Mortality In Breast Cancer Patients Research Articles

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<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.

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<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.

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.

Small extracellular vesicles in breast cancer brain metastasis and the prospect of clinical application.

Extracellular vesicles (EVs) are nanoscale extracellular particles that have received widespread scientific attention for carrying a variety of biomolecules such as nucleic acids and proteins and participating in the process of intercellular information exchange, making them become a research hotspot due to their potential diagnostic value. Breast cancer is the leading cause of cancer-related death in women, approximately 90% of patient deaths are due to metastasis complications. Brain metastasis is an important cause of mortality in breast cancer patients, about 10-15% of breast cancer patients will develop brain metastasis. Therefore, early prevention of brain metastasis and the development of new treatments are crucial. Small EVs have been discovered to be involved in the entire process of breast cancer brain metastasis (BCBM), playing an important role in driving organ-specific metastasis, forming pre-metastatic niches, disrupting the blood-brain barrier, and promoting metastatic tumor cell proliferation. We summarize the mechanisms of small EVs in the aforementioned pathological processes at the cellular and molecular levels, and anticipate their potential applications in the treatment of breast cancer brain metastasis, with the hope of providing new ideas for the precise treatment of breast cancer brain metastasis.

Differences between zoledronic acid and denosumab for breast cancer treatment.

Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects include the prevention of osteoporosis induced by cancer-treatment bone loss, treatment and prevention of bone metastasis, and improvement of survival directly or indirectly by maintaining bone health. Interestingly, zoledronic acid and denosumab have different anticancer activities, and they may be associated with the improvement of survival of breast cancer patients under different mechanisms. Zoledronic acid is the most potent bisphosphonate. It provides significant benefits for improving breast cancer mortality in patients with suppressed estrogen level such as in postmenopausal or ovarian suppression condition. Although denosumab's anticancer activity has not been clearly proven compared with zoledronic acid's anticancer activity, denosumab is promising in preventing BRCA1 mutant breast cancer because RANKL is a targetable pathway in BRCA1-associated tumorigenesis. Further studies and more effective clinical use of these agents are anticipated to contribute to the improvement of the clinical outcome of breast cancer patients.

Abstract P6-14-09: Non-canonical Wnt/Ror2 signaling regulates tumor cell invasion and dissemination in breast cancer through cell-matrix crosstalk

Abstract BACKGROUND: Metastasis is the main cause of mortality for breast cancer patients. The early steps of cancer metastasis require that tumor cells actively invade and disseminate from the primary tumor to distant organs. Cell-extracellular matrix (ECM) interactions represent fundamental interactions during tumor invasion and metastasis, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic dissemination remains elusive. OBJECTIVES: Wnt signaling is a known regulator of cell fate, migration, and polarity during various key biological processes. We previously discovered an inverse correlation between the canonical Wnt signature and a non-canonical Wnt receptor, Ror2, across breast cancers in TCGA. The objective of this study is to investigate how canonical and non-canonical Wnt signaling orchestrate tumor cell behavior during cancer invasion and metastasis. METHODS: We used clinically relevant syngeneic TP53-null Genetically Engineered Mouse Model (GEMM) tumors that molecularly reflect the different breast cancer intrinsic subtypes. In vivo transplantation of GEMM models and in vitro 3D tumor organoids were employed to elucidate the molecular mechanism underlying the migration, invasion, and metastasis of tumor cells upon genetic perturbation of Wnt/Ror2 signaling. RESULTS/DISCUSSION: From 3-dimensional (3D) tumor organoid models, we identified novel transcriptional alterations encompassing cell-cell adhesion, cytoskeletal remodeling, and ECM organization upon Ror2 loss. At protein levels, we discovered a significant increase in collagen fibril organization and integrin-α5 and integrin-β3 expression following Ror2 depletion. In addition, the matrisomal protein fibronectin (FN) was concomitantly upregulated and assembled in Ror2-deficient tumor cells at sites of invasion. Consequently, we observed FAK activation and actin cytoskeleton alterations in Ror2-deficient tumor cells, leading to a promigratory tumor cell behavior. The altered cytoskeleton and cell-ECM interaction enhanced the rigidity of the Ror2-depleted cells. Furthermore, Inhibition of either integrin or FAK activation abrogated the increased invasion driven by Ror2-loss. Unexpectedly, these changes were distinct from processes regulated by Wnt/ß-catenin activation. From both spontaneous metastasis and experimental metastasis models, we discovered a shift from canonical to non-canonical Wnt signaling throughout the progression of lung metastasis, indicating that the balance of Wnt signaling may serve as a switch to dictate cell functions at different stages of metastatic development. Consistently, we found enhanced initial colonization in the lungs when Ror2 is depleted in these breast cancer cells. Together, these studies provide new insight into how canonical and alternative Wnt pathways coordinate cell-cell and cell-ECM exchanges during breast cancer progression and metastasis. Supported by grant NIH-CA016303 Citation Format: Hongjiang Si, Na Zhao, Andrea Pedroza, Chad Creighton, Jeffrey Rosen, Kevin Roarty. Non-canonical Wnt/Ror2 signaling regulates tumor cell invasion and dissemination in breast cancer through cell-matrix crosstalk [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-09.

Estrogen therapy after breast cancer diagnosis and breast cancer mortality risk

PurposeThe safety of local estrogen therapy in patients on adjuvant endocrine treatment is questioned, but evidence on the issue is scarce. This nested case–control registry-based study aimed to investigate whether estrogen therapy affects breast cancer mortality risk in women on adjuvant endocrine treatment.MethodsIn a cohort of 15,198 women diagnosed with early hormone receptor (HR)-positive breast cancer and adjuvant endocrine treatment, 1262 women died due to breast cancer and were identified as cases. Each case was matched with 10 controls. Exposure to estrogen therapy with concurrent use of aromatase inhibitors (AIs), tamoxifen, or both sequentially, was compared between cases and controls.ResultsNo statistically significant difference in breast cancer mortality risk was seen in patients with exposure to estrogen therapy concurrent to endocrine treatment, neither in short-term or in long-term estrogen therapy use.ConclusionsThe study strengthens current evidence on local estrogen therapy use in breast cancer survivors, showing no increased risk for breast cancer mortality in patients on adjuvant AIs or tamoxifen.

The modified Glasgow prognostic score (MGPS) and the mortality prediction model II (MPM II) can predict mortality in patients with breast cancer admitted to intensive care: A retrospective cohort study

Background/Aim: Breast cancer is the second most common cause of cancer-related death in women worldwide. Predicting the prognosis in breast cancer with very high mortality is important in terms of disease treatment and increasing life expectancy. In our study, we aimed to examine the importance of some inflammatory markers and scoring systems in predicting prognosis in patients with breast cancer who were hospitalized in the intensive care unit. Methods: This retrospective cohort study was conducted in the Department of Medical Oncology and Intensive Care Unit between 2014 and 2020. Breast cancer patients who were admitted to the intensive care unit at any stage of their treatment during the study and followed up and treated in the medical oncology department of the hospital were included in the study. All data were compared between groups (discharged or exitus) based on survival status. Socio-demographic information, laboratory findings (hemoglobin, leukocytes, neutrophils, lymphocytes, platelets, eosinophils, monocytes, C-reactive protein [CRP], albumin, lactate dehydrogenase [LDH], clinical status [co-morbidities, length of stay in intensive care, mechanical ventilation, and reason for hospitalization in the intensive care unit]), and survival data of the patients were collected retrospectively from hospital medical records. We also recorded treatment-related data and relapse/progression information. Neutrophil–lymphocyte, platelet–lymphocyte, and lymphocyte–monocyte ratios (NLR, PLR, and LMR, respectively) were calculated. Results: Thirty-seven (52.1%) patients died and 34 (47.9%) patients survived. The NLR (P=0.021), Modified Glasgow Prognostic score (P<0.001), APACHE II score (P<0.001) and mortality probability model (MPM II) upon admission (P<0.001) were significantly higher in the exitus group than in the survivors. The lymphocyte_monocyte ratio (P=0.030) and prognostic nutritional index (P=0.004) were significantly higher in the discharged group than in the death group. When we evaluated performance of the prognostic scores to predict mortality, we found that the APACHE II score (area under the curve [AUC]: 0.939, 95% confidence interval [CI]: 0.888–0.990), MPM II-Admission (AUC: 0.936, 95% CI: 0.880–0.992), and modified Glasgow Prognostic Score ([mGPS] AUC: 0.727, 95% CI: 0.600–0.854) had the highest area under curve values. Multivariable regression revealed that longer chemotherapy duration (≥2 weeks), an mGPS score of two points, and high MPM-II (≥36 points) were independently associated with mortality. Conclusion: Among the inflammatory markers and scores examined, mGPS and MPM-II were found to be independently associated with mortality in breast cancer patients who were hospitalized in the intensive care unit. In addition, patients with longer chemotherapy duration had a higher risk of mortality, but this result was limited by various possible confounders.

205 SGLT-2 INHIBITOR DAPAGLIFLOZIN REDUCES ANTHRACYCLINE-MEDIATED CARDIOMYOPATHY IN PRECLINICAL MODELS THROUGH REDUCTION OF MYOCARDIAL NF-KB, MYD-88 AND NLRP3 EXPRESSION: A BIOCHEMICAL AND HISTOLOGICAL 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. 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.

PCR268 The Impact of Radiotherapy Non-Compliance on the Recurrence and Mortality of Breast Cancer Patients: A Systematic Review

PCR268 The Impact of Radiotherapy Non-Compliance on the Recurrence and Mortality of Breast Cancer Patients: A Systematic Review

Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients: A Five-Year Retrospective Study in 10 Centers.

Cardiotoxicity as a result of anthracycline chemotherapy has been linked to increased morbidity and mortality in breast cancer patients. There is a need for early detection through risk factor identification. To date, no large multicenter study has been conducted to describe the incidence, risk factors and clinical and demographic profiles of breast cancer patients with anthracycline-induced cardiotoxicity (AIC) in the Philippines. This was a nationwide multicenter retrospective cohort study among adult breast cancer patients who underwent anthracycline chemotherapy from 2015 to 2020 in 10 sites in the Philippines. Baseline characteristics and possible risk factors for AIC were retrieved from medical records and cancer registries. AIC was defined as a reduction of left ventricular ejection fraction (LVEF) by > 10% from baseline to a value of < 53% or the development of overt left ventricular systolic dysfunction or heart failure (HF). Odds ratios from logistic regression were computed to determine risk factors associated with AIC using STATA-15.0 software. Out of 341 patients included, 33 had AIC, accounting for an incidence of 9.68%. Nine patients (2.6%) had clinical HF. AIC patients had a mean age of 53.91 ± 10.84 years. Breast cancer AIC patients were significantly older and had lower body mass index (BMI) than those without AIC. AIC patients had significantly more comorbidities, especially hypertension and atrial fibrillation. Multivariate analysis showed that patients with any preexisting comorbidity are approximately 12.37 times as likely to have AIC, while those with concurrent chemotherapy are 0.07 times or 93% less likely to have AIC. Among adult breast cancer patients undergoing anthracycline chemotherapy, we determined a high incidence of cardiotoxicity at 9.68%. Having preexisting comorbidities gave patients 12 times increased odds of developing anthracycline cardiotoxicity. The presence of concurrent non-anthracycline chemotherapy showed an inverse association with the development of AIC which we attribute largely to patient selection in a retrospective study. The significantly higher propensity for AIC development in patients with preexisting comorbidities may warrant closer monitoring and control of patient comorbidities such as hypertension among patients undergoing anthracycline chemotherapy.

Abstract 10603: Dapagliflozin Increases Ampk, Reduces Fibrosis/Hypertrophy and Nlrp-3, Il-6 and Galectin-3 Levels in Short-Term Doxorubicin-Treated Mice Improving Cardiac Function

Introduction: 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. Hypothesis: 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&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&lt;0.005). Hystology evaluation indicate reduction in hypertrophy, fibrosis and cardiac necrosis in DOXO-DAPA vs DOXO. Conclusions: 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 12402: Sacubitril-Valsartan Increases Pampk and Reduces Inflammasome, Myddosome, Il-6 and Galectin-3 Levels in Short-Term Doxorubicin-Treated Mice Improving Longitudinal Strain and Ejection Fraction

Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. Hypothesis: We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function 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), LCZ-696 at 60 mg/kg (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, 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: LCZ 696 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-LCZ group compared to DOXO mice (p&lt;0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in LCZ-696-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 LCZ-696-DOXO group vs DOXO (p&lt;0.005). Conclusions: LCZ-696 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 Sacubitril-valsartan in prevention of cardiomyopathies induced by anthracyclines in cancer patients.

Sacubitril-valsartan activates pAMPK and reduces NLRP3, MyD88, cytokines/growth factors and DAMPs in doxorubicin-treated mice improving longitudinal strain and ejection fraction

Abstract Background Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. Purpose We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function 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), LCZ-696 at 60 mg/kg (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, 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 LCZ 696 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-LCZ 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 LCZ-696 indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in LCZ-696-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 LCZ-696-DOXO group vs DOXO (p&amp;lt;0.005). Conclusion In this preclinical study, LCZ-696 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 Sacubitril-valsartan in prevention of cardiomyopathies induced by anthracyclines in cancer patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Ricerca Corrente, Ministero della Salute

Cav2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization

Distant metastasis is the main cause of mortality in breast cancer patients. Using the breast cancer genomic data from The Cancer Genome Atlas (TCGA), we identified brain specific Cav2.2 as a critical regulator of metastasis. Cav2.2 expression is significantly upregulated in breast cancer and its higher expression is inversely correlated with survival suggesting a previously unappreciated role of Cav2.2 in breast cancer. Cav2.2 is required for breast cancer migration, invasion, and metastasis. Interestingly, Cav2.2 promotes invadopodia formation and extracellular matrix (ECM) degradation through the stabilization of invadopodia component cortactin in a proteosome-dependent manner. Moreover, deubiquitinating enzyme USP43 mediated the functions of Cav2.2 in cortactin stabilization, invadopodia formation, ECM degradation, and metastasis. Interestingly, Cav2.2 upregulates USP43 expression through NFAT2 dephosphorylation and nuclear localization. Our study uncovered a novel pathway that regulates cortactin expression and invadopodia formation in breast cancer metastasis.

DIRAS3, GPR171 and RAC2 were identified as the key molecular patterns associated with brain metastasis of breast cancer.

ObjectiveBrain metastasis is a primary cause of morbidity and mortality in breast cancer patients. Therefore, elucidation and understanding of the underlying mechanisms are essential for the development of new therapeutic strategies.MethodsDifferential gene analysis was performed for those with and without distant metastasis in The Cancer Genome Atlas (TCGA) database and those with and without recurrence in the brain in the dataset GSE12276. The differentially expressed genes procured from the two databases were intersected to obtain the intersecting genes associated with brain metastasis. Thereafter, the intersecting genes were subjected to LASSO model construction to screen for prognostic genes. The expression of the obtained genes in metastatic breast cancer was observed, and survival analysis was performed. Finally, GSEA analysis of the obtained genes was performed, and the relationship between them and immune cells was explored.ResultsA total of 335 differential genes for the occurrence of distant metastases were obtained based on the TCGA database. A total of 1070 differential genes for recurrence to the brain were obtained based on the dataset GSE12276. The Venn diagram showed 24 intersecting genes associated with brain metastasis. The LASSO prognostic model contained a total of five genes (GBP2, GPR171, DIRAS3, RAC2, and CACNA1D). Expression difference analysis showed that GBP2, GPR171, DIRAS3, and RAC2 were significantly down-regulated in expression in metastatic breast cancer compared with primary breast cancer tumors. Only GPR171, DIRAS3, and RAC2 were strongly correlated with the overall survival of breast cancer patients. Their correlation analysis with immune cells showed that the correlation coefficient between the expression levels of DIRAS3 and immune cells was low, and the expression levels of GPR171 and RAC2 were more closely correlated with B cells and macrophages.ConclusionsThe expression of DIRAS3, GPR171 and RAC2, genes associated with brain metastasis, was reduced in metastatic breast cancer, and GPR171 was found to promote brain metastasis of breast cancer cells by inducing B cells and thereby.

14P Sacubitril-valsartan increases pAMPK and reduces NLRP3, MyD88, interleukin-6 and galectin-3 in short-term doxorubicin-treated mice improving longitudinal strain and ejection fraction

Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function.

Mitigating Breast Cancer Disparities by Addressing the Obesity Epidemic.

Purpose of ReviewObese breast cancer patients have poorer outcomes compared to non-obese patients. The intent of this review is to discuss recent studies and analyses regarding the status of the obesity epidemic and its effect on breast cancer incidence and outcomes. Subsequently, we will introduce a program implemented at a New York City hospital to reduce the morbidity and mortality of breast cancer patients with obesity.Recent FindingsThe prevalence of obesity among adult Americans is 42%, spanning all racial and socioeconomic groups. Importantly, obesity is associated with multiple chronic diseases including cancer. Among breast cancer patients, obesity is linked to higher mortality and poorer clinical outcomes, including but not limited to distant recurrence and secondary malignancies.SummaryCurrent treatment of breast cancer patients does not address the link between obesity and poorer prognosis. Here, we present a general strategy for reducing the morbidity and mortality of obese breast cancer patients by addressing the obesity epidemic.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12609-022-00460-4.

Cancer-specific mortality in breast cancer patients with hypothyroidism: a UK population-based study

PurposeEpidemiological studies have indicated a higher prevalence of hypothyroidism in breast cancer patients, possibly related to shared risk factors and breast cancer treatments. However, few studies have evaluated how hypothyroidism impacts survival outcomes in breast cancer patients. We aimed to determine the association between hypothyroidism and breast cancer-specific and all-cause mortality.MethodsWe conducted a population-based study using the Scottish Cancer Registry to identify women diagnosed with breast cancer between 2010 and 2017. A matched comparison cohort of breast cancer-free women was also identified. Using hospital diagnoses and dispensed prescriptions for levothyroxine, we identified hypothyroidism diagnosed before and after breast cancer diagnosis and determined associations with breast cancer-specific and all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for potential confounders.ResultsA total of 33,500 breast cancer patients were identified, of which 3,802 had hypothyroidism before breast cancer diagnosis and 565 patients went on to develop hypothyroidism after. Breast cancer patients had higher rates of hypothyroidism compared with cancer-free controls (HR 1.14, 95% CI 1.01–1.30). Among breast cancer patients, we found no association between hypothyroidism (diagnosed before or after) and cancer-specific mortality (before: HR 0.99, 95% CI 0.88–1.12, after: HR 0.97, 95% CI 0.63–1.49). Similar associations were seen for all-cause mortality.ConclusionIn a large contemporary breast cancer cohort, there was little evidence that hypothyroidism, either at diagnosis or diagnosed after breast cancer, was associated with cancer-specific or all-cause mortality.