' and 'cancer immunotherapy by PD-1 blockade' pathways being significantly up-regulated in TNBC samples. Overexpression of CTLA4, IDO1, PDL1 and PDL2 as well as Treg marker genes, such as FOXP3 and LAG3, which are involved in immunosuppressive pathways, was observed in TNBC. In race-wise comparisons of non-TNBC and TNBC sample between CA and AA patients, we found that AA non-TNBC tumors had higher Treg cell scores. On the other hand, CA TNBC samples had higher Th1 and CD8+ T-cell scores compared to AA TNBC. The pathway prediction from differentially expressed genes between CA and AA non-TNBC samples showed complement activation pathway to be down-regulated in AA patients, which could be associated with an increased presence of Treg cells. Further, when comparing CA vs AA TNBC samples, we found significant up-regulation of oncogene BMI1 and down-regulation of genes involved in T-cell activation such as CD47, CD44, FOS, and S100A8 in AA TNBC, supporting their more aggressive nature. In conclusion, our data show that TNBC patients have a higher infiltration of immune cells, which remain suppressed due to the presence of Treg cells and PD1 signaling pathway. The presence of higher Treg cells in AA non-TNBC and lower Th1 and CD8+ T-cells in AA TNBC samples suggests an overall immune suppressed microenvironment in AA patients compared to CA patients. Overall, our data suggest that TNBC could be good candidate for immune therapy. Citation Format: Amod Sharma, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Mohammad Aslam Khan, Mohammad Tahir, James Elliot Carter, Cindy Nelson, Ajay P Singh, Seema Singh. Subtype- and race-specific differences in immune landscape of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB312.

Endocrine Resistance in Breast Cancer: The Role of mTOR Signaling in Mediating Resistance to Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) have been widely prescribed and effective as a first-line endocrine therapy to treat ER+ breast cancer. Tamoxifen, the most used SERM in the treatment of breast cancer, has been shown to be effectively anti-proliferative in breast tissue and has made a tremendous contribution to reducing breast cancer mortality. Vast experimental evidence from seven sources supports tamoxifen’s ability in repressing the expression of estrogen-responsive genes involved in cancer growth. The binding of tamoxifen to the estrogen receptor prevents the recruitment of coactivators to the complex and instead promotes the recruitment of corepressors and histone deacetylases, thus inhibiting transcriptional activation of target genes. However, the issue of endocrine resistance remains a predominant problem with this therapy. Sources have found that endocrine resistance can arise due to dysregulations in the mTOR signaling pathway. Experiments have revealed some hope regarding a mechanism by which we can re-sensitize the breast cancer cells to the therapy, notably by knocking down YAP/TAZ or PSAT1 in the mTOR pathway. Despite this discovery, endocrine resistance prevails due to irregularities in additional pathways. Therefore, subsequent research is crucial to identify more targets that, when knocked down, enable re-sensitization of resistant cells, restoring full therapeutic ability of SERMs in afflicted women.

Abstract LB418: Time to adjuvant chemotherapy and its predictors among postoperative breast cancer patients at Cancer Treatment Center of Hawassa University Comprehensive Specialized Hospital in Hawassa, Ethiopia in 2022: A retrospective follow-up study

Abstract Background The incidence of breast cancer is rising and is becoming a major public health problem in Ethiopia, posing a substantial threat to countries with limited oncology centers. Adjuvant chemotherapy is the most important treatment option for breast cancer initiated after definitive surgical management. Adjuvant chemotherapy decreases the risk of breast cancer mortality, reduces the recurrence rate, and improves the long-term overall survival. The time between surgery and the first adjuvant chemotherapy appears to have an impact on the overall survival (OS) and disease-free survival (DFS) in patients with breast cancer. Objective This study aimed to determine the time to start adjuvant chemotherapy and its predictors in post-operative breast cancer patients at oncology center of Hawassa University Comprehensive Specialized Hospital between September 2020 and March 2022. Method This institution based retrospective follow-up study was conducted at the Hawassa University Comprehensive Hospital Cancer Treatment Center between September 2020 and March 2022, among all women with breast cancer. All eligible patients whose medical records were available and accessed in the hospital during the study period were enrolled. The checklists were prepared using Google Forms. The data were then exported to Excel and sent to SPSS software version 26 for data analysis. A stratified Cox regression model was used to identify potential predictors. The adjusted hazard ratio (AHR) with 95% confidence interval (CI) was reported to indicate the strength of the association. This study was conducted between February 22 and April 8, 2022. Result In this study, the median time to adjuvant chemotherapy was 69 days Interquantile range (IQR)=26) with a range of 28-157 days. Twenty (12.9%) patients started chemotherapy in less than 30 days, 36 (23.2%) patients waited for 31-60 days, 68 (43.9%) patients initiated chemotherapy within 61-90 days while 31 (20%) patients took more than 90 days to start their adjuvant chemotherapy. Patients who experienced surgical complications were 1.5 times more likely to initiate adjuvant chemotherapy earlier than those without such complications, with an adjusted hazard ratio (AHR) of 1.512 (95% CI: 1.287-3.140). Patients with a BMI classified as underweight were1.5 times high likely to receive adjuvant chemotherapy earlier (AHR 1.569, 95% CI: (1.336-3.887)). Post-operative breast cancer patients with co-morbidity had a 25% lower likelihood of receiving adjuvant chemotherapy earlier than those without comorbidity (AHR=0.751,95%CI: 0.474-0.817), and illiteracy (AHR=0.829, 95% CI: (0.458-0.950)) was also a significant predictor of time to adjuvant chemotherapy. Conclusion The duration of initiation of the adjuvant chemotherapy was longer than the recommended initiation time. Body Mass Index, presence of surgical complications, presence of comorbidity, and educational status were predictors of delayed time to adjuvant chemotherapy Citation Format: Adugna Getahun Deboch. Time to adjuvant chemotherapy and its predictors among postoperative breast cancer patients at Cancer Treatment Center of Hawassa University Comprehensive Specialized Hospital in Hawassa, Ethiopia in 2022: A retrospective follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB418.

Socioecologic Factors and Racial Differences in Breast Cancer Multigene Prognostic Scores in US Women

Disproportionately aggressive tumor biology among non-Hispanic Black women with early-stage, estrogen receptor (ER)-positive breast cancer contributes to racial disparities in breast cancer mortality. It is unclear whether socioecologic factors underlie racial differences in breast tumor biology. To examine individual-level (insurance status) and contextual (area-level socioeconomic position and rural or urban residence) factors as possible mediators of racial and ethnic differences in the prevalence of ER-positive breast tumors with aggressive biology, as indicated by a high-risk gene expression profile. This retrospective cohort study included women 18 years or older diagnosed with stage I to II, ER-positive breast cancer between January 1, 2007, and December 31, 2015. All data analyses were conducted between December 2022 and April 2023. The primary outcome was the likelihood of a high-risk recurrence score (RS) (≥26) on the Oncotype DX 21-gene breast tumor prognostic genomic biomarker. Among 69 139 women (mean [SD] age, 57.7 [10.5] years; 6310 Hispanic [9.1%], 274 non-Hispanic American Indian and Alaskan Native [0.4%], 6017 non-Hispanic Asian and Pacific Islander [8.7%], 5380 non-Hispanic Black [7.8%], and 51 158 non-Hispanic White [74.0%]) included in our analysis, non-Hispanic Black (odds ratio [OR], 1.33; 95% CI, 1.23-1.43) and non-Hispanic American Indian and Alaska Native women (OR, 1.38; 95% CI, 1.01-1.86) had greater likelihood of a high-risk RS compared with non-Hispanic White women. There were no significant differences among other racial and ethnic groups. Compared with non-Hispanic White patients, there were greater odds of a high-risk RS for non-Hispanic Black women residing in urban areas (OR, 1.35; 95% CI, 1.24-1.46), but not among rural residents (OR, 1.05; 95% CI, 0.77-1.41). Mediation analysis demonstrated that lack of insurance, county-level disadvantage, and urban vs rural residence partially explained the greater odds of a high-risk RS among non-Hispanic Black women (proportion mediated, 17%; P < .001). The findings of this cohort study suggest that the consequences of structural racism extend beyond inequities in health care to drive disparities in breast cancer outcome. Additional research is needed with more comprehensive social and environmental measures to better understand the influence of social determinants on aggressive ER-positive tumor biology among racial and ethnic minoritized women from disadvantaged and historically marginalized communities.

Associations of pre-diagnosis physical activity with treatment tolerance and treatment efficacy in breast cancer patients with neoadjuvant chemotherapy.

Higher pre-diagnosis physical activity (PA) is associated with lower all-cause mortality in breast cancer (BCa) patients. However, the association with pathological complete response (pCR) is unclear. We investigated the association between pre-diagnosis PA level and chemotherapy completion, dose delay, and pCR in BCa patients receiving neoadjuvant chemotherapy (NACT). 180 stage I-III BCa patients receiving NACT (mean [SD] age of diagnosis: 60.8 [8.8]years) in the Sister Study were included. Self-reported recreational and total PA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). The pCR was defined as no invasive or in situ residual in breast or lymph node (ypT0 ypN0). Multivariable logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs) for treatment outcomes. In this sample, 45 (25.0%) BCa patients achieved pCR. Higher pre-diagnosis recreational PA was not associated with lower likelihood of chemotherapy completion (highest vs. lowest tertile: OR = 0.87, 95% CI = 0.30-2.56; Ptrend = 0.84), greater dose delay (OR = 1.45, 95% CI = 0.54-3.92; Ptrend = 0.46), or greater odds of pCR (OR = 1.28, 95% CI = 0.49-3.34; Ptrend = 0.44). Associations were similar for pre-diagnosis total PA. Meeting the recommended level of recreational PA was not associated with pCR overall (≥ 7.5 vs. < 7.5 MET-hrs/wk: OR = 1.33, 95% CI = 0.59-3.01). Although small sample size and limited information on exercise closer to time of diagnosis limit interpretation, pre-diagnosis PA was not convincingly associated with treatment tolerance or treatment efficacy in BCa patients receiving NACT. Future investigations are needed to better understand the impact of pre-diagnosis PA on BCa treatment.

The VEGF-Hypoxia Signature Is Upregulated in Basal-like Breast Tumors from Women of African Ancestry and Associated with Poor Outcomes in Breast Cancer.

Black women experience the highest breast cancer mortality rate compared with women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry. We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n = 182) and the University of Chicago (Chicago, IL; n = 161). We also analyzed RNA sequencing data from Nigeria (n = 84) and The Cancer Genome Atlas (TCGA) datasets (n = 863). Patient prognosis was analyzed using multiple datasets. The VEGF-hypoxia signature was highest in the basal-like subtype compared with other subtypes, with greater expression in Black women compared with White women. In TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared with non-necrosis tumors (P < 0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation, and necrosis. T-cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in TCGA dataset. Finally, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (P < 0.0001) and SCAN-B datasets (P = 0.002). These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.

IJCM_156A: A Cross-sectional study on the Prevalence of Risk Factors of Breast Cancer and Awareness of Breast Cancer Screening in Women of age group 30 to 70 years in Karamadai Block of Coimbatore Health Unit District

Background: Breast cancer, the most common malignancy among women globally, recorded over 2.26 million new cases and almost 685,000 deaths in the same year. Evidence indicates breast cancer risk links to both modifiable and non-modifiable lifestyle factors. Promoting education and access to screening programs is crucial for early detection and intervention in breast cancer. This approach ultimately enhances the effectiveness of prevention efforts and reduces complications and mortality of breast cancer. Objective: To estimate the prevalence of risk factors of breast cancer and to assess the awareness of breast cancer screening in women of age group 30-70 years in Karamadai Block of Coimbatore Health Unit District. Methodology: A cross sectional study was conducted among 150 women in Coimbatore using a semi-structured questionnaire and statistical analysis was done using SPSS 21 version. Results: Out of 150 participants, the mean age of subjects was 50 ± 11 years, with 98% being married women. The prevalence of modifiable and non- modifiable risk factors of breast cancer were found to be 61% and 9% respectively. 54% were aware of government facility-based breast cancer screening. But only 25% had undergone screening for breast cancer. Individuals who underwent breast cancer screening in the last one year found to be aware of breast cancer screening compared to those who did not. (OR 2.5, 95% CI 2.02-3.18). Conclusion: Awareness and screening for breast cancer are low among the study participants. Women =30 years of age attending all outpatient departments in any health facility should be educated regarding the importance of screening of breast cancer.

396 Unraveling the Immunological Basis of Lobular Involution in Breast Cancer Development

OBJECTIVES/GOALS: Reveal common immune mechanisms in dysregulated age-related lobular involution (ARLI) and post-partum lobular involution (PPLI) to understand their link to increased breast cancer risk, challenging the traditional view of their distinctiveness. Ultimately, to improve breast cancer risk assessment and personalized prevention METHODS/STUDY POPULATION: The Mayo Clinic Benign Breast Disease (BBD) cohort comprises of ~20,000 women with benign biopsies, including ~1000 women with sequential benign biopsies. Lobular involution (LI) status was assessed by selecting perimenopausal women, ages 45-55, with sequential biopsies, comparing acini number and lobule size between initial and subsequent biopsies. NanoString IO360/ BC360 RNA profiling identified differentially expressed genes associated with dysregulated LI. Using multiplex immunofluorescence (mIF), I'll analyze and spatially map immune biomarkers related to dysregulated ARLI and PPLI in BBD tissue from perimenopausal women who did or did not go on to develop breast cancer, assessing the commonality of ARLI and PPLI markers and exploring their potential as risk biomarkers for breast cancer. RESULTS/ANTICIPATED RESULTS: Preliminary findings link patients who display dysregulated ARLI with an increased breast cancer risk and identify vital PPLI biomarkers in perimenopausal women. I expect the biopsies of women who developed post-menopausal breast cancer (PMBC) and post-partum breast cancer (PPBC) to exhibit elevated levels of dysregulated ARLI immune biomarkers and PPLI biomarkers. Spatially mapping these markers promises to provide a more comprehensive understanding of their interactions, potentially revealing common immunological pathways. These findings could transform our current paradigm of ARLI and PPLI as distinct processes and demonstrate their interconnection in shaping breast cancer risk. DISCUSSION/SIGNIFICANCE: PMBC and PPBC dominate majority of breast cancer cases. Both involve activation of the understudied process of lobular involution, which has been shown to have pro-tumorigenic traits. Elucidating these mechanisms will aid more efficient risk stratification and personalized prevention to reduce incidence and mortality of breast cancer.

Breast cancer mortality in Chinese women and men from 1990 to 2019: Analysis of trends in risk factors.

This study aimed to examine the relative risk of risk factor in male and female breast cancer (BC) deaths in China and analyzed the changing trends in BC mortality rates from 1990 to 2019. Open data from the Global Burden of Disease database from 1990 to 2019 were analyzed to assess the number of BC deaths and age-standardized mortality rates (ASMR) in China. The age-period-cohort model was employed to study age effects, period effects, cohort effects, as well as local drift and net drift of the data, determining the impact of changing risk factors on crude mortality rates and ASMR of BC. In 2019, the number of BC deaths across all age groups in China increased by 130.38% compared to 1990, with an increase of 125.68% in females and 648.80% in males. The ASMR for BC and male BC increased in 2019, while female BC ASMR declined. Overall, alcohol consumption and smoking as risk factors contributed to increased mortality rates of BC with advancing age. Over the entire study period, the net drift of alcohol consumption in females for BC was 0.06% (95% confidence interval [CI]: -0.24% to 0.36%), while for smoking it was -0.64% (95% CI: -0.83% to -0.45%). For males, the net drift of alcohol consumption for BC was 6.75% (95% CI: 5.55% to 7.96%), and for smoking, it was 6.09% (95% CI: 2.66% to 9.64%). Hence, improving awareness of BC-related risk factors and implementing prevention strategies are necessary to alleviate future BC burdens.

Uncovering the relationship between YAP/ WWTR1 (TAZ) genes expression and LncRNAs of SNHG15, HCP5 and LINC01433 in breast cancer tissues

In spite of the decrease in breast cancer (BC) death rates, it has remained a significant public health concern. Dysregulation of the Hippo pathway contributes to breast cancer development and progression by enhancing cancerous cell proliferation, survival, invasion, and migration. Investigating the connection between specific lncRNAs (SNHG15, HCP5, and LINC01433) and YAP and WWTR1, and the impact of these lncRNAs on the expression of YAP and WWTR1 proteins in the Hippo pathway, may offer valuable understanding for BC diagnosis and treatment. Forty BC tissue samples were acquired from the Tumor Bank and utilized for RNA and protein extraction. Real-time PCR and western blotting techniques were performed to assess the gene and protein expressions, respectively. Correlations between variables and their associations with clinicopathological features in BC were evaluated using Mann-Whitney U or Student's t-test. Additionally, the analysis of the GEO database was utilized to validate the findings. In cancerous tissue, the up-regulation of YAP, WWTR1, HCP5, SNHG15, and Linc01433 at both the mRNA and protein levels corresponds to the findings in GEO datasets. A significant association was found between YAP and histological grade, while WWTR1 showed a correlation with family history and HER-2. The distinct and notable expression of YAP, WWTR1, SNHG15, HCP5, and Linc01433 in BC tissues, together with the results of combined ROC curve analysis derived from our finding and GEO database suggest that a combined panel of these 5 RNAs may have great potential in predicting of BC and its management.

Prospects for liquid biopsy using microRNA and extracellular vesicles in breast cancer.

Among the analytes circulating in body fluids, microRNAs, a type of non-coding RNA and known to exist 2655 in primates, have attracted attention as a novel biomarker for cancer screening. MicroRNAs are signaling molecules with important gene expression regulatory functions that can simultaneously control many gene functions and multiple different pathways in living organisms. These microRNAs are transported in extracellular vesicles (EVs), which are lipid bilayers with 50-150 nm in diameter, and are used as communication tools between cells. Furthermore, the EVs that carry these microRNAs circulate in the bloodstream and have other important implications for understanding the pathogenesis and diagnosis of breast cancer. The greatest benefit from cancer screening is the reduction in breast cancer mortality rate through early detection. Other benefits include reduced incidence of breast cancer, improved quality of life, prognosis prediction, contribution to personalized medicine, and relative healthcare cost containment. This paper outlines the latest developments in liquid biopsy for breast cancer, especially focusing on microRNA and EV diagnostics.

Tumor-infiltrating lymphocytes and breast cancer mortality in racially and ethnically diverse participants of the Northern California Breast Cancer Family Registry.

Stromal tumor-infiltrating lymphocyte (sTIL) enrichment in pretreatment breast tumors has been associated with superior response to neoadjuvant treatment and survival. In a population-based cohort, we studied sTIL-survival associations by race and ethnicity. We assessed associations of continuous sTIL scores and sTIL-enriched breast cancers (defined as percent lymphocytic infiltration of tumor stroma or cell nests at cutoffs of 30%, 50%, and 70%) with clinical and epidemiologic characteristics and conducted multivariable survival analyses. Although we identified no difference in sTIL score by race and ethnicity, higher continuous sTIL score was associated with lower breast cancer-specific mortality only among non-Hispanic White and Asian American but not African American and Hispanic women. This finding suggests that complex factors influence treatment response and survival, given that sTIL enrichment was not associated with a survival advantage among women from minoritized groups, who more often experience health disparities. Further study of patient selection for sTIL-guided treatment strategies is warranted.

Multi-Pronged Solutions Addressing Barriers to Breast Screening Access in Appalachia

&lt;i&gt;Annual mammography screening is recommended by the US Preventive Services Task Force (USPSTF) and American Cancer Society (ACS) to reduce mortality through early detection of breast cancer. In rural Appalachia, rates of later-stage breast cancer incidence and mortality are higher than national averages. We explored the ways that providers and staff at breast cancer screening facilities employed novel approaches to overcome patient- and facility-level barriers to access to breast cancer screening in the Appalachian region. We conducted 23 semi-structured interviews with 28 clinical providers and staff of breast health facilities in Appalachia. Themes reflect how limiting features of breast screening facilities influenced access to care; the way patient-level barriers presented challenges to access to breast screening; and that external and regulatory forces presented obstacles to access to care. In addition, the unique geographical and geographical attributes of the Appalachian region shaped access and adherence to mammography screening recommendations. Thematic findings highlight that facilities implemented patient-centered strategies to overcome access-related barriers. Results may inform the ways breast cancer screening facilities address suboptimal access to breast health screening. They may also inform future resource allocations to enable facilities to reach breast cancer screening performance goals.&lt;/i&gt;

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies

PurposeRecruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer.MethodsWe used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala.Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala.ResultsWe recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001).ConclusionGuatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Abstract 6121: Racial differences in the intratumoral immune cell infiltrate in luminal breast cancer

Abstract Background: Black women have a higher rate of breast cancer mortality compared with their non-Hispanic White (NHW) counterparts, with an 80% higher likelihood of breast cancer death from axillary node-negative, ER-positive (a.k.a. luminal) tumors (Hoskins et al, JAMA Oncol 2021). Black women are 30% more likely to have ER-positive tumors with a high-risk gene expression profile, indicating a role for tumor biology in this disparity (Hoskins et al, JAMA Oncol 2023). The underlying biological mechanisms responsible are unknown. The aim of this study was to investigate the immune cell infiltrate in ER-positive breast tumors as a potential driver of disproportionately aggressive luminal tumor biology among Black women. Methods: Gene expression data from ER-positive tumors diagnosed in women identified as Black or NHW in The Cancer Genome Atlas (TCGA) were deconvoluted with the CIBERSORT tool to estimate the relative intratumoral proportion of 22 immune cell types within each tumor. Differential analysis of imputed immune cell fractions comparing race was conducted with the Mann-Whitney test. P-values were adjusted for multiple comparisons with the false discovery rate (FDR) method. Linear regression of previously reported ancestry estimates for breast cancer patients in TCGA (Huo, et al, JAMA Oncol 2017) was used to test for association between African ancestry and proportion of regulatory T cells (Tregs) in tumors from Black women. Results: CIBERSORT analysis of tumors found a significantly increased proportion of Tregs in tumors from Black (n=86) than NHW (n=534) patients, with log2 fold-change= 0.74 (FDR-corrected p-value= 0.01). Plasma cells, T follicular helper cells and M0 macrophages were increased in tumors from Black women with uncorrected p-values &amp;lt; 0.05, but racial differences in these cell types were not significant after FDR correction (p &amp;gt;0.1). Ancestry analysis among Black women indicated that African ancestry was not associated with the intratumoral proportion of Tregs (1 SD change in proportion African ancestry was associated with 0.06 standard deviation increase in Tregs, p &amp;gt; 0.3). Confirmation of findings with a racially diverse breast tumor TMA from an independent cohort is ongoing and results will be presented. Conclusions: Increased pro-tumorigenic Treg infiltrate in ER-positive breast tumors from Black women may contribute to a disproportionately aggressive tumor phenotype and racial survival disparity. The findings could have therapeutic implications and suggest that immune checkpoint inhibitors may have increased activity against luminal breast cancer in Black patients. Although this study did not show a statistically significant effect for genetic admixture within African Americans, larger studies are needed to distinguish the contribution of ancestry vs. social context, environmental, and behavioral factors as the driver of this racial difference in tumor biology. Citation Format: Neha Hippalgaonkar, George Chlipala, Dezheng Huo, Garth Rauscher, Naiche Adler, Jan Kitajewski, Kent Hoskins. Racial differences in the intratumoral immune cell infiltrate in luminal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6121.

Abstract 2137: Racial disparities in triple-negative breast cancer (TNBC) mortality rates in Hampton Roads Virginia and the effects of SIAH expression on prognosis

Abstract Background: While high-resolution imaging and advancements in therapies have significantly improved breast cancer survival rates, 43,170 breast cancer patients will die in the United States in 2023 alone. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and disproportionately affects BRCA1 mutation carriers and young black women. Black/African American (AA) patients have the highest mortality and the shortest survival of any racial/ethnic group in the US. Persistent cancer racial disparities remain due to a variety of risk factors. The SEER/CDC data show an 8% lower breast cancer incidence rate and a 41% higher mortality rate in Black/AA patients compared to their white counterparts. Methods: Chart review was conducted using Sentara MD Office/EPIC and VOA iKnowMedicine portals to update tumor relapse, metastasis, and survival in 577 TNBC patients. Supported by strong evidence in developmental, evolutionary, and cancer biology, we hypothesize that persistent EGFR/K-RAS/SIAH pathway activation is a major driving force of TNBC malignancy, racial disparity, early relapse, and high mortality. We propose to integrate SIAH expression to augment the existing clinicopathological parameters to improve patient risk stratification, therapy quantification, and relapse/survival prediction at the 1st-line neoadjuvant settings. Results: We report that cancer disparity and high mortality rates are even more pronounced in our racially-diverse communities in Hampton Roads Virginia. We discovered that SIAH is a tumor-specific, therapy-responsive, and prognostic biomarker in TNBC. High SIAH expression in residual tumors reflects tumor-driving EGFR/K-RAS/SIAH pathway activation (ON) that will predict cancer disparity, treatment resistance, early relapse, and poor survival. Low SIAH expression in residual tumors reflect EGFR/K-RAS/SIAH pathway inactivation (OFF) that will predict tumor remission and prolonged survival. Conclusion: We detect a major racial disparity of TNBC patients at Sentara-EVMS-VOA. Our local Black/AA TNBC patients have a 1.6-fold higher mortality rate than their White counterparts. Encouraged by our preliminary data, we aim to develop a SIAH-centered biomarker panel by measuring the EGFR/K-RAS/SIAH pathway activation (ON)/inactivation (OFF), and use SIAH as a new prognostic biomarker to risk stratify patients, detect cancer racial disparities, forecast tumor relapse, and predict patient survival at 1st-line neoadjuvant settings. By targeting SIAH, individualized treatments can be created to allow for increased survival rates in at risk individuals with more aggressive TNBCs. Citation Format: Claire B. Piatak, Taylor N. Drake, Ashleigh Hannah, Jonathan Baker, Caroline L. Dasom, Emily L. Breeding, Janet S. Winston, Billur Samli, Rick Jansen, Michael Danso, Richard A. Hoefer, Amy H. Tang. Racial disparities in triple-negative breast cancer (TNBC) mortality rates in Hampton Roads Virginia and the effects of SIAH expression on prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2137.