Mortality In Breast Cancer Patients Research Articles

The association of systemic immune-inflammation index with incident breast cancer and all-cause mortality: evidence from a large population-based study

BackgroundChronic low-grade inflammation is recognized as a significant factor in various health outcomes, including the development and progression of breast cancer. The Systemic Immune-Inflammation Index (SII), a novel marker derived from routine blood counts, has been suggested as a predictor of all-cause mortality and cardiovascular mortality. However, its predictive value in a nationwide representative population, particularly for breast cancer incidence and mortality, is not well-established.MethodsThis study aimed to assess the association of SII and the risk of breast cancer incidence and all-cause mortality in breast cancer patients within the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. SII was calculated from complete blood count parameters. We used multifactor regression models to examine the associations between SII and the outcomes of interest.ResultsA total of 21,058 female participants were included in the study, of which 557 (2.7%) were identified as having breast cancer. After adjusting for multiple potential confounders, the relationship between SII and the incidence of breast cancer revealed an inverse L-shaped association. The optimal inflection point for SII/100 was determined to be 5.09. Below this threshold, there was a significant increase in the risk of breast cancer (OR=1.05, 95% CI: 1.02-1.09). Within the breast cancer population, SII exhibited a J-shaped relationship with all-cause mortality. The optimal inflection point for SII/100 in this context was 5.22, and above this threshold, there was a marked escalation in all-cause mortality (HR=1.09, 95% CI: 1.04-1.14).ConclusionThe SII, as a novel inflammatory composite index, is significantly associated with the risk of breast cancer incidence and all-cause mortality in breast cancer patients. These findings highlight the importance of monitoring systemic inflammation and suggest that SII could serve as a valuable prognostic tool.

A Neighborhood-Level Hispanic Paradox: the Interaction between Hispanic Density, Neighborhood Disadvantage, and Survival in Breast Cancer Patients.

To evaluate the impact of Hispanic ethnic enclaves (EE) on the relationship between neighborhood disadvantage and overall survival (OS) in breast cancer (BCa) patients. Data from BCa patients with stage I-IV disease diagnosed between 2005-2017 was used to analyze the effects of Area Deprivation Index (ADI) scores, a measure of neighborhood disadvantage, and census-tract level Hispanic density, a measure of EE, on OS using mixed-effects Cox regression models. The final model included the following individual-level factors (age, income, race, Hispanic/Latino origin, nativity, insurance status, and comorbidities (hypertension, diabetes, and body mass index) and clinical factors (National Comprehensive Cancer Network guideline-concordant treatment, stage, and receptor subtype). 5,387 patients were analyzed. 52% resided in Hispanic EE. Enclave residents were predominantly White (93%), with Cubans the predominant subgroup (37%). Overall, there were 1,040 deaths within the cohort. Patients residing in highly disadvantaged neighborhoods (ADI Tertile 3 [ADIT3]) within Hispanic EE experienced reduced HR compared to those outside of EE, evidenced by the interaction effect [EE x ADIT3 - HR (95% CI): 0.66 (0.44, 0.98)]. Hispanic EE may protect against mortality in BCa patients, suggesting positive social factors help combat negative effects of neighborhood disadvantage for patients. Understanding protective attributes of EE can help create effective cancer interventions and promote more equitable outcomes in minority populations. This study found that EE may protect against mortality in BCa patients, suggesting positive social factors may help mitigate the negative effects caused by the neighborhood.

Prognosis value of circulating telomere repeat binding factor 2 and leukocyte telomere length in breast cancer mortality

Telomere repeat binding factor 2 (TRF2) is currently a novel tumor marker, yet its clinical implication has not been investigated. The aim of this study was to investigate the prognostic value of circulating TRF2 and leukocyte telomere length in 5-year mortality in breast cancer patients. In this cohort retrospective study, breast cancer patients were included and the length of telomeres and circulating TRF2 were quantified. Receiver operating characteristics and the Youden index were used to determine the optimal cut-off. To analyze the overall survival rate in 5 years, Kaplan Meier analysis was used, while the prognostic value of both variables was analyzed in Cox proportional hazard regression on both univariate and multivariate models. Our data indicated that the optimal cut-off points for TRF2 and leukocyte telomere length were 598 pg/mL and 0.93 kb, respectively. Based on the optimal cut-off points, the participant’s data was grouped, and our data indicated that the high TRF2 group had a poorer overall survival rate in comparison to the low group (91.3% vs 83.87%; log-rank test; p<0.01). The overall survival between short and long telomeres was comparable (88.24% vs 88.37%; log-rank test; p=0.64). TRF2 (hazard ratio (HR): 3.66; 95%CI: 1.45–9.29) and molecular subtype (p=0.04) were identified as independent factors to predict mortality. In conclusion, a high circulating TRF2 in breast cancer participants was associated with lower overall 5-year survival rates in comparison with the low TRF2 group. Moreover, high TRF2 could predict the mortality of the breast cancer population to be 3.66 times higher than the lower group. In contrast, telomere length was not associated with overall survival rate nor predicting mortality in five years.

Exploring Key Factors Influencing Mortality in Breast Cancer

The purpose of this study is to develop a statistical model capable of predicting mortality in breast cancer patients based on a comprehensive set of demographic and clinical attributes. Data were analyzed using logistic regression to assess variables such as age, menopausal status and type of treatment. This approach helps to observe the interactions between these variables and their impact on survival outcomes. While logistic regression is effective for understanding linear relationships between variables, it has notable limitations when dealing with the complex, nonlinear nature of breast cancer progression. As a result, this model might not completely capture all aspects of patient prognosis. More advanced statistical techniques are needed to improve the accuracy of predictions in future studies. This strategy could potentially enhance the efficiency of clinical decision making, by allowing for better and more accurate predictions regarding which patients will die and guiding personalized treatment strategies. This strategy would provide an important advancement in both risk stratification and individualized intervention for patients with breast cancer.

Breast pericytes: a newly identified driver of tumor cell proliferation.

Effective treatment of breast cancer remains a formidable challenge, partly due to our limited understanding of the complex microenvironmental factors that contribute to disease pathology. Among these factors are tissue-resident perivascular cells, which play crucial roles in shaping vascular basement membranes, maintaining vessel integrity, and communicating with adjacent endothelial cells. Despite their essential functions, perivascular cells have been relatively overlooked. Identifying them by immunostaining has been challenging due to their low abundance, inherent heterogeneity, and shared marker expression with other cell types. These challenges have hindered efforts to purify pericytes and generate primary cell models for studying their biology. Using a recently developed FACS method, we successfully identified and purified each cell type from breast tissues, allowing us to deep-sequence their transcriptomes and generate primary cell models of each cell type-including pericytes. Here, we used these data to analyze cell-type-specific gene expression in tumors, which revealed a strong association between pericyte-specific genes and breast cancer patient mortality. To explore this association, we defined the heterogeneity of breast pericytes using single-cell RNA sequencing and identified a broad marker for visualizing perivascular cells in breast tumors. Remarkably, we discovered perivascular cells dissociated from vessels and emerged as a dominant mesenchymal cell type in a subset of breast tumors that contrasted with their normal perivascular location. Moreover, when we purified pericytes from the breast and cultured them alongside breast tumor cells, we discovered that they induced rapid tumor cell growth significantly greater than isogenic fibroblast controls. These findings identify perivascular cells as a key microenvironmental factor in breast cancer, highlighting the critical need for further research to explore their biology and identify specific stimulatory mechanisms that could be targeted therapeutically.

B3GALT4 modulates tumor progression and autophagy by AKT/mTOR signaling pathway in breast cancer

Backgroundβ-1,3-Galactosyltransferase-4 (B3GALT4), a member of the β-1,3-galactosyltransferase gene family, is essential to the development of many malignancies. However, its biological function in breast cancer is still unknown.MethodPublically accessible datasets, as well as quantitative real-time PCR, western blot, and immunohistochemistry on our patient cohort were used to investigate the expression levels of B3GALT4 in breast cancer. The correlation of B3GALT4 expression with clinical histopathological data and mortality in breast cancer patients was investigated. The effects of B3GALT4 in breast cancer in vitro and in vivo were investigated. RNA-seq, western blot, autophagolysosomes, and the fluorescence intensity of LC3 were used to explore the effects of B3GALT4 on autophagy. Western blot and gene set enrichment analysis (GSEA) were used to identify the AKT/mTOR pathway.ResultsB3GALT4 was significantly overexpressed in breast cancer tissues and was positively correlated with some aspects of clinicopathological status and poor prognosis. B3GALT4 overexpression significantly promoted cell proliferation, migration, and invasion, both in vitro and in vivo. B3GALT4 inhibition suppressed breast cancer cell proliferation, migration, and invasion in vitro. Suppression of B3GALT4 triggered autophagy and hindered the AKT/mTOR signaling pathway.ConclusionAccording to the present research, B3GALT4 blocked autophagy via the AKT/mTOR pathway and accelerated the growth of breast cancer. B3GALT4 may be an effective target for patients with breast cancer.

Abstract C128: Influence of hypertension management on all-cause mortality in a multiethnic cohort of women with metastatic breast cancer

Abstract Purpose: Breast cancer (BC) mortality rates have been declining over time; however, the decline is not consistent across racial/ethnic groups. Prior studies suggest that comorbidities, including hypertension, are associated with treatment delays, increased hospitalizations, and higher mortality in BC patients, but these studies have been limited to women with non-metastatic BC. The influence of common comorbidities on BC mortality, and their contribution to survival disparities in patients with metastatic BC (mBC), remains unknown. We examined the influence of hypertension on all-cause mortality, and if this disparity can be mitigated by better pharmacologic management of hypertension in a diverse cohort. Methods: This longitudinal cohort included 1,332 women diagnosed with de novo mBC between 2008-2020 at Kaiser Permanente Southern California (KPSC). We extracted data on cancer-related variables, sociodemographic, and clinical variables from KPSC’s cancer registry, pharmacy dispensings, and electronic health records. Deaths were identified from in-patient and national death databases. We followed patients electronically from mBC diagnosis until patients died or reached study’s end (12/31/2021), whichever occurred first. We computed person-year rates of all-cause mortality by use of antihypertensive medication (monotherapy [one drug class] or polytherapy [multiple drug classes]). Multivariable Cox regression with time-varying antihypertensive drug use status was used to estimate the association [HR, 95% CI] between overall mortality and use of antihypertensives. Results: The cohort consisted of 46.1% women of color. Overall, 48.4% patients had hypertension at mBC diagnosis, with Black patients (64.5%) having the highest prevalence, followed by White (46.3%), Hispanic (46.1%), and Asian/Pacific Islander (API) patients (42.7%). During follow-up, 52.8% were treated with antihypertensive medications (20.3% received monotherapy; 32.5% polytherapy). Overall mortality rates were lower in those treated with antihypertensive polytherapy (21.3/100 PY) vs. monotherapy (28.50/100 PY). Compared to monotherapy, the percent mortality rate reduction was greater in those treated with polytherapy, particularly in Black patients (35.7% reduction), followed by White (28.7%), Hispanic (15.9%) and API patients (7.60%) (P<0.05). After adjusting for age, SES, cancer treatments, other comorbidities and covariate medications, mortality risk was 44% lower (HR=0.56; 95%CI: 0.43-0.75) among those treated with polytherapy vs. monotherapy; this protection was even greater in Black women (HR=0.43; 0.19-0.97) and Hispanic women (HR=0.47; 0.24-0.95). Conclusion: In women with de novo mBC, hypertension was the most common comorbidity, and highest in Black women. All-cause mortality risk was lower among those treated with polytherapy vs. monotherapy for hypertension, with the greatest attenuation seen amongst Black and Hispanic women. Pharmacologic management of hypertension in women with mBC may potentially help extend life and mitigate mortality disparities. Citation Format: Reina Haque, Amrita Mukherjee, Lie Hong Chen, Tiffany Hogan, Moira Brady-Rogers, Zheng Gu, Ariel Silverman, Lauren P. Wallner. Influence of hypertension management on all-cause mortality in a multiethnic cohort of women with metastatic breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C128.

Abstract PO2-24-09: Prolonged Effects of Hypoxia in Luminal Breast Cancer Cells Promotes an Aggressive Phenotype

Abstract Aidan Moriarty Mentor: Dr. Min Yu Hypoxic Memory in Breast Cancer Cells Metastasis is the main cause of tumor-related mortality in breast cancer patients. Improving our understanding of the metastatic cascade is imperative to improve patient outcomes. Prior research indicates cancer cells with increased metastatic potential have acquired adaptive properties induced by factors in the tumor microenvironment (TME), including hypoxia. However, previous hypoxia research has been primarily focused on signaling changes that occur when cancer cells are in the hypoxic TME and does not account for long-term changes that may occur once cancer cells re-enter normoxia, such as when they metastasize. Our research in patient-derived circulating tumor cell (CTCs) lines and breast cancer cell lines has indicated that certain transcriptional changes are maintained after cells leave hypoxia, and that these post-hypoxic CTCs maintain a higher metastatic potential compared to cells not exposed to hypoxia. Taking an un-biased approach to define changes in hypoxia-exposed breast cancer cells upon reoxygenation, we performed bulk RNA-Seq on luminal breast cancer cell lines in various oxygen conditions over time. We found that a subset of genes that were differentially expressed in hypoxic conditions were maintained as up- or down-regulated after cells were reoxygenated, indicating a “hypoxic memory”. Additionally, a subset of genes were differentially expressed in the post-hypoxic cells compared to normoxia controls, demonstrating novel and prolonged gene expression changes induced by hypoxia exposure. We performed functional assays and observed that this post-hypoxic state is associated with a more aggressive phenotype in vitro. Current research in our lab is on-going to understand the epigenetic changes that may be responsible for this hypoxic memory to further understand the consequences of hypoxic memory in CTC biology and metastasis. Finally, we have designed a dual-reporter hypoxia-tracing system to validate our findings in vivo. This research will improve our understanding of the prolonged influence of hypoxia on metastatic potential in breast cancer cells and has the potential to inform future therapeutic strategies. Citation Format: Aidan Moriarty, Oihana Iriondo, Desirae Mecenas, Yilin Li, Yonatan Amzaleg, Remi Klotz, Min Yu. Prolonged Effects of Hypoxia in Luminal Breast Cancer Cells Promotes an Aggressive Phenotype [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-24-09.

Comparing the effects of various β-blockers on cardiovascular mortality in breast cancer patients

BackgroundCardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual β-blockers have been investigated to manage CV complications, various β-blockers have not been compared for their effects on CV death in this population. We aimed to compare CV mortality in older BC patients taking one of the commonly used β-blockers.MethodsThis retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) - Medicare data (2010–2015). Patients of age 66 years or older at BC diagnosis receiving metoprolol, atenolol, or carvedilol monotherapy were included. The competing risk regression model was used to determine the risk of CV mortality in the three β-blocker groups. The multivariable model was adjusted for demographic and clinical covariates. The adjusted hazard ratio (HR) and 95% confidence intervals (CI) were reported for the risk of CV mortality.ResultsThe study cohort included 6,540 patients of which 55% were metoprolol users, 30% were atenolol users, and 15% were carvedilol users. Metoprolol was associated with a 37% reduced risk of CV mortality (P = 0.03) compared to carvedilol after adjusting for the covariates (HR = 0.63; 95% CI 0.41–0.96). No significant difference in the risk of CV mortality between atenolol and carvedilol users was observed (HR = 0.74; 95% CI 0.44–1.22).ConclusionsOur findings suggest that metoprolol is associated with a reduced risk of CV mortality in BC patients. Future studies are needed to confirm these findings and understand the mechanism of action.

Abstract 6837: Prolonged effects of hypoxia in luminal breast cancer cells

Abstract Metastasis is the main cause of tumor-related mortality in breast cancer patients. Improving our understanding of the metastatic cascade is imperative to improve patient outcomes. Prior research indicates cancer cells with increased metastatic potential have acquired adaptive properties induced by factors in the tumor microenvironment (TME), including hypoxia. However, previous hypoxia research has primarily focused on signaling changes that occur when cancer cells are in the hypoxic TME and does not account for long-term changes that may occur once cancer cells re-enter normoxia, such as when they metastasize. Our research in patient-derived circulating tumor cell (CTCs) lines and breast cancer cell lines indicates that certain transcriptional changes are maintained after cells leave hypoxia, and that these post-hypoxic cells maintain a higher metastatic potential compared to cells not exposed to hypoxia. Taking an un-biased approach to define changes in hypoxia-exposed breast cancer cells upon reoxygenation, we performed bulk RNA-Seq on post-hypoxic luminal breast cancer cell lines compared to normoxic controls cultured either in adherent or suspension conditions, the latter to mimic the physiological context of CTCs. We found that a subset of genes that were differentially expressed in hypoxic conditions were maintained as up- or down-regulated after cells were reoxygenated, indicating a “hypoxic memory”. Additionally, a subset of differentially expressed genes were unique to the post-hypoxic cells, demonstrating both prolonged and novel gene expression changes induced by hypoxia exposure. We also performed functional assays and observed that this post-hypoxic state is associated with a more aggressive phenotype. Current research in our lab is on-going to understand the epigenetic changes that may be responsible for this hypoxic memory. Overall, this research will improve our understanding of the prolonged consequences of hypoxia on CTC biology and metastasis. Citation Format: Aidan Moriarty, Oihana Iriondo, Yonatan Amzaleg, Remi Klotz, Min Yu. Prolonged effects of hypoxia in luminal breast cancer cells [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 6837.

Abstract 5485: Spatial characterization of the immunosuppressive tumor microenvironment in estrogen receptor positive breast cancer at single cell level

Abstract We characterized immune cell exclusion in estrogen receptor positive (ER+) breast cancer through the study of spatial relationships among various subsets of cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and other immune cells using a novel in-situ spatial transcriptomic technology. ER+ breast cancer is the most common breast cancer subtype. While endocrine therapy and immune checkpoint inhibitors have considerably reduced relapse and mortality for breast cancer patients, tumor resistance to treatment remains a major challenge. The tumor microenvironment (TME) plays an important role in this mechanism of resistance. Our previous spatial proteomic analysis of ER+ breast FFPE samples demonstrated the intricate relationship between tumor and immunosuppressive cells such as CAFs and TAMs via the CXCR4-CXCL12 axis associated with the exclusion of CD8 T cells from the TME. However, the limited number of antibodies in the panel made it challenging to investigate the diversity of those CAF and TAM populations and better understand their contribution to T cell exclusion. For this purpose, we further characterized the TME of 4 human ER+ breast cancer FFPE cores using the Xenium in-situ transcriptomic platform with a breast cancer-focused panel of 280 genes from 10x Genomics plus 100 additional genes selected from literature and publicly available single cell datasets to delineate CAF and TAM sub-populations. Image analysis enabled the quantification and spatial mapping of the target genes within each cell boundary. Cells were manually annotated through unsupervised clustering of over 1 million cells. The cell phenotyping analysis allowed us to annotate major cell types including tumor cells, macrophages, T cells and fibroblasts. With our curated panel, we further characterized CAF and TAM sub-populations by identifying myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) in addition to M1 and M2-like macrophages as reported in the literature. We then performed spatial neighborhood analysis based on the similarity of the cell type composition in the vicinity of each cell. The results showed that myCAFs and M2-like macrophages are found in proximity to tumor cells and may play a role in T-cell exclusion. In addition, iCAFs mainly express CXCL12, a chemokine known to attract immunosuppressive cells such as regulatory T cells and M2-like macrophages as well as repel cytotoxic T cells from infiltrating the tumor via the CXCR4-CXCL12 axis. Overall, our work shows the potential of spatial transcriptomics to elucidate the spatial distribution of cells and their contribution to the immunosuppressive TME, which may enable researchers to improve understanding of tumor biology and drug target discovery efforts. Citation Format: Julien Tessier, Sandra Curras-Alonso, Joon Sang Lee, Fabien Delahaye, Hong Ma, Katie Malley, Dinesh Bangari, Donald Jackson, Angela Hadjipanayis. Spatial characterization of the immunosuppressive tumor microenvironment in estrogen receptor positive breast cancer at single cell level [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 5485.

LSD1 modulates the bone metastasis of breast cancer cells through hnRNPA2B1-mediated sorting of exosomal miRNAs

Bone metastasis is a key contributor to morbidity and mortality of breast cancer patients. We have previously shown that exosomal miRNAs derived from LSD1 knockdown (KD) breast cancer cells inhibit osteoblast differentiation and promote osteoclast differentiation. However, how LSD1 regulates exosomal miRNAs and whether miRNAs promote bone metastasis through the formation of pre-metastatic niches remains unclear. In vivo experiments demonstrates that exosomes derived from LSD1 KD breast cancer cells significantly promoted bone metastasis. To explore the mechanism underlying the effect of LSD1 on exosomes in breast cancer cells, exosomal and cellular miRNAs from control, LSD1 KD, and rescue cells were sequenced. Interestingly, approximately 80% of LSD1-associated miRNAs were downregulated in exosomes from LSD1 KD cells. The consensus sequence UAGGGC, was identified in many miRNAs downregulated in LSD1 KD exosomes. We found that hnRNPA2B1 regulated the exosomal sorting of miR-6881-3p and some other miRNAs. LSD1 deficiency reduced hnRNPA2B1 expression in breast cancer cells by decreasing the level of H3K9me2 demethylation in the promoter region of the hnRNPA2B1 gene. Our study revealed that LSD1 plays a crucial role in the regulation of exosomal sorting of miRNA.

Mortality comparison between axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SND) among breast cancer pantient: A meta-analysis and systematic review study

Introduction: Axillary lymph node dissection (ALND) is a crucial surgical procedure for breast cancer. It has guaranteed locoregional control of the disease, guided adjuvant therapy, and functioned as a staging tool. However, over the past 25 years, a more conservative approach has become the standard for surgical management of the axilla. Because sentinel lymph node biopsy (SNB) is less invasive and less morbid than axillary lymph node dissection (ALND), it has become the standard surgical procedure for axillary staging of clinically node-negative breast cancer. This study aimed to compare the mortality of breast cancer patients receiving ALND and SNB procedure. Methods: Our review includes randomized controlled trials of breast cancer patients undergoing ALND or SNB surgical techniques. A systematic literature search was performed from PubMed on December 2023 to search for articles reporting on survival rates between ALND vs SNB among breast cancer patients. The data obtained then underwent statistical evaluation, and a meta-analysis was conducted using Review Manager 5.4. In order to represent primary outcomes, the risk ratio was estimated using an inverse variance technique with a random-effects model. Heterogeneity was presented with total values, 95% confidence intervals (CI), and I values. Results: As many as 208 articles were found in the PubMed database search, and only six studies were included in this study. The six included trials all used chemotherapy and radiotherapy for systematic treatment. The length of follow-up varied from 33 months to 15 years. The total number of patients in the trials was 3,585, and the study period was from 2011 to 2023. The pooled analysis of the mortality outcomes showed that the heterogeneity of the data was low (I2 21%, p = 0.4). In the pooled analysis, the mortality of patients with SNB for surgical treatment was not significantly different compared to patients with ALND (OR:0.88; 95% CI:0.65-1.19). Conclusion: The mortality of patients undergoing SNB and ALND does not differ significantly, according to this pooled study. It demonstrates that the group without axillary dissection had a primary survival outcome that was not inferior to that of the dissection group.

Dual-microRNA-Controlled Electrochemiluminescence Biosensor for Breast Cancer Diagnosis and Supplemental Identification of Breast Cancer Metastasis.

Breast cancer remains the most frequently diagnosed cancer globally, and the metastasis of this malignancy is the primary cause of mortality in breast cancer patients. Hence, prompt diagnosis and timely detection of metastatic breast cancer are critical for effective therapeutic intervention. Both progression and metastasis of this malignancy are closely associated with aberrant expression of specific microRNAs (miRNAs) and enzymes. To facilitate breast cancer diagnosis and concomitant identification of metastatic breast cancer, we have engineered an innovative electrochemiluminescence (ECL)-based sensing platform integrated with enzyme-free DNA amplification circuits for dual functionality. Specifically, microRNA-21 (miR-21) is employed as a biomarker for breast cancer, and miR-21 induces the quenching of the ECL signal from luminophores via a strategically designed catalytic three-hairpin assembly (CTHA) circuit. Subsequently, miR-105 levels are measured via toehold-mediated strand displacement reactions (TSDR). Here, miR-105 restores the initially quenched ECL signal, enabling the assessment of the metastatic propensity. Our experimental data demonstrate that the devised ECL biosensor offers broad linear detection ranges and low detection limits for both miR-21 and miR-105. Importantly, our novel platform was also successfully validated by using cellular and serum samples. This biosensor not only discriminates breast cancer cell lines MCF-7 and MDA-MB-231 from nonbreast cancer cells like HepG2, TPC-1, and HeLa, but it also distinguishes between malignant MCF-7 and metastatic MDA-MB-231 cells. Consequently, our novel approach holds significant promise for clinical applications and precise cancer screening.

Prognostic nomograms for breast cancer with lung metastasis: a SEER-based population study

BackgroundLung metastasis is a significant adverse predictor of prognosis in patients with breast cancer. Accurate estimation for the prognosis of patients with lung metastasis and population-based validation for the models are lacking. In the present study, we aimed to establish the nomogram to identify prognostic factors correlated with lung metastases and evaluate individualized survival in patients with lung metastasis based on SEER (Surveillance, Epidemiology, and End Results) database.MethodsWe selected 1197 patients diagnosed with breast cancer with lung metastasis (BCLM) from the SEER database and randomly assigned them to the training group (n = 837) and the testing group (n = 360). Based on univariate and multivariate Cox regression analysis, we evaluated the effects of multiple variables on survival in the training group and constructed a nomogram to predict the 1-, 2-, and 3-year survival probability of patients. The nomogram were verified internally and externally by Concordance index (C-index), Net Reclassification (NRI), Integrated Discrimination Improvement (IDI), Decision Curve Analysis (DCA), and calibration plots.ResultsAccording to the results of multi-factor Cox regression analysis, age, histopathology, grade, marital status, bone metastasis, brain metastasis, liver metastasis, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), surgery, neoadjuvant therapy and chemotherapy were considered as independent prognostic factors for patients with BCLM. The C-index in the training group was 0.719 and the testing group was 0.695, respectively. The AUC values of the 1-, 2-, and 3-year prognostic nomogram in the training group were 0.798, 0.790 and 0.793, and the corresponding AUC values in the testing group were 0.765, 0.761 and 0.722. The calculation results of IDI and NRI were shown. The nomograms significantly improved the risk reclassification for 1-, 2-, and 3-year overall mortality prediction compared with the AJCC 7th staging system. According to the calibration plot, nomograms showed good consistency between predicted and actual overall survival (OS) values for the patients with BCLM. DCA showed that nomograms had better net benefits at different threshold probabilities at different time points compared with the AJCC 7th staging system.ConclusionsNomograms that predicted 1-, 2-, and 3-year OS for patients with BCLM were successfully constructed and validated to help physicians in evaluating the high risk of mortality in breast cancer patients.

Extracellular vesicles in the breast cancer brain metastasis: physiological functions and clinical applications.

Breast cancer, which exhibits an increasing incidence and high mortality rate among cancers, is predominantly attributed to metastatic malignancies. Brain metastasis, in particular, significantly contributes to the elevated mortality in breast cancer patients. Extracellular vesicles (EVs) are small lipid bilayer vesicles secreted by various cells that contain biomolecules such as nucleic acids and proteins. They deliver these bioactive molecules to recipient cells, thereby regulating signal transduction and protein expression levels. The relationship between breast cancer metastasis and EVs has been extensively investigated. In this review, we focus on the molecular mechanisms by which EVs promote brain metastasis in breast cancer. Additionally, we discuss the potential of EV-associated molecules as therapeutic targets and their relevance as early diagnostic markers for breast cancer brain metastasis.

SGLT2 i Dapagliflozin reduces NF-kB expression in heart and kydneys of preclinical models exposed to doxorubicin through MYd-88 and NLRP3 pathways: an hystological study

Abstract Background Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Purpose We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p<0.005). Hystology evaluation indicate reduction NF-kB expression in myocardial and renal tissue in DOXO-DAPA vs DOXO. Radial strain (RS) is 38.8% in DAPA-DOXO vs 14.1% in DOXO groups (P < 0.05); longitudinal strain (LS) is – 23.4 % in DAPA-DOXO vs – 10.5% in DOXO groups (P < 0.001) Conclusion In this preclinical study, DAPA is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.

Abstract 15030: Dapagliflozin Reduces Myocardial and Renal NF-kB Expression in Preclinical Models Exposed to Doxorubicin Through Myd-88 and NLRP3 Pathways: An Hystological Study

Background: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and HFrEF, conditions that commonly coexist and are interrelated pathophysiologically. Hypothesis: We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p<0.005). Hystology evaluation indicate reduction NF-kB expression in myocardial and renal tissue in DOXO-DAPA vs DOXO. Radial strain (RS) is 38.8% in DAPA-DOXO vs 14.1% in DOXO groups (P < 0.05); longitudinal strain (LS) is - 23.4 % in DAPA-DOXO vs - 10.5% in DOXO groups (P < 0.001) Conclusion: The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.

Direct and indirect effects of COVID-19 on short-term mortality of breast cancer patients.

We studied the COVID-19 impact in newly-diagnosed breast cancer (7,349 patients in 2019, and 5,563 in 2020). In 2020 there were two diagnostic drops: -37.2% (March-May), -15.8% (October-December). Early-stage at presentation (76.4% vs. 74.4%, p=0.0013), conserving surgery (71.0% vs. 67.0%, p<0.0001), chemotherapy (86.2% vs. 53.4%, p<0.0001), and radiotherapy (65.7% vs. 42.1%, p<0.0001) decreased in 2020 compared to 2019. COVID-19 occurred in 250 patients (4.49%). The time-dependent COVID-19 effect was associated with mortality (multivariable Cox analysis HR [95% CI] 2.26 [1.35-3.74]; p=0.0018). Survival within the year of diagnosis was 97.6% in 2020 and 98.3% in 2019; 30-day mortality was 1.13% in 2020 (1.07 in uninfected patients), and 0.61% in 2019. The year of diagnosis lost its prognostic relevance after adjusting for stage and treatment. These findings emphasize the critical role of continuity of care, which was disrupted during the pandemic, and underscore the need for policies minimizing treatment initiation delay in newly diagnosed breast cancer patients.

Breast Cancer Prognosis: A Study on Mortality Indicators.

Background: The prognosis of breast cancer patients is critical for tailored treatment options. While previous observational studies have identified various prognostic markers, a consensus in their clinical application is lacking. This single-center retrospective study aimed to validate the most frequent risk factors associated with increased mortality in breast cancer patients. Methods: Our study spanned an 8-year interval (2014-2020) and included 213 female patients with stage IIA-IIIB breast cancer. Key variables such as age, disease stage, and type of treatment were analyzed in relation to one-year survival as the primary outcome measure. Results: Elevated preoperative levels of tumor markers ACE and CA 15-3, larger tumor size, and advanced lymph nodal invasion were significantly associated with increased mortality. Immunohistochemistry indicated that the presence of Estrogen and Progesterone Receptors (ER and PR) were protective factors, whereas Human Epidermal Growth Factor Receptor 2 (HER2) was a negative prognostic indicator. Among molecular subtypes, Luminal A demonstrated protective effects, whereas HER2-positive and Triple-negative subtypes were identified as risk factors. Conclusion: This study confirms the significant role of tumor size, lymph node stage, and specific molecular markers in predicting breast cancer mortality. These findings contribute to a nuanced understanding of disease prognosis and offer crucial insights for clinicians in managing treatment plans.