Anthracycline Treatment Research Articles

Evaluating high-sensitivity cardiac troponin I for early detection of treatment-related cardiotoxicity in HER2-positive breast cancer patients

Background: Trastuzumab-related cardiotoxicity is a common adverse effect of HER2-positive breast cancer treatment, especially when combined with anthracyclines. However, to date, no definitive prognostic markers have been found to predict trastuzumab-related cardiotoxicity. Methods: Patients diagnosed with HER2-positive breast cancer, scheduled to receive anthracyclines followed by 12 months of trastuzumab or with pertuzumab, were prospectively followed up for 27 months. Measurements of left ventricular ejection fraction LVEF, high-sesitivity troponin I hs-Tn I, and a full cardiac examination were performed at baseline, after anthracycline treatment, and after four cycles of anti-HER2 agents. Subsequently, LVEF measurement and full cardiac examination were conducted every 3 months until the end of the follow-up. Cardiotoxicity was defined as an absolute decrease in LVEF of ≥15%, or a drop in LVEF of ≥10% from the baseline to <50%. Results: Among 78 patients, cardiotoxicity occurred in 13 (16.7%). A higher risk of cardiotoxicity was linked to hs-Tn I measured after four cycles of anti-HER2 agents (P < 0.001), with a significant cutoff of >84 ng/L. No short-term effects of the anthracycline agents (doxorubicin or epirubicin), were found. However, there was a slightly higher tendency to develop cardiotoxicity (P = 0.046) in patients treated with trastuzumab plus pertuzumab. Conclusion: Hs-Tn I measured after four cycles of trastuzumab in HER2-positive breast cancer patients could be an important predictor of cardiotoxicity induced by chemotherapy followed by anti-HER2 agents, particularly in the first year post-treatment, with a different cutoff value than that used in other cardiac conditions.

Development of cancer therapy-related cardiac dysfunction in anthracycline-treated breast cancer patients: a retrospective study

PurposeCardiac dysfunction as a result of anthracycline treatment is a major concern regarding the management of patient life after therapy. The aim of the present study was to determine the clinical characteristics of cancer patients at high risk of developing cancer therapy-related cardiac dysfunction (CTRCD), in order to improve the risk management for the appropriate treatment.MethodsThis is a single-center, retrospective study of patients with breast cancer who underwent anthracycline treatment and had regular consultations with cardiologists. To investigate the incidence of CTRCD and the risk factors related to its occurrence, left ventricular ejection fraction (LVEF), cardiac troponin I (TnI), and brain natriuretic peptide (BNP) were assessed in 177 patients at the start of anthracycline treatment, and again at 3, 6, 9, and 12 months.ResultsEight patients (4.5%) developed CTRCD (CTRCD group). The comparisons between the CTRCD group and those without CTRCD (non-CTRCD group) showed significant differences in pre-treatment cancer stage and neutrophil/lymphocyte ratio (NLR). Multivariate analysis showed a strong association between pre-treatment cancer stage, NLR, and type of anthracycline administered (epirubicin or doxorubicin).ConclusionHigh NLR, the more advanced stages of cancer, and doxorubicin administration were suggested as possible risk factors for the development of CTRCD. Special attention should be warranted for patients with any of these risk factors.

Abstract 4118086: Doxorubicin Induces a Cytotoxic T-cell Inflammatory Response That Contributes to Cardiac Fibrosis and Systolic Dysfunction

Background: Doxorubicin (DR), the most commonly used chemotherapy, results in dose-dependent cardiotoxicity in part by causing oxidative stress, cardiomyocyte death, and cardiac fibrosis. Whether these elicit a cardiac immune response that contributes to DR cardiomyopathy and could be targeted for cardio-protection is unknown. We hypothesized that an aberrant T-cell immune response secondary to cardiac damage contributes to DR cardiomyopathy. Methods: We treated wild type (WT) mice and CD8 + T-cell antigen restricted OTI mice with 5.0 mg/kg of DR or PBS weekly for 4 or 8 weeks and performed targeted antibody depletion of CD8 + and CD4 + T-cells. Primary mouse T-cells and cardiac fibroblasts (CFB) were used for mechanistic studies. Whole blood was analyzed by flow cytometry and proteomics in human and canine lymphoma patients before and after DR initiation. Results: DR treated mice exhibited cardiac CD8 + T-cell infiltration alongside hallmarks of DR cardiomyopathy, including declined ejection fraction (EF) measured by echocardiography, cardiac cell death, and fibrosis determined by TUNEL and picrosirius red stain. Cardiac CD8 + T-cells co-localized with αSMA + CFB and had enhanced expression of the degranulation marker CD107a and IFNγ in DR compared to PBS treated mice. DR hearts also showed increased gene and protein expression of the IFNγ inducible chemokines Cxcl9 and Cxcl10 . DR resulted in increased circulating CD8 + T-cells and the frequency of activated CD8 + cells in the cardiac draining lymph nodes. Targeted antibody depletion of CD8 + but not CD4 + T-cells in the onset of DR treatment improved EF and decreased cardiac fibrosis. OTI mice were protected from DR induced EF decline, cardiac T-cell infiltration, and cardiac fibrosis, indicating an antigen-specific CD8 + T-cell response . Mechanistically, DR induced ICAM-1 expression on CFB and ICAM-1 dependent adhesion of activated CD8 + T-cells, which in turn increased CFB αSMA expression. Contact between CD8 + T-cells and DR-treated CFB caused CD8 + T-cell degranulation and Granzyme B release that contributed to CFB activation. Human and canine cancer patients followed longitudinally had increased circulating CD8 + T-cells after anthracycline treatment, and human plasma levels of CXCL9/CXCL10 correlated with decreased EF post DR. Conclusion: Our data demonstrate a novel role for cytotoxic T-cells in DR cardiomyopathy across 3 species, through CXCL9/10-dependent cardiotropism and CD8 + T-cell dependent fibrosis.

Accuracy of mitral annular plane systolic excursion in diagnosing anthracycline-induced subclinical cardiotoxicity in patients with breast cancer - a retrospective cohort study

BackgroundThe mitral annular plane systolic excursion (MAPSE) is used to analyze the left ventricle longitudinal function. However, the accuracy of MAPSE in diagnosing oncological populations is unclear. In this study, we aimed to assess the accuracy of MAPSE in diagnosing subclinical cardiotoxicity in women with breast cancer undergoing anthracycline treatment.MethodsThis retrospective cohort study included echocardiographic assessments of patients with breast cancer who underwent anthracycline treatment as part of their therapeutic regimen. Assessments were performed before treatment, after administering the first dose of anthracycline, after completing anthracycline treatment, and 6 and 12 months after treatment. Left ventricular ejection fraction was calculated using the modified biplane Simpson method. The performances of MAPSE and global longitudinal strain (GLS) were analyzed using receiver operating characteristic (ROC) curves. Their accuracies were measured using the area under the ROC curves.ResultsSixty-one patients were included in this study. Of them, 8.2% presented cardiotoxicity 6 months after treatment completion. Patients with cardiotoxicity had lower LVEF (47% vs. 63%; p < 0.001), MAPSE (10.23 mm vs. 12.25 mm; p = 0.012), and LV GLS (16.13% vs. 19.05%; p = 0.005) values than those without. A 12% reduction in the GLS exhibited sensitivity, specificity, and overall accuracy of 80%, 70%, and 78%, respectively. A relative reduction of 15% in MAPSE exhibited a sensitivity, specificity, and accuracy of 80%, 77%, and 81.2%, respectively. An absolute MAPSE reduction of 2 mm exhibited a sensitivity, specificity, and accuracy of 80%, 73.21%, and 81.2%, respectively. No differences were observed between the ROC curves.ConclusionMAPSE showed similar accuracy to GLS in diagnosing subclinical cardiotoxicity in women with breast cancer undergoing anthracycline treatment.

Sodium-Glucose Cotransporter 2 Inhibitors, Malnutrition, Cachexia, and Survival in Patients With Heart Failure With a History of Anthracycline Treatment.

Patients undergoing anthracycline-based cancer treatments have an increased risk of heart failure or worsening preexisting heart failure as well as adverse metabolic outcomes such as malnutrition and cachexia. This retrospective study explored the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on these outcomes in patients with heart failure previously treated with anthracyclines. Using the TriNetX research network, we identified 1545 patients with a history of SGLT2i use and 17,681 patients without a history of SGLT2i use. We then performed 1:1 propensity score matching resulting in 1323 patients within each cohort. Patients were analyzed over a 5-year period. SGLT2i use was associated with significantly reduced risks of cachexia {hazard ratio (HR) 0.453, 95% confidence interval (CI) [0.286-0.718]}, malnutrition (HR 0.702, 95% CI [0.547-0.900]), adult failure to thrive (HR 0.489, 95% CI [0.345-0.693]), and all-cause mortality (HR 0.490, 95% CI [0.423-0.568]). These findings call for additional research to determine whether SGLT2i may indeed improve nutritional status and survival in patients with heart failure receiving anthracycline therapy.

Assessment of right ventricular dysfunction in breast cancer patients undergoing anthracycline and trastuzumab treatment

Abstract Background Anthracyclines and trastuzumab continue to be within the most popular systemic agents used in breast cancer treatment. Nonetheless, their cardiotoxic effects contribute to significant morbidity and mortality, which have been extensively studied and acknowledged. Left ventricular impairment and remodeling due to chemo- and target-therapy induced cardiotoxicity has been well described. However, effects on right ventricular function have not been fully elucidated and are incompletely understood. Purpose We aim to comprehensively assess right ventricular function in breast cancer patients before and during treatment with anthracyclines and trastuzumab. Methods We prospectively evaluated echocardiographic right ventricle (RV) parameters in 160 women (median age 48, IQR 43.00 - 57.00) diagnosed with breast cancer undergoing treatment with doxorubicin, trastuzumab or its combination. These patients were referred to a national cardiac reference centre to assess cancer therapy related cardiovascular dysfunction (CTRCD) risk. Two-dimensional echocardiography with speckle tracking imaging of left ventricle (LV) and RV was performed at baseline, 3 and 6 months. Right ventricular function was assessed with tricuspid annular plane systolic excursion (TAPSE), S’wave of the tricuspid annulus (S'), fractional area change (FAC), and free wall strain (RV-FWS). We designed a composite variable of right ventricular dysfunction constituted by any decrease in systolic function as evidenced by standard cutoff values of TAPSE, FAC, S’wave and RV-FWS. Descriptive statistics were calculated. Categorical values were compared using either the Fisher’s exact test or Chi-squared test and differences between means were assessed with the Kruskal-Wallis test or the Wilcoxon test as appropriate. Results TAPSE and S’ were significantly reduced from baseline, at 3 and 6 months, respectively (TAPSE: 21.62 ± 2.22, 21.00 ± 1.83, 20.72 ± 1.99, P=&amp;lt;0.001; S’:12.16 ± 1.91, 11.70 ± 1.76, 11.51 ± 1.53, P = 0.012) (Table 1). There were no significant changes in right ventricular echocardiographic parameters comparing patients with and without CTRCD, nevertheless, a notable proportion in both groups was observed (see Table 2). Conclusions There is a progressive decline in right ventricular systolic function over treatment with anthracyclines and trastuzumab. Even though RV dysfunction does not significantly differ between patients with or without cardiotoxicity, the high proportion observed highlights the need for comprehensive echocardiographic assessments.

Validation of the HFA-ICOS risk assessment tool with real-world data from a prospective cohort of breast cancer patients in treatment with anthracyclines and trastuzumab

Abstract Background The increasing prevalence of cancer therapy-related cardiovascular toxicity (CTRCD) poses a significant challenge to patient management, necessitating accurate risk assessments. Previous methodologies have struggled with precise risk stratification, partly due to varying definitions of CTRCD and the specificity of cancer treatments. Purpose This study aimed to evaluate the assessment tool proposed by the Heart Failure Association and the International Cardio-Oncology Society (HFA-ICOS) in predicting the risk of CTRCD in patients undergoing anthracycline and trastuzumab treatment for breast cancer at a national reference center. Methods A prospective cohort study was conducted, encompassing 172 patients treated from January 2022 to July 2023. Patients were assessed at baseline, three months, and six months post-treatment initiation, with exclusion criteria including baseline left ventricular ejection fraction (LVEF) &amp;lt;50%, history of heart failure, and stage IV breast cancer. The study utilized the HFA-ICOS tool for risk stratification and CTRCD was defined with the current criteria of the European Society of Cardiology guideline. Descriptive statistics were calculated, and incidence rates and Cox proportional-hazards models were developed according to the risk category. Results In our study, 138 (80.2%) patients were classified as low risk, 23 (13.4%) as moderate risk and 11 (6.4%) as high risk. We identified 81 (47.1%) patients that developed CTRCD in follow-up. Descriptive characteristics can be found in Table 1. The global incidence rate for CTRCD in our cohort was of 2.4 new cases per 1000 person-days, however no differences in incidence rates were found when stratifying by risk category (Figure 1A). Moreover, patients with moderate to high risk according to the HFA-ICOS tool did not show a significantly increased hazard ratio for cardiotoxicity (HR 0.41, 95%CI 0.15-1.12, p=0.082 and HR 1.39, 95%CI 0.50-3.86, p=0.5, respectively) as shown in Figure 1B. Conclusion While the HFA-ICOS tool provides a structured framework for assessing cardiotoxicity risk, its predictive value in this cohort was limited. The findings underscore the complexity of cancer therapy-related cardiotoxicity and the need for enhanced, individualized risk assessment tools. Future research should focus on refining risk prediction models, incorporating broader clinical and genetic factors to improve patient outcomes in cardio-oncology.Table 1.Clinical CharacteristicsFigure 1.Incidence rates and Cox models

A study to assess the ability of the HFA-ICOS risk stratification tool to predict cancer therapy-related cardiac dysfunction for patients receiving anthracycline chemotherapy

Abstract Introduction The use of anthracycline chemotherapy is complicated by the risk of developing cancer therapy-related cardiac dysfunction (CTRCD). The Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) have jointly published a novel cardiovascular risk stratification tool for patients receiving anthracycline chemotherapy which categorises patients according to their risk of CTRCD (1). The risk tool has not yet been validated for use in the United Kingdom. Purpose In this study, we test the ability of the HFA-ICOS risk stratification tool to predict CTRCD for patients receiving anthracycline chemotherapy. Methods A retrospective study of patients ≥18 years who received anthracycline chemotherapy between January 2019 to January 2023 at two cardio-oncology centres in the United Kingdom. Patients were eligible if they had ≥1 follow up echocardiogram after the end of anthracycline treatment. Patients receiving HER-2 targeted therapies were excluded. Patients were classified into low/medium/high/very-high risk categories using the HFA/ICOS tool. The prevalence of CTRCD was assessed during the follow up period; a minimum of 6 months after the end of chemotherapy. Results 288 patients met eligibility criteria for the study. 59 patients (20%) were treated for leukaemia, 104 (36%) lymphoma, 63 (22%) sarcoma and 49 (17%) breast cancer. The mean age was 49±18yrs, with 56% females. The mean cumulative dose of doxorubicin (or equivalent) was 235±104mg/m2. Using the HFA/ICOS tool, 50% of patients were deemed low risk, 31% medium risk, 16% high risk and 3% very high risk at baseline. Using guideline recommended CTRCD definitions, there was an overall incidence of 9% of symptomatic CTRCD and 22% of asymptomatic CTRCD (Table 1). The incidence of symptomatic CTRCD significantly increased as the baseline risk of CTRCD increased. 20% of patients deemed high or very-high risk at baseline subsequently developed symptomatic CTRCD (Fig 1). Furthermore, patients at high or very-high risk were 4.4 times more likely to develop symptomatic CTRCD than patients who were low risk (OR 4.4, 95% CI 1.7-11.6, p=0.003). There was no association with baseline risk and the development of asymptomatic CTRCD. The incidence of mild asymptomatic CTRCD may be underestimated due to the lack of routine surveillance with cardiac biomarkers and left ventricular global longitudinal strain (LV GLS) imaging for asymptomatic disease during the study period. Conclusion The novel HFA/ICOS risk stratification tool is useful in predicting patients who will develop symptomatic CTRCD in a contemporary UK setting.

Sodium-glucose co-transporter-2 inhibitors : a potential cardioprotective agent?

Abstract Background Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are one of the cornerstones in the treatment of patients with heart failure (HF) , regardless the ejection fraction (EF) or the presence of diabetes mellitus (DM). Other types of medications used in the treatment of heart failure , like angiotensin converting enzyme inhibitors (ACEi) or beta-blockers (BB) have shown some degree of cardioprotection in high risk patients receiving cardiotoxic chemotherapy, but data on SGLT2i are very limited. Purpose To examine the possible differences in the development of anthracycline cardiotoxicity in diabetic patients receiving SGLT2i compared to those who don’t. Methods We retrospectively analysed the data from the oncological as well as hematological patients of our hospital. Group 1 (SGLT2) included patients with cancer who received anthracycline treatment and diabetes on treatment with SGLT2i. Group 2 (control) included patients with cancer who received anthracycline treatment and diabetes but with treatment other than SGLT2i. We recorded the basic demographic parameters, the development of cardiotoxicity (heart failure incidence, heart failure admissions, new cardiomyopathy [&amp;gt;10% decline in ejection fraction to &amp;lt;50%], and clinically significant arrhythmias) as well as the abnormal levels of troponin I (tnI) and natriuretic peptides (NTproBNP). Results Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. The mean duration of the follow up was 2 years. In the SLT2 group were included 86 patients and in the control group 97. The rates of the cardiotoxicity events were recorded as follow : (SGLT2 vs control) Heart failure (7.4% vs 31.9%, p&amp;lt;0.01), heart failure admissions (3.4% vs 12.3%, p&amp;lt;0.05), new cardiomyopathy (6.1% vs 27.2%, p&amp;lt;0.05), arrhythmias (2.7% vs 24.3%, p&amp;lt;0.01), abnormal tnI levels (4.2% vs 14.7% , p&amp;lt; 0.01), abnormal NTproBNP levels (6.4% vs 30.9%, p&amp;lt;0.01) Conclusions SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Further studies are needed in order to test the possible cardioprotective effects of SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis

Acute myeloid leukemia (AML) is a deadly hematopoietic malignancy. Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure. These refractory patients pose a treatment challenge, as they do not respond to salvage therapy or allogeneic stem cell transplant. Herein, we show that AML patients who experience induction failure have elevated expression of the NF-κB target gene tumor necrosis factor alpha-induced protein-3 (TNFAIP3/A20) and impaired necroptotic cell death. A20High AML are resistant to anthracyclines, while A20Low AML are sensitive. Loss of A20 in AML restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML. These findings suggest that NF-κB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML.

Knock-down of FOXO3, GATA2, NFE2L2 and AHR promotes doxorubicin-induced cardiotoxicity in human cardiomyocytes

Recent advances in cancer therapy have substantially increased survival rates among patients, yet the prolonged effect of current treatment regimens with anthracyclines (ACs) often include severe long-term complications, notably in the form of anthracycline-induced cardiotoxicity (AIC). Despite known associations between AC treatment and AIC, a comprehensive understanding of the underlying molecular pathways remains elusive. This gap is highlighted by the scarcity of reliable therapeutic interventions, with dexrazoxane being the sole FDA-approved drug to mitigate AIC risks. This study aims at elucidating the transcriptional response of human cardiomyocytes (hCMs) to AC exposure by analyzing a previously generated RNA-sequencing dataset of cardiac spheroids subjected to clinically relevant doses of ACs. The analysis revealed a robust transcriptional response identified across various time points. We aimed at identifying important transcription factors (TFs) mediating AIC by employing predictive algorithms to highlight key TFs for further experimental validation. Using shRNA constructs, we further assessed the impact of these TFs on hCM response to doxorubicin (DOX) and revealed that these TFs had a notable impact on hCM survival upon DOX exposure. TFs FOXO3, GATA2, AHR and NFE2L2 were further investigated for their role in AIC including cell viability, DOX uptake, DNA damage repair and induction of apoptosis through Cleaved-Caspase 3. Our study demonstrated that eliminating FOXO3 and GATA2 made hCMs more vulnerable to DOX and the lack of GATA2, NFE2L2 and AHR led to significantly higher intracellular levels of DOX. Additionally, FOXO3 played a role in the repair of hCM DNA damage as we observed markedly enhanced levels of CDKN1A. We also noted significant increases in DNA damage through COMET-assays when FOXO3, GATA2, NFE2L2 and AHR were absent. Furthermore, we investigated the clinical relevance by comparing our results with those from a study based on hiPSC-CMs derived from patients with doxorubicin-induced cardiotoxicity, identifying overlapping TFs and their regulatory roles in critical cellular processes like the cell cycle and DNA repair. This approach not only advances the understanding of the molecular mechanisms behind AIC but also opens possible windows for new therapeutic approaches to mitigate the negative side-effects from patient AC treatment.

Inflammation in Chemotherapy-Induced Cardiotoxicity.

In this review we describe the role of inflammation in chemotherapy-induced cardiotoxicity with a particular focus on anthracycline-induced cardiomyopathy (AIC). First, we discuss inflammation associated with anthracyclines at a cellular level. Next, we discuss the clinical implications of these inflammatory mechanisms for early detection and cardioprotective strategies in patients undergoing anthracycline treatment. Key inflammatory pathways identified in AIC include cytokine release, upregulation of the innate immune system via toll-like receptors, and activation of the inflammasome. Emerging evidence suggests a role for inflammatory biomarkers in detecting subclinical AIC. Advanced imaging techniques, such as cardiac PET with novel tracers targeting inflammation, may enhance early detection. Both traditional cardioprotective strategies and novel anti-inflammatory therapies show potential in preventing and treating AIC. Understanding the inflammatory mechanisms involved in AIC provides new opportunities for early detection and targeted cardioprotective strategies in patients undergoing anthracycline treatment and informs our understanding of other forms of chemotherapy-induced cardiotoxicity.

A-221 The effect of Anthracycline treatment on primary cutaneous T-cell lymphoma cells

A-221 The effect of Anthracycline treatment on primary cutaneous T-cell lymphoma cells

Previous Anthracycline Treatment For Breast Cancer Impairs Exercise-induced Improvement In Cardiorespiratory Fitness

Previous Anthracycline Treatment For Breast Cancer Impairs Exercise-induced Improvement In Cardiorespiratory Fitness

The additional value of myocardial T1ρ mapping to T1 and T2 mapping for predicting subsequent cancer therapy-related cardiac dysfunction in breast cancer patients who received anthracyclines with/without trastuzumab

ObjectivesWe aimed to describe changes in parameters derived from myocardial T1ρ, T1, and T2 mapping and assess whether incorporating T1ρ mapping improves the predictive performance of T1 and T2 mapping for subsequent cancer therapy-related cardiac dysfunction (CTRCD) in breast cancer patients treated with anthracyclines with/without trastuzumab. MethodsFrom March 2021 to May 2023, 82 participants with breast cancer treated with anthracyclines with/without trastuzumab were prospectively recruited. Cardiac magnetic resonance was performed at baseline, 3 and 6 months in relation to baseline. T1ρ, T1 and T2 values were measured and compared by repeated measures analyses of variance. Logistic regression and receiver operating characteristic analysis were used to assess the performance in predicting subsequent CTRCD. ResultsNineteen (23.17 %) participants developed CTRCD. T1ρ and T1 values progressively increased over time (all p < 0.001), while T2 values increased at 3 (p < 0.001 and p = 0.002, respectively) and 6 months (all p < 0.001) compared to baseline in both the CTRCD (+) and CTRCD (−) groups. The changes in T1ρ (OR, 3.892, p = 0.003) and T1 (OR, 1.082, p = 0.002) from baseline to 3 months were associated with subsequent CTRCD. The combination of the changes in T1ρ and T1 from baseline to 3 months obtained an improved area under the curve of 0.853. ConclusionT1ρ, T1 and T2 increased after treatment of anthracyclines with/without trastuzumab. Myocardial T1ρ mapping provides additional predictive value to T1 mapping for subsequent CTRCD in breast cancer patients who received anthracyclines with/without trastuzumab. Clinical relevance statementMyocardial T1ρ mapping offers additional predictive value to T1 and T2 mapping for subsequent CTRCD in breast cancer patients who received anthracyclines with/without trastuzumab. This may facilitate accurate prediction of cardiotoxicity and personalized treatment decision making in breast cancer.

From setbacks to success: building a promising path for strain-guided cardioprotection during anthracycline treatment.

From setbacks to success: building a promising path for strain-guided cardioprotection during anthracycline treatment.

Real-world efficacy, safety data and predictive clinical parameters for treatment outcomes in advanced soft tissue sarcoma treated with combined immunotherapy and antiangiogenic therapy

BackgroundThe combination of immunotherapy and antiangiogenic therapy has shown potential in the treatment of numerous malignant tumors, but limited evidence was available for soft tissue sarcomas (STS). Therefore, the aim of the present study is to assess the efficacy and safety of immunotherapy in conjunction with antiangiogenic therapy in patients diagnosed with advanced STS (aSTS).MethodsThe study enrolled patients with aSTS from January 2014 to October 2022. Eligible participants had previously received anthracycline-based chemotherapy, presented with an anthracycline-resistant sarcoma subtype, or were ineligible for anthracycline treatment due to medical conditions. Following enrollment, these patients received a combination of immunotherapy and antiangiogenic therapy. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS), while the secondary endpoints included the disease control rate (DCR), overall survival (OS), and the incidence of adverse events.ResultsFifty-one patients were included in this cohort study. The median duration of follow-up was 15.8 months. The ORR and DCR were 17.6%, and 76.5%, respectively. The median PFS (mPFS) was 5.8 months (95% CI: 4.8–6.8) for all patients, and the median OS had not been reached as of the date cutoff. Multivariate analysis indicated that Eastern Cooperative Oncology Group performance status of 0–1 and ≤ second-line treatment were positive predictors for both PFS and OS. Patients with alveolar soft part sarcoma or clear cell sarcoma had longer mPFS (16.2 months, 95% CI: 7.8–25.6) when compared to those with other subtypes of STS (4.4 months, 95% CI: 1.4–7.5, P < 0.001). Among the observed adverse events, hypertension (23.5%), diarrhea (17.6%), and proteinuria (17.6%) were the most common, with no treatment-related deaths reported.ConclusionThe combination of immunotherapy and antiangiogenic agents showed promising efficacy and acceptable toxicity in patients with aSTS, especially those with alveolar soft part sarcoma or clear cell sarcoma.

Abstract Mo007: Molecular Basis of Sepsis-Induced Cardiomyopathy Under Anthracycline Treatment: Insights from Mouse Model

Anthracyclines constitute a fundamental component in numerous paediatric chemotherapy regimens. However, its myelosuppressive &amp; cardiotoxic nature put patients at risk of sepsis and sepsis-induced cardiomyopathy (SIC). When anthracycline-treated patients develop SIC, successful treatment of sepsis is sufficient for the restoration of cardiac function, giving rise to the 'transient cardiac dysfunction' phenomenon. Although transient it poses compromised clinical outcomes &amp; the mechanism driving this phenomenon remains elusive. We hypothesise that the molecular regulators of the phenomenon lie within cardiac cell populations &amp; is controlled by transcriptional activation. Thus, we aim to model 'transient cardiac dysfunction' in mice and conduct transcriptomics on their heart tissues. ‘Transient cardiac dysfunction’ was modelled in male juvenile C57BL6 mice treated with a cumulative of 10mg/kg doxorubicin followed by sepsis induction via cecal ligation &amp; perforation (CLP) to induce SIC. To recapitulate ‘transient cardiac dysfunction’, antibiotics were administered 20h post-CLP to treat sepsis &amp; restore cardiac function. Controls against doxorubicin (saline treatment) was established. Echocardiography and biological sample curation were conducted at pre-SIC (before CLP), onset-SIC (10h post-CLP) &amp; post-SIC (60h post-CLP). Sepsis was verified based on procalcitonin fold change as compared to pre-SIC (n=3-6). Procalcitonin was 15±1.6 folds higher in dox- (n=3) &amp; 10±0.39 folds higher in saline-treated (n=3) mice at onset-SIC. The infection was more aggressive in dox-treated mice as procalcitonin remained elevated at post-SIC (17.1±2.0, n=4), whereas in saline-treated mice, procalcitonin was reduced by post-SIC (7.9±1.0, n=3). In saline-treated mice, LVEF(%) was reduced at onset-SIC (49.0%±3.0, n=7) from pre-SIC (58.1±1.1, n=7) and recovered to baseline by post-SIC (61.8±1.7, n=5). In the contrary, LVEF in dox-treated mice (n=7) was increased at onset-SIC (62.5±1.7) from pre-SIC (56.0±0.8) &amp; sustained till post-SIC (60.1±1.0), suggesting cardioprotection. Normal distribution was verified before statistical hypothesis testing. In conclusion, ‘transient cardiac dysfunction’ was modelled in saline-treated mice, &amp; novel cardio protective effect was observed in dox-treated mice. Moving forward, longitudinal snRNA-seq will be conducted on whole hearts to identify cardiac cell populations &amp; genes responsible for ‘transient cardiac dysfunction’ &amp; cardioprotection.

High-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE RCT

Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Anthracycline therapy induces an early decline of cardiac contractility in low-risk patients with breast cancer

AimsCancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy. CTRCD most frequently appears in patients with cardiovascular risk factors (CVR) or known cardiovascular disease. However, limited data exist on incidence and course of anthracycline-induced CTRCD in patients without preexisting risk factors.We therefore aimed to longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease (NCT03940625).Methods and resultsWe enrolled 59 women with primary breast cancer and scheduled anthracycline-based therapy, but without CVR or preexisting cardiovascular disease. We conducted a longitudinal assessment before, immediately and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping.Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3% immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation, two of them were symptomatic. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired.ConclusionIn every single patient anthracyclines induce a decline of myocardial contractility, even among patients without pre-existing risk factors for CTRCD. Our data suggest to thoroughly evaluate whether this may lead to an increased risk of future cardiovascular events.Graphical Reduced myocardial contractility in low-risk patients receiving anthracycline-based cancer therapy. This study included 59 otherwise healthy women with primary breast cancer undergoing anthracycline-based chemotherapy. CMR was performed at baseline, directly and 12 months after cancer therapy. A decline in left ventricular function was observed in every single patient accompanied by transient edema. More than 50% were diagnosed with cancer therapy related cardiovascular dysfunction. LVEF: left ventricular function, CTRCD: cancer therapy related cardiovascular dysfunction, GLS = Global longitudinal strain, hs-TnT= high sensitive Troponin T, NT-pro BNP = NT-pro brain natriuretic peptide