Mortality In Breast Cancer Patients Research Articles

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.

Potential anti-cancer activity of Moringa oleifera derived bio-active compounds targeting hypoxia-inducible factor-1 alpha in breast cancer.

Breast cancer (BC) will become a highly detected malignancy in females worldwide in 2023, with over 2 million new cases. Studies have established the role of hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls cellular response to hypoxic stress, and is essential for BC spread. HIF-1 is implicated in nearly every critical stage of the metastatic progression, including invasion, EMT, intravasation, extravasation, angiogenesis, and the formation of metastatic niches. HIF-1 overexpression has been associated with poor prognosis and increased mortality in BC patients. This is accomplished by controlling the expression of HIF-1 target genes involved in cell survival, angiogenesis, metabolism, and treatment resistance. Studies have indicated that inhibiting HIF-1 has an anti-cancer effect on its own and that inhibiting HIF-1-mediated signaling improves the efficacy of anti-cancer therapy. Approximately 74 % of recognized anti-cancer drugs are sourced from plantspecies. Studies on anti-cancer characteristics of phytochemicals derived from Moringa oleifera (MO), also known as the 'Tree of Life', have revealed a high therapeutic potential for BC. In this review, we have highlighted the various mechanisms through which bioactive compounds present in MO may modulate HIF and its regulatory genes/pathways, toprove their efficacy in treating and preventing BC.

Opposite trends in incidence of breast cancer in young and old female cohorts in Hungary and the impact of the Covid-19 pandemic: a nationwide study between 2011-2020.

This nationwide study examined breast cancer (BC) incidence and mortality rates in Hungary between 2011-2019, and the impact of the Covid-19 pandemic on the incidence and mortality rates in 2020 using the databases of the National Health Insurance Fund (NHIF) and Central Statistical Office (CSO) of Hungary. Our nationwide, retrospective study included patients who were newly diagnosed with breast cancer (International Codes of Diseases ICD)-10 C50) between Jan 1, 2011 and Dec 31, 2020. Age-standardized incidence and mortality rates (ASRs) were calculated using European Standard Populations (ESP). 7,729 to 8,233 new breast cancer cases were recorded in the NHIF database annually, and 3,550 to 4,909 all-cause deaths occurred within BC population per year during 2011-2019 period, while 2,096 to 2,223 breast cancer cause-specific death was recorded (CSO). Age-standardized incidence rates varied between 116.73 and 106.16/100,000 PYs, showing a mean annual change of -0.7% (95% CI: -1.21%-0.16%) and a total change of -5.41% (95% CI: -9.24 to -1.32). Age-standardized mortality rates varied between 26.65-24.97/100,000 PYs (mean annual change: -0.58%;95% CI: -1.31-0.27%; p=0.101; total change: -5.98%;95% CI: -13.36-2.66). Age-specific incidence rates significantly decreased between 2011 and 2019 in women aged 50-59, 60-69, 80-89, and ≥90 years (-8.22%, -14.28%, -9.14%, and -36.22%, respectively), while it increased in young females by 30.02% (95%CI 17,01%- 51,97%) during the same period. From 2019 to 2020 (in first COVID-19 pandemic year), breast cancer incidence nominally decreased by 12% (incidence rate ratio [RR]: 0.88;95% CI: 0.69-1.13; 2020 vs. 2019), all-cause mortality nominally increased by 6% (RR: 1.06; 95% CI: 0.79-1.43) among breast cancer patients, and cause-specific mortality did not change (RR: 1.00; 95%CI: 0.86-1.15). The incidence of breast cancer significantly decreased in older age groups (≥50 years), oppositely increased among young females between 2011 and 2019, while cause-specific mortality in breast cancer patients showed a non-significant decrease. In 2020, the Covid-19 pandemic resulted in a nominal, but not statistically significant, 12% decrease in breast cancer incidence, with no significant increase in cause-specific breast cancer mortality observed during 2020.

Breast conservation therapy decreased heart-specific mortality in breast cancer patients compared with mastectomy

AimTo investigate the impacts of breast conservation therapy (BCT) and mastectomy on heart-specific mortality in breast cancer patients.MethodsPatients with primary breast cancer registered in the Surveillance, Epidemiology, and End Results (SEER) database between Jan 1998 and Dec 2015 were included. Patients were divided into either breast conservation therapy or mastectomy group. To compare mortality caused by heart diseases in breast cancer patients with BCT or mastectomy, univariate and multivariate regression after propensity score matching (PSM) were performed. Kaplan-Meier analysis was also used to evaluate heart-specific survival between two groups.Results132,616 patients with breast cancer were enrolled in this study. After PSM, four risk factors including age, race, marital status and types of surgery were identified significantly associated with death from heart diseases. Heart-specific survival analysis further showed that overall, BCT poses a lower risk to heart-specific mortality compared with mastectomy.ConclusionCompared with mastectomy, BCT significantly decreased heart-specific mortality in breast cancer patients.

Post-Diagnostic Statin Use and its Association with Cancer Recurrence and Mortality in Breast Cancer Patients: A Systematic Review and Meta-analysis.

Statins are widely acknowledged for their application in patients with hypercholesterolemia to reduce cardiovascular morbidity and mortality. More recently, their potential to exert pleiotropic effects, particularly in impeding the proliferation of neoplastic cells, has attracted considerable attention. Prior studies have demonstrated that statins may mitigate cancer progression and micrometastasis. However, the benefits of statins in breast cancer have been inconclusive. The aim of this meta-analysis was to evaluate the impact of statin use following a breast cancer diagnosis on breast cancer recurrence and mortality. We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until 30th May 2023. Hazard ratios (HR) were pooled using a random-effect model. The primary outcome of interest was the risk of breast cancer recurrence. The secondary outcomes included breast cancer-specific mortality and all-cause mortality. A total of 15 studies with 156,448 patients were included in the final analysis. The mean age of patients between statin users and non-users was 64.59 and 59.15 years, respectively. Statin use was associated with a reduction in the recurrence of breast cancer (HR 0.76, 95%CI: 0.67-0.87) compared with non-statin users. This trend was similar among lipophilic statin users (HR 0.73, 95%CI: 0.63-0.85) but not for hydrophilic statin users (HR 1.17, 95%CI: 0.82-1.68). Furthermore, all-cause mortality (HR 0.82, 95%CI: 0.66-1.02) and breast cancer mortality (HR 0.87, 95% CI: 0.69-1.10) were comparable between statin and non-statin users. However, lipophilic statins demonstrated a reduction in both all-cause mortality (HR 0.84, 95%CI: 0.75-0.93) and breast cancer mortality (HR 0.85, 95%CI: 0.74-0.99) compared to non-statin users. Among patients with breast cancer, statin use post-diagnosis decreases the risk of breast cancer recurrence. Furthermore, lipophilic statins exhibit an additional advantage of reducing both all-cause and breast cancer-specific mortality.

Dapagliflozin improves radial and longitudinal strain, increases pAMPK and reduces myocardial and renal NF-kB expression in preclinical models of doxorubicin cardiotoxicity through NLRP3 and Myd-88

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente, Ministero della Salute. 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&amp;lt;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&amp;lt;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 &amp;lt; 0.05); longitudinal strain (LS) is – 23.4 % in DAPA-DOXO vs – 10.5% in DOXO groups (P &amp;lt; 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.

C12 DAPAGLIFLOZIN INCREASES PAMPK AND REDUCES MYOCARDIAL AND RENAL NF–KB EXPRESSION IN PRECLINICAL MODELS OF SHORT–TERM DOXORUBICIN CARDIOTOXICITY THROUGH MYD–188 AND NLRP3 PATHWAYS

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&amp;lt;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&amp;lt;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 &amp;lt; 0.05); longitudinal strain (LS) is – 23.4 % in DAPA–DOXO vs – 10.5% in DOXO groups (P &amp;lt; 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.

Research on Breast Cancer Classification and Prediction Model Based on Principal Component Analysis and Machine Learning

In recent years, breast cancer has become one of the biggest threats to women's health, accounting for the majority of cancer deaths among women. Because early treatment of breast cancer has a great effect on the recovery of breast cancer, the diagnosis of breast cancer is particularly important. Machine learning, as the most popular method, is also used for model construction in this field. This study is based on data from breast tumors, which contain 10 morphological features of breast tumor nucleus. In this study, homogenization, standardization and feature selection were used to process the data and KNN algorithm was used to construct the classification prediction model, with principal component analysis (PCA) used to optimize the model. Finally, the original 30 variables were reduced to 3 variables and the model parameters were adjusted in order to achieve the best model with the accuracy of 98.54%. The final model achieves the highest operating efficiency and accuracy. In this study, through the visualization of PCA and the comparison of different models, the classification effect of the final model can be the best. This model can be applied to the clinical diagnosis of breast cancer patients, which is helpful to the early treatment efficiency and greatly reduce the mortality of breast cancer patients

Alcohol consumption and breast cancer prognosis after breast cancer diagnosis: a systematic review and meta‑analysis of the Japanese Breast Cancer Society Clinical Practice Guideline, 2022 edition

Alcohol consumption is internationally recognized as one of the compelling risk factors for breast cancer, but it does not necessarily correlate with the prognosis of breast cancer patients. Alcohol consumption in breast cancer patients was addressed in the 2022 Breast Cancer Clinical Practice Guidelines. A systematic review and meta-analysis of epidemiological studies on alcohol consumption and breast cancer recurrence, breast cancer-related mortality, all-cause mortality, and cardiovascular disease mortality in breast cancer patients was performed. The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant publications reporting cohort or case–control studies published until March 2021. A total of 33 studies (32 cohort studies and 1 case–control study) met the eligibility criteria; 4638 cases of recurrence, 12,209 cases of breast cancer-specific mortality, and 21,945 cases of all-cause mortality were observed. With regard to breast cancer recurrence, 7 studies assessed pre-diagnosis alcohol consumption (relative risk (RR) 1.02, 95% confidence interval (95% CI) 0.77–1.37, p = 0.88) and 3 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.85–1.10, p = 0.57), and no significant increase or decrease in risk was observed. With regard to breast cancer-related mortality, 19 studies assessed pre-diagnosis alcohol consumption (RR 1.02, 95% CI 0.93–1.11, p = 0.69), 9 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.77–1.19, p = 0.70), and no significant increase or decrease in risk was observed. With regard to all-cause mortality, 18 studies assessed pre-diagnosis alcohol consumption (RR 0.90, 95% CI 0.82–0.99, p = 0.02), 8 studies assessed post-diagnosis alcohol consumption (RR 0.88, 95% CI 0.74–1.02, p = 0.08), and pre-diagnosis alcohol consumption was associated with a significantly decreased risk. With regard to cardiovascular disease mortality and alcohol consumption, 2 studies assessed it, and the RRwas 0.47 (95% CI 0.28–0.79, p = 0.005), showing that alcohol consumption was associated with a significantly decreased risk. The limitations of this study are that drinking status was mainly based on a questionnaire survey, which is somewhat inaccurate and has many confounding factors, and the cut-off value for the maximum alcohol intake in many studies was low, and it is possible that the actual intake was only an appropriate amount. In many countries, a standard drinking amount is set, and wise decisions are required.