Understanding cardiac events in breast cancer (UCARE): pilot cardio-oncology assessment and surveillance pathway for breast cancer patients.

PURPOSE: In Ireland, over 3000 patients are diagnosed with breast cancer annually, and 1 in 9 Irish women will be diagnosed with breast cancer in their lifetime. There is evidence that female breast cancer survivors are more likely to die of cardiovascular disease than their age-matched counterparts. Specific services for cancer patients suffering from cancer therapy related cardiovascular toxicity have led to a higher incidence of safe anti-cancer treatment completion. Such services are not widely available in our jurisdiction, and the purpose of this trial is to remedy this situation. METHODS: This protocol describes a prospective, single arm, pilot feasibility study implementing a dedicated Cardio-Oncology assessment and surveillance pathway for patients receiving multimodal breast cancer treatment. It incorporates novel biomarker and radiomic surveillance and monitoring approaches for cancer-therapy related cardiac dysfunction into routine care for breast cancer patients undergoing adjuvant systemic chemotherapy. RESULTS: Declaration of results will via peer reviewed academic journals, and communicated directly to key knowledge users both nationally and internationally. This engagement will be critical to enable to healthcare services and policy sector make informed decisions or valuable changes to clinical practice, expenditure and/or systems development to support specialized Cardio-Oncology clinical pathways. All data is to be made available upon request. CONCLUSION: Dedicated cardio-oncology services have been recommended in recent literature to improve patient outcomes. Our protocol describes a feasibility study into the provision of such services for breast cancer.

Sodium-Glucose Cotransporter 2 Inhibitors During Cancer Therapy: Benefits, Risks, and Ongoing Clinical Trials.

PURPOSE OF REVIEW: The goal of this paper is to summarize the data pertaining to the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) for the prevention of cardiotoxicity in patients receiving anthracyclines for cancer treatment. We discuss the potential efficacy of this class of medications, incorporating insights from existing literature and ongoing studies. RECENT FINDINGS: SGLT2i are a class of medications which were initially developed for treatment of Type 2 diabetes and later extended to treat heart failure with reduced and preserved ejection fraction regardless of diabetes status. There remains a need for effective and safe treatments to preventing cardiotoxicity in anthracycline-treated patients. It has been proposed that SGLT2i may provide protection against the cardiotoxic effects of anthracyclines. Some of the proposed mechanisms include beneficial metabolic, neurohormonal, and hemodynamic effects, renal protection, as well as a decrease in inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ion homeostasis. There is emerging evidence from basic science and observational studies that SGLT2i may play a role in the prevention of chemotherapy-induced cardiotoxicity. Randomized controlled trials are needed to conclusively determine the role of SGLT2 inhibitors as a cardioprotective therapy in patients receiving anthracyclines for the treatment of cancer.

Are Sodium-Glucose Cotransporter-2 Inhibitors the Cherry on Top of Cardio-Oncology Care?

The increasing aging of the population combined with improvements in cancer detection and care has significantly improved the survival and quality of life of cancer patients. These benefits are hampered by the increase of cardiovascular diseases being heart failure the most frequent manifestation of cardiotoxicity and becoming the major cause of morbidity and mortality among cancer survivor. Current strategies to prevent cardiotoxicity involves different approaches such as optimal management of CV risk factors, use of statins and/or neurohormonal medications, and, in some cases, even the use of chelating agents. As a class, SGLT2-i have revolutionized the therapeutic horizon of HF patients independently of their ejection fraction or glycemic status. There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.

Assessment of cancer therapy-related cardiac dysfunction in breast cancer women using a new speckle tracking echocardiography index: The GAVS.

BACKGROUND: Recently, peak atrial longitudinal strain (PALS) has emerged as a possible predictor of Cancer therapy-related cardiac dysfunction (CTRCD) in cancer patients (CP), in addition to left ventricular global longitudinal strain (GLS). Thus, considering the link between left atrium and left ventricle, the aim of this study was to assess the global atrio-ventricular strain (GAVS) in CP, to detect early cardiotoxicity. METHODS: A prospective study was carried out enrolling 131 breast cancer women (mean age 51.4 ± 10.4 years) receiving anti-cancer treatment. Clinical and echocardiographic evaluation was performed at baseline (T0), 3 (T1), 6 (T2) and 12 months (T3) after starting treatment. CTRCD was defined according to the 2022 ESC Cardio-Oncology guidelines. RESULTS: Forty-four patients developed CTRCD (3 moderate and 41 mild CTRCD group A) and 87 patients did not (group B). In group A, significant changes in GLS, PALS, GAVS, LASi (left atrial stiffness index) and LVEF/GLS occurred earlier than LVEF, that reduced significantly only at T3 (p-value < .05). Significant changes in LASi, PALS and GAVS occurred even in group B but reduction in GAVS (-21% vs. -5%) and PALS (-24% vs. -12%) was significantly greater in group A compared to group B (p-value = .04). CONCLUSIONS: Our study confirms high sensitivity of speckle tracking echocardiography in detecting subclinical myocardial damage in CP and the usefulness of a multiparametric echocardiographic evaluation including PALS and GLS (GAVS) for having a global evaluation of the phenomenon cardiotoxicity.

Prophylaxis to Prevent Cardiotoxicity in Patients Receiving Anthracycline for Breast Cancer: A Combined Bayesian and Frequentist Network Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: The benefits in survivorship gained with anthracycline (ANT)-based chemotherapies for breast cancer are unfortunately mitigated for some patients by irreversible cardiotoxicity. Randomised controlled trials (RCTs) have explored multiple cardioprotection options, however, it remains unclear which drug is most effective in preserving left ventricular ejection fraction (LVEF). This study aimed to perform a systematic review and network meta-analysis, using Bayesian and frequentist approaches, of RCTs evaluating cardioprotective agents. METHODS: Two authors searched four databases (CENTRAL, Cochrane Reviews, MEDLINE, SCOPUS), to find RCTs evaluating cardioprotective agents. Trial populations were limited to patients with breast cancer without prior ANT exposure. The primary outcome was mean LVEF change pre and post ANT dosing. Our primary analysis utilised a Bayesian approach, while our sensitivity analysis used frequentist methodology (Prospero registration number CRD42020199580). RESULTS: From 4,007 search results, we identified 12 RCTs, with their various trial arms considered separately-nine beta-blocker (BB), two angiotensin-converting enzyme inhibitor /angiotensin receptor blockers [(AA)+BB=AABB], one AA, one spironolactone, one statin-evaluating 1,126 patients (age 50.5 years). Bayesian network meta-analysis showed no difference in LVEF preservation between AA (1.3%, 95% credible interval [-0.20, 2.9]), BB (0.77, [-0.21, 1.8]), AABB (0.84 [-1.1, 2.8]), spironolactone (0.72, [-2.3, 3.7]) or statin (0.60, [-2.4, 3.6]) when compared against placebo. However, the frequentist analysis showed benefits from using AA (mean difference, 1.32% [0.32, 2.33]) and BB (mean difference, 0.76% [0.12, 1.4]). CONCLUSIONS: There is insufficient evidence to support prophylactic cardioprotection to prevent EF reduction. However, frequentist analysis suggested that AA or BBs provide cardioprotection. Thus, for those already on other anti-hypertensives, switching to AA or BBs could be considered.

The Role of Multimodality Cardiac Imaging in Patients Undergoing Cancer Treatment.

PURPOSE OF REVIEW: Modern therapeutics have led to improved survival for many types of cancer but have also been associated with adverse effects including potentially life-threatening cardiotoxicities. We sought to review the uses of multimodality cardiac imaging for risk stratification, prevention, and identification of cardiotoxicities in patients undergoing cancer treatment. RECENT FINDINGS: Advancements in both echocardiography and emerging modalities, like cardiac magnetic resonance imaging and cardiac computed tomography, continue to improve the pre- and during therapy cardiac evaluation of cancer patients. Echocardiography and cardiac magnetic resonance imaging, with the incorporation of global longitudinal strain, can identify overt and subclinical cancer therapy-related cardiac dysfunction and myocarditis, and stress echocardiography and cardiac computed tomography can noninvasively screen and monitor for coronary artery disease. Multimodality cardiac imaging is an evolving and critical tool for the pre-therapy screening and risk stratification, as well as during therapy surveillance of cancer treatment-related cardiotoxicity.

Advancing The Cardiovascular Care in Cancer Patients on Chemotherapy.

Cardiotoxicity associated with chemotherapy, also known as Cancer Therapy-Related Cardiac Dysfunction (CTRCD), affects 10% of patients undergoing chemotherapy and is the most undesirable side effect of chemotherapy. Over time, it is anticipated that there would be an increase in the number of cancer patients receiving treatments that could harm their cardiovascular systems. Physicians should choose whether to continue, halt, delay, or reduce the dose of chemotherapeutic drugs to reduce the impact of cardiotoxicity. Cardiotoxicity screening and diagnosis need a variety of methods, primarily echocardiography to evaluate Left Ventricular Ejection Fraction (LVEF) and Global Longitudinal Strain (GLS). Depending on the clinical state, these procedures may be carried out prior to, during, or following chemotherapy. It's critical to reduce cardiovascular risk factors and offer advice on leading a healthy lifestyle before giving cancer patients medicines. There are a lot of cancer treatment facilities all around the world that don't have evidence-based perspective cardiotoxicity scores to stratify the risk of cardiovascular problems caused by cancer therapy. Additionally, comorbid conditions like diabetes and hypertension are frequently present in cancer patients, which can have a significant impact on clinical outcomes and cancer treatment. Therefore, this article aims to discuss assessment methods, clinical practice guidance, and prevention of CTRCD.

Advanced Echocardiographic Techniques in Cardio-Oncology: the Role for Early Detection of Cardiotoxicity.

PURPOSE OF REVIEW: Implementation of advanced echocardiographic techniques in cardio-oncology is a growing need as they are the cornerstone of early detection of cancer therapy-related cardiovascular toxicity (CTR-CVT). RECENT FINDINGS: Three-dimensional echocardiography and myocardial deformation techniques have shown more accuracy and reproducibility than classic 2D measurements in detecting cardiovascular adverse effects in patients undergoing anticancer therapies. Application of advanced echo techniques to daily monitoring of patients with cancer helps to identify those at risk of developing CTR-CVT during and after cancer treatment. Furthermore, advanced echo parameters improve early initiation of cardioprotective treatments in order to minimize cardiovascular events and cancer treatment interruption.

Potential Role of Neutrophil Extracellular Traps in Cardio-Oncology.

Cardiovascular toxicity has emerged as the leading cause of death in patients undergoing cancer treatment. Thus, cardio-oncology (CO) care must also focus on the prevention and management of related cardiovascular (CV) complications caused by cancer therapy. Neutrophil extracellular traps (NETs)-entities with released DNA, proteases, proinflammatory and prooxidative substances from blasted neutrophils-play an important role in cancer proliferation, propagation metastasis, and incident CV events (acute coronary syndrome, thromboembolic events, and heart failure). Although NETs have been shown to be involved in cancer progression and incident CV events, little is known about their relationship with cardio-oncology, especially on cancer treatment-related cardiovascular toxicity (CTRCT). This review aims to explore the evidence of the impact of NETs on cancer, CV events, and CTRCT, and the possible solutions based on the mechanism of NETs activation and NETs released toxic substances.

Cardiovascular Complications Associated with Contemporary Lung Cancer Treatments.

OPINION STATEMENT: Lung cancer is the most common form of cancer in humans and the leading cause of cancer-related death worldwide. Traditionally, lung cancer has been diagnosed as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). However, recent developments in molecular pathology have revolutionized the diagnosis and treatment of the disease, thus improving patient prognosis and increasing the number of survivors. In advanced NSCLC cases, molecularly targeted drugs for patients with positive driver gene mutation/rearrangement, and immune checkpoint inhibitors for those with a positive biomarker, have changed the standard of care. SCLC is a highly malignant entity. In addition to the chemotherapy and radiotherapy, immune checkpoint inhibitors have recently provided some hope for extended-stage SCLC. Smoking cessation is related to decreased morbidity. However, early metastasis remains a significant challenge. Recently, cancer therapy-related cardiovascular disease (CTRCD) has emerged as diverse pathophysiology, including fulminant myocarditis, fatal arrhythmia, pericarditis, hypertension, and thrombosis, that emerged with modern lung cancer therapies. Cardio-oncology is a new interdisciplinary collaboration to develop methodologies to manage cardiovascular risk factors and CTRCDs with the common goal of minimizing unnecessary interruption of cancer treatment and maximizing outcomes of lung cancer survivors.

Erlotinib-Induced Cardiomyopathy in a Patient with Metastatic Non-Small Cell Lung Cancer.

Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is a targeted drug used for the treatment of non-small cell lung cancer (NSCLC). Erlotinib is considered relatively safe and generally well-tolerated, with rarely reported cardiac side effects. Herein, we report a case of cardiomyopathy that developed during erlotinib treatment for NSCLC. Two months after erlotinib initiation, our 70 year-old female patient complained of progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating erlotinib-induced cardiomyopathy. We believed that continued administration of erlotinib would exacerbate her heart failure, while treatment of the heart failure with intensive monitoring would allow the administration of erlotinib to be continued. This case report highlights the potential cardiotoxic effects of erlotinib and suggests the need for close clinical and echocardiographic follow-up of patients receiving erlotinib.

Cardio-toxicity among patients with sarcoma: a cardio-oncology registry.

BACKGROUND: Chemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracyclines (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutics related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (LVEF) reduction of > 10%, to a value below 53%. The aim of our study was to estimate the prevalence of CTRCD in patients diagnosed with sarcoma and to describe the baseline risk factors and echocardiography parameters among that population. METHODS: Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), enrolling all patients evaluated in the cardio-oncology clinic at our institution. The registry was approved by the local ethics committee and is registered in clinicaltrials.gov (Identifier: NCT02818517). All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. non-CTRCD group. RESULTS: Among 43 consecutive patients, 6 (14%) developed CTRCD. Baseline cardiac risk factors were more frequent among the non-CTRCD group. Elevated left ventricular end systolic diameter and reduced Global Longitudinal Strain were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the non-CTRCD group. CONCLUSIONS: CTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.

Acute and Chronic Effects of Cancer Drugs on the Cardiovascular System.

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.

Biomarkers in cancer therapy related cardiac dysfunction (CTRCD).

Biomarkers are at the cornerstone of preventive measures and contribute to the screening process. More recently, biomarkers have been used to gauge the biological response to the employed therapies. Since it is ubiquitously used to detect subclinical disease process, biomarkers also have found its place in cancer therapy related cardiac dysfunction (CTRCD). The aim of this review is to comprehensively present up-to-date knowledge of biomarkers in CTRCD and highlight some of the future biomedical technologies that may strengthen the screening process, and/or provide new insight in pathological mechanisms behind CTRCD.

Baseline Immunoglobulin E Levels as a Marker of Doxorubicin- and Trastuzumab-Associated Cardiac Dysfunction.

RATIONALE: There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD). OBJECTIVE: We aimed to discover new biomarkers associated with doxorubicin- and trastuzumab-induced CTRCD using high-throughput proteomic profiling. METHODS AND RESULTS: Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from 3 cases with CTRCD and 4 age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography-mass spectrometry. From these analyses, 862 proteins were identified from case/control pairs 1 and 2 and 1360 proteins from case/control pair 3. Proteins with a >1.5-fold change in cases compared with controls with a P<0.05 either at the time of CTRCD diagnosis or across all time points were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E, with higher levels detected at baseline and across all time points in controls without CTRCD as compared with matched CTRCD cases (P<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline immunoglobulin E levels were associated with a significantly lower risk of CTRCD (P=0.018). CONCLUSIONS: In patients receiving doxorubicin and trastuzumab, high baseline immunoglobulin E levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin- and trastuzumab-induced cardiac dysfunction.

Strategies for early detection of cardiotoxicities from anticancer therapy in adults: evolving imaging techniques and emerging serum biomarkers.

Significant advances have been made in detecting cancer therapeutics-related cardiac dysfunction with serum biomarkers, cardiovascular MRI, echocardiography and multi-modality approaches. Serum biomarkers, notably cardiac troponins and natriuretic peptides, have been evaluated for their prognostic ability in predicting left ventricular dysfunction. Imaging modalities, such as cardiovascular MRI and echocardiography, have been used for cardiac surveillance of patients with cancer undergoing chemotherapy. Developments in imaging, specifically myocardial deformation imaging, also known as strain, have been shown to be sensitive tools in detecting early changes in cardiac function. This review aims to synthesize the evidence that supports emerging serum biomarkers and complementary imaging modalities that continue to enhance the detection of cancer therapeutics-related cardiac dysfunction.

Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab.

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Extracellular volume measured by whole body CT scans predicts chronic cardiotoxicity in breast cancer patients treated with neoadjuvant therapies based on anthracyclines: A retrospective study.

INTRODUCTION: Neoadjuvant chemotherapies for breast cancer (BC) are effective but potentially cardiotoxic, and expose long survivors at risk of chemotherapy-related cardiac dysfunction (CTRCD). Unfortunately, early screening for CTRCD has actual diagnostic limits. Myocardial extracellular volume (mECV) is a radiological marker used in cardiac CT scans and cardiac magnetic resonance for diagnosis and follow-up of CTRCD. It can be measured in whole-body CT (WB-CT) scan, routinely performed in patients at high risk of relapse, to evaluate CTRCD occurrence during oncological follow-up. METHODS: 82 WB-CT scans were examined at baseline (T0) and during oncological follow-up at first year (T1) and fifth year (T5) after the end of neoadjuvant treatment. mECV was measured at 1 min (PP) and 5 min (DP) after contrast injection. 31 echocardiograms were retrieved in T1 to perform a linear correlation between mECV and left ventricular ejection fraction (LVEF). RESULTS: mECV values in T0 were similar between the two groups both in PP and in DP. Significant results were found for PP values in T1 (37.0 % vs 32 %, p = 0.0005) and in T5 (27.2 % vs 31.2 %, p = 0.025). A cut-off value of 35 % in PP proved significant in T1 (OR = 12.4, p = 0.004), while mECV was inversely correlated with LVEF both in PP (adj-S = -3.54, adj-p = 0.002) and in DP (adj-S = -2.51, adj-p = 0.0002), suggesting a synergistic action with the age at diagnosis (p < 0.0001, respectively). CONCLUSIONS: WB-CT scans performed during oncological reassessment in patients at high-risk of recurrence could be used for CTRCD screening in cardiovascular low-risk patients, especially in aging patients with mECV values above 35 %.

Hypothesis paper: GDF15 demonstrated promising potential in Cancer diagnosis and correlated with cardiac biomarkers.

BACKGROUND: Cardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction). METHODS: Analysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG). RESULTS: GDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort. CONCLUSION: GDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.