Anthracycline Therapy Research Articles

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.

Effects of SGLT2 inhibitors on the cardiovascular outcomes in patients with cancer: a systematic review and meta-analysis

Abstract Introduction The incidence of cardiovascular diseases in cancer survivors has gradually increased due to well-documented drug-associated cardiotoxicity and the expanding population resulting from advances in cancer treatment. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have demonstrated efficacy in reducing cardiovascular risk in patients with type 2 diabetes mellitus, independent of glycemic control. Previous bench and animal research, along with several cohort studies, suggest potential benefits of SGLT2 inhibitors on cardiovascular outcomes in patients with cancer, with or without anthracycline therapy. This systematic review and meta-analysis aim to explore the potential of SGLT2 inhibitors as a therapeutic intervention to reduce cardiovascular risks in cancer patients, especially those undergoing chemotherapy. Methods We systematically searched Cochrane, PubMed, and Embase from inception until February 29, 2024, without language restrictions. Observational cohort studies with a follow-up period of at least 1 year were included to analyze the effects of SGLT2 inhibitors on cardiovascular outcomes in type 2 diabetes patients with cancer. Inclusion and exclusion criteria were predefined. Using random-effects models, we calculated odds ratios (OR) and 95% confidence intervals (CI). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and explore the impact of SGLT2 inhibitors on mitigating cardiotoxicity. Primary outcomes of interest were mortality, heart failure hospitalization, sepsis, and diabetic ketoacidosis. Results Six studies involving 2959 patients in the SGLT2i group and 29169 patients in the non-SGLT2i group were included. Type 2 diabetes patients receiving SGLT2i exhibited significantly lower odds of mortality than those without SGLT2i (OR=0.34, 95% CI=[0.26-0.46], I²=77%). Subgroup analysis revealed a similar reduction in mortality among patients on SGLT2i treated with anthracyclines (OR=0.44, 95% CI=[0.23-0.82], I²=69%). Odds ratios for heart failure hospitalization and sepsis were also significantly lower in the SGLT2i group than the non-SGLT2i group (OR=0.46, 95% CI=[0.35-0.60], I²=0%, and OR=0.28, 95% CI=[0.20-0.40], I²=0%, respectively). The risk for diabetic ketoacidosis was not increased in the SGLT2i group (OR=0.66, 95% CI=[0.20-2.17], I²=0%). Conclusion SGLT2 inhibitors demonstrate a reduction in mortality, heart failure hospitalization, and sepsis in type 2 diabetes cancer patients treated with or without anthracyclines in cohort studies. Our findings support the need for further investigation through randomized controlled trials.Forest plots of mortality with subgroupForest plots of other primary outcomes

Clinical validated risk prediction model for development of heart failure after contemporary breast cancer treatment

Abstract Background Patients receiving breast cancer (BC) treatment are at risk for heart failure and cardiomyopathy (HF/CM). European Society of Cardiology (ESC) cardio-oncology guidelines recommend baseline cardiovascular (CV) assessment, however, there is limited data about cardiotoxicity risk specific to patients with BC. Our aim was to develop and validate model for prediction of HF/CM in women receiving contemporary treatment for invasive early-stage BC. Methods We assembled a cohort women diagnosed with Stage I-III BC from 2008-2020 and followed through 2021 in a large health care plan. Women age >80, with history of HF/CM, and women who received both anthracyclines and trastuzumab were excluded, leaving N=26,044 for analysis. Study cohort was randomly split into derivation (60%) and validation (40%) datasets. Elastic-net penalized Cox proportional hazard model was created using the derivation dataset to select risk factors and to calculate the panelized coefficient which defined the HF/CM risk score. Risk score system was assessed by Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve (AUC). Event rates of <5% constituted low risk; 5-14% moderate; and >15% high risk category. Incident HF/CM events were examined using Kaplan-Meier approach in derivation and validation datasets. Results HF/CM risk score had high discrimination ability and sufficiently good model of fit regarding HF/CM events (P value=0.163 and 0.667 from Hosmer–Lemeshow test;AUC 0.751 and 0.764, in derivation and validation sets, respectively). There were 10% of women in the high risk; 30% in moderate; and 60% in low-risk group. Variables associated with the higher HF/CM risk score included age, receipt of anthracycline-based chemotherapy or anti-HER2 therapy, presence of hypertension, diabetes, or history of other CV conditions at baseline. The score pattern showed major effect of age, with anthracycline and anti-HER2 therapy increasing the risk across all age groups (Figure 1). Kaplan-Meier analysis of incident HF/CM over 14 years after BC diagnosis showed significantly lower number of HF/CM events in low risk compared to moderate and high-risk score groups (p<0.0001, Figure 2). Conclusion Our robust risk prediction model for HF/CM among women with early-stage BC provides a new tool to identify women at higher CV risk and inform cardiac function monitoring during and after BC treatment. Our findings may guide further validation studies and build evidence for the cardiotoxicity risk stratification in patients with BC.Risk Score for HF/CM by Age/ChemoTxK-M curves of freedom from HF/CM

New onset of left ventricular dysfunction and diastolic dysfunction are uncommon in patients with her2+ breast cancer after completion of cancer therapy

Abstract Background Cardiotoxicity from anthracyclines and trastuzumab is common among patients with breast cancer during therapy. However, there are limited data on new onset of cardiotoxicity (systolic or diastolic dysfunction) after completion of therapy. This knowledge has implications to guide long-term follow-up. Purpose The aim of this study was to evaluate the incidence of cancer therapy related cardiac systolic dysfunction (CTRCD) and diastolic dysfunction (DD) in women with HER2+ breast cancer after completion of cancer therapy and compare to incidence during cancer therapy. Methods We conducted a prospective cohort study of women with HER2+ breast cancer who were treated with sequential anthracycline and trastuzumab therapy, with or without radiation therapy (The EMBRACE-MRI trial, NCT02306538). Comprehensive surveillance echocardiograms were performed at baseline and every 3 months during treatment, early post-trastuzumab, then at years 1, 2, and 3 post trastuzumab completion. CTRCD was defined as a reduction in 3D-left ventricular ejection fraction (LVEF) by ≥ 10% from baseline to < 55%. Diastolic dysfunction was defined as per the American Society of Echocardiography guidelines. Results A total of 136 female patients, with a mean age of 51.1 ± 9.2 years were recruited. Among them, 15.4% had hypertension, 3.7% had diabetes mellitus, and 10.3% had dyslipidemia. The mean cumulative doxorubicin equivalent dose was 203.9 ± 12.5 mg/m2, 120 patients received radiation therapy with the mean heart dose of 170.8 ± 75.9 cGy. During cancer treatment, 27 out of 136 patients (19.9%) developed CTRCD. In long-term follow-up, due to death or interruption due to the COVID-19 pandemic, follow-up was available in 128 patients at 1 year, 117 at 2 years and 111 at 3 years. 5 of the 27 patients still had persistent LV dysfunction (3 at 1 year, 1 at 2 year and 1 at 3 year), however, there were no new diagnosis of CTRCD post completion of therapy. Of 129 patients with baseline normal or indeterminate diastolic function, new DD was identified in 25/129 patients (19.4%) during cancer treatment (17 grade I, 2 grade II, 6 unable to grade). After completion of cancer therapy, 5 patients had persistent DD. In patients with no DD during therapy and completed 3 year follow-up, 5 patients developed new DD after therapy (2 grade I, 3 unable to grade). Figure 1 illustrates the percentage of patients with new CTRCD or new diastolic dysfunction at each timepoint. None of the patients developed clinical heart failure. Conclusion Although both CTRCD and diastolic dysfunction are common during sequential therapy with anthracyclines and trastuzumab in women with HER2+ breast cancer, new onset after treatment completion is rare during a careful follow-up. These findings have implications for long-term surveillance.

Can the presence of aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma be used as a predictor of MACE?

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR <60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

Comparison of two anthracycline regimens for treatment of breast cancer and the incidence of cardiac injury

Abstract Background Anthracycline based breast cancer treatment regimens have evolved over time. Whether the risk of myocardial injury is different between regimens is unclear. Purpose To compare the incidence and significance of high sensitivity troponin-I (TpI) levels immediately post anthracycline therapy in women with breast cancer treated with two different anthracycline regimens. Methods We prospectively recruited women with early-stage breast cancer who received either dose-dense doxorubicin and cyclophosphamide (ddAC) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) with or without subsequent HER2 therapy. The ddAC regimen comprises 4 cycles of doxorubicin given every 2 weeks (240mg/m2), whereas FEC consists of 3 cycles of epirubicin given every 3 weeks (total epirubicin dose of 300mg/m2, which is doxorubicin equivalent dose of 240mg/m2 using a cardiovascular toxicity dose ratio of 0.80 as per the 2022 ESC Cardio-oncology guidelines). Clinical characteristics were collected and TpI levels were measured before anthracyclines and 4-6 weeks post last dose. Comprehensive echocardiograms were conducted at baseline and post-therapy. Results 236 female participants were enrolled; 103 (43.6%) received ddAC and 133 (56.4%) received FEC. Compared to FEC, patients receiving ddAC were older (mean age 58.1±10.2 vs 51.0±9.3 years; p < 0.001) received similar cumulative doxorubicin equivalent dose (237.4±23.4 vs 239.9 ± 11.9 mg/m2; p=0.30), had similar baseline LVEF (62.1 ± 4.8 vs 61.3 ± 3.6%, p=0.14), and TpI levels (median (IQR) 2.0 (2.0-2.0) vs 2 (2.0-3.0) ng/L, p=0.12) respectively. Baseline risk factors were similar (hypertension 21% vs 17%, p=0.34; diabetes 7% vs 5%, p=0.44; dyslipidemia 15% vs. 8%, p=0.12). Post-anthracycline, the ddAC group had higher TpI level compared to patients in the FEC group (median (IQR) 12 (7-29) vs 6 (4-11) ng/L; p<0.001). The proportion of patients with abnormal TpI levels (>99th percentile, >16.0 ng/L) was higher in the ddAC group (43.7% vs 15.0%; p < 0.001). In a multivariable linear regression model that included age, treatment regimen, baseline TpI, hypertension, diabetes mellitus and dyslipidemia, ddAC remained significantly associated with higher post anthracycline TpI levels (β=15.5, 95%CI: 8.7-22.3; p<0.001). There was no significant difference in the mean LVEF post-anthracycline (59.9 ± 5.1 vs 60.0 ± 3.8; p=0.91). No patients developed clinical heart failure. Conclusion Despite similar doxorubicin equivalent doses, the incidence of abnormal TpI levels was ~3 fold higher with DD-AC than FEC. Given that DD-AC is now more commonly used especially with immunotherapy this knowledge is clinically relevant. The difference in proportion with troponin elevation could be due to differences in the number of cycles (3 vs 4) and the frequency of chemotherapy administration (every 2 vs 3 weeks) between the regimens. However, this did not translate into a larger reduction in LVEF. But longer-term follow-up is needed.

Serum Carnitine Concentrations and Cardiac Function in Pediatric, Adolescent and Young Adult Oncology Patients Receiving High-Dose Anthracyclines

OBJECTIVE Anthracycline chemotherapy agents have significant dose-dependent cardiotoxic effects. ­Carnitine, a non-essential amino acid, is involved in long chain fatty acid oxidation, and carnitine deficiency can result in cardiomyopathy and cardiac arrhythmias. If administered concurrently with chemotherapy, carnitine supplementation could be a potential strategy to prevent cardiotoxicity. However, the association between serum carnitine concentrations and anthracycline cardiotoxicity during cancer treatment in the childhood, adolescent, and young adult (CAYA) age range has not been established. METHODS This prospective pilot cohort study characterized changes in serum carnitine concentrations and cardiac function before, during, and approximately 1 year after large-dose anthracycline therapy in newly diagnosed CAYA cancer patients. RESULTS Among 21 patients with a mean cumulative anthracycline dose exposure of 409 mg/m2 of ­doxorubicin equivalents, left ventricular ejection fraction and relative wall thickness decreased, indicating an overall decline in cardiac function. A reversible decrease in serum carnitine concentrations was also observed. A non-statistically significant positive correlation was observed; for every 1 mmol/L decrease in serum carnitine concentration, there was a 0.09% decrease in LVEF (p = 0.2). CONCLUSIONS These findings from this small pilot study suggest that there may be a relationship between serum carnitine concentrations and cardiac function after anthracycline therapy that should be evaluated in larger studies.

Use of cardiac biomarkers to improve initiation of cardioprotective therapy in patients with breast cancer receiving cardiotoxic chemotherapy in a multidisciplinary cancer center.

344 Background: Treatment for breast cancer commonly includes anthracyclines and anti-Her2 directed therapy, both of which carry a known cardiovascular risk. In high-risk patients, ESMO guidelines recommend consideration of cardiac biomarker (hs-cardiac troponin) testing for patients undergoing potentially cardiotoxic chemotherapy. Prophylactic use of cardioprotective medications such as angiotensin converting enzyme (ACE) inhibitors, angiotensin renin blockers (ARBs) or beta-blockers (BBs) can be considered to reduce development of cardiotoxicity. We aimed to identify the rates of cardiac biomarker testing performed and rates of abnormalities in patients considered to be high risk for cardiovascular disease undergoing breast cancer treatment with potentially cardiotoxic medication in hope of improving prevention efforts. Methods: We performed a retrospective chart review of patients with breast cancer treated with either anthracycline or anti-Her2 based therapy at our ambulatory cancer center from 2020 to 2023. Pre-treatment cardiovascular risk score was determined based on initial cardiac assessment at time of consultation with cardio-oncology. Completion of troponin biomarker testing and initiation of cardioprotective medication therapy was assessed. Patients who were not established with cardio-oncology or not on active cardiotoxic chemotherapy were excluded. Results: A total of 172 patients (66 on anthracycline based therapy and 106 on anti-HER2 therapy) were assessed. The average age of all patients was 57 years. 47 patients were assessed as high risk for cardiovascular disease. Of these high-risk patients, troponin was checked in 42 of 47 (89.4%) and found to be elevated in 23 of 42 (55%). Rate of troponin elevation was statistically significant for high risk patients compared to all other patients (p<0.05). Cardioprotective medications were utilized in 28 of the 47 patients considered to be high risk (59.6%). Conclusions: In patients with breast cancer who require treatment with a potentially cardiotoxic medication, a clinical risk assessment with cardiology can be utilized to select those who may benefit from additional cardiac biomarker monitoring and potential earlier initiation of cardioprotective therapy. This single center study reveals that the use of clinical assessment of high vs low/medium risk allows us to predict patients with increased risk of cardiotoxicity. Our population had cardiac biomarkers checked in nearly all high-risk patients and troponin was elevated 55% of the time. Further study is needed to investigate if biomarker directed initiation of cardio-protective therapy could reduce cardio-toxicity.

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

Left Atrial Strain as a Predictor of Early Anthracycline-Induced Chemotherapy-Related Cardiac Dysfunction: A Pilot Systematic Review and Meta-Analysis.

Background: Chemotherapy-related cardiac dysfunction (CTRCD) significantly affects patients undergoing anthracycline (AC) therapy, with a prevalence ranging from 2% to 20%. Reduced left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (LV GLS) are prognostic parameters for CTRCD detection. Our study aimed to investigate the role of emerging parameters such as left atrial strain (LAS). Methods: We searched multiple databases for studies comparing LAS changes post-AC versus pre-AC therapy in patients with cancer. Primary outcomes included left atrial reservoir strain (LASr), left atrial conduit strain (LAScd), and left atrial contractile strain (LASct). RevMan (v5.4) was used to pool the standardized mean difference (SMD) under a random effects model, with p < 0.05 as the threshold for statistical significance. Results: In an analysis of 297 patients across five studies, AC therapy significantly lowered LASr (SMD = -0.34, 95% CI:-0.55, -0.14, I2 = 0%, p = 0.0009) and LAScd (SMD = -0.41, 95% CI: -0.59, -0.23, I2 = 0%, p < 0.00001) levels. Conversely, LASct demonstrated no significant change (SMD = 0.01, 95% CI: -0.21, 0.23, I2 = 9%, p = 0.95). AC therapy also significantly reduced LV GLS (SMD = -0.31, 95% CI: -0.51, -0.11, I2 = 0%, p = 0.003). While not statistically significant, LVEF decreased (SMD = -0.20, 95% CI: -0.42, 0.03, I2 = 0%, p = 0.09), and left atrial volume index trended higher (SMD = 0.07, 95% CI: -0.14, 0.27, I2 = 0%, p = 0.52) after AC therapy. Conclusions: AC treatment led to reduced LAS and LV GLS values, indicating its potential as an early CTRCD indicator. Larger trials are required to fully explore their clinical significance.

Timing of cardio-oncological rehabilitation and cardiorespiratory fitness in patients receiving cardiotoxic chemotherapy: a longitudinal observational study.

Anthracycline-based chemotherapy has well-known cardiotoxic effects, butmay also cause skeletal muscle myopathy and negatively affect cardiorespiratory fitness and quality of life. The effectiveness of exercise training in improving cardiorespiratory fitness and quality of life during chemotherapy is highly variable. We set out to determine how the effect of exercise training on cardiorespiratory fitness (primary outcome) and quality of life (secondary outcome) in cancer patients is affected by the type of therapy they receive (cardiotoxic therapy with or without anthracyclines; non-cardiotoxic therapy) and the timing of the exercise training (during or after therapy). Consecutive patients with cancer who participated in an exercise-based cardio-oncology rehabilitation programme at a university hospital in Switzerland between January 2014 and February 2022 were eligible. Patients were grouped based on chemotherapy (anthracycline vs non-anthracycline) and timing of exercise training (during vs after chemotherapy). Peak oxygen uptake (VO2) was assessed with cardiopulmonary exercise testing (n = 200), and quality of life with the Functional Assessment of Cancer Therapies questionnaire (n = 77). Robust linear models were performed for change in peak VO2including type and timing of cardiotoxic therapies, age, training impulse and baseline peak VO2; change in quality of life was analysed with cumulative linked models. In all patients with valid VO2(n = 164), median change in peak VO2from before to after exercise training was 2.3 ml/kg/min (range: -10.1-15.9). The highest median change in peak VO2was 4.1 ml/kg/min (interquartile range [IQR]: 0.7-7.7) in patients who completed exercise training during non-anthracycline cardiotoxic or non-cardiotoxic therapies, followed by 2.8 ml/kg/min (IQR: 1.2-5.3) and 2.3 ml/kg/min (IQR: 0.1-4.6) in patients who completed exercise training after anthracycline and after non-anthracycline cardiotoxic or non-cardiotoxic therapies, respectively. In patients who completed exercise training during anthracycline therapy, peak VO2decreased by a median of -2.1 ml/kg/min (IQR: -4.7-2.0). In the robust linear model, there was a significant interaction between type and timing of cancer treatment for anthracycline therapy, with greater increases in peak VO2when exercise training was performed after anthracycline therapy. For quality of life, higher baseline scores were negatively associated with changes in quality of life. In our cohort, the increase in cardiorespiratory fitness was diminished when exercise training was performed concurrently with anthracyclines. For patients with cardiotoxic treatments other than anthracyclines, cardiorespiratory fitness and quality of life was not associated with timing of exercise training.

Effect on cardiovascular outcome of sodium-glucose co-transporter-2 (SGLT2) inhibitors among patients with cancer treated with anthracycline: A systematic review and meta-analysis.

e24001 Background: Sodium-glucose-co-transporter-2 (SGLT2) inhibitors have shown benefit in reducing cardiovascular outcomes in diabetes patients. Anthracycline therapy is associated with a risk of cardiomyopathy. However, the impact of SGLT2 inhibitors in the prevention of cardiomyopathy and heart failure in cancer patients undergoing anthracycline treatment remains unclear. Thus, we conducted a systematic review and meta-analysis to explore the effect of the prevention of cardiovascular outcomes in patients with cancer and diabetes who had received anthracycline therapy. Methods: We systematically reviewed Medline and EMBASE databases from inception to January 2024 for studies focusing on cancer patients with a history of anthracycline therapy. Eligible studies had to report relative risk (RR) with 95% confidence intervals for the clinical endpoints of mortality outcomes and the risk of HF exacerbation, comparing cohorts with and without SGLT2 inhibitor use. Results: Our study included 4 retrospective cohort studies in the meta-analysis (n = 6,708, 24% received SGLT2). There was significantly lower all-cause mortality in the SGLT2 inhibitors group (pooled RR of 0.52, 95% CI 0.35-0.77, I2 64%). However, there were no differences in the risk of heart failure exacerbation (pooled RR of 0.67, 95% CI 0.39-1.14, I2 17%). Conclusions: Our study found that anthracycline-treated cancer patients using SGLT2 inhibitors experienced lower all-cause mortality compared to the control group. A randomized clinical trial is necessary to further elucidate these findings.

Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.

e13032 Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF &lt; 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.

Investigation of cardiotoxicity with concomitant use of anthracyclines and checkpoint inhibitors.

e24022 Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and currently are the standard of care for early stage triple negative breast cancer in combination with anthracyclines (AC). It is known that both ICI and AC carry risk of cardiotoxicity. Studies have also shown that there is increased risk of cardiotoxicity with dual ICI. However no studies have evaluated the risk with concomitant use of ICI and AC. Here we investigated if there is increased cardiotoxicity risk with this combination regimen in a retrospective study. Methods: We did a retrospective analysis of patients with stage II and stage III triple negative breast cancer treated with combined AC and ICI at University of South Alabama Mitchell Cancer Institute Mobile, AL from January 2020 until June 2023. Data included demographics, cardiovascular (CV) risk factors and treatment. CV risk factors were detailed from 2022 ASCO guidelines. Echocardiograms were used to evaluate left ventricular ejection (LVEF). Therapy related cardiovascular toxicity was defined by ESC guidelines 2022 as any new decrease in LVEF to &lt; 40% or any decrease in LVEF &lt; 50% and 10 percentage points decrease from baseline. Adverse events (AE) and risk analysis were calculated. Results: Of the total 49 patients, all were female with a mean age of 53 years old (30-82). 55% of patients had less than 2 CV risk factors (n = 27) and 45% had more than 2 (n = 22). 84% completed all 4 cycles of neoadjuvant AC course without dose adjustment. The median number of cycles of Pembrolizumab was 12 with a range of 7 to 17 cycles including adjuvant Pembrolizumab. All patients had a baseline echo with LVEF &gt; 55%. Two patients (0.04%) developed cardiotoxicity. One patient had LVEF that decreased to EF 45-50% while on surveillance. Another patient developed myocarditis during treatment with EF 25-30% and died from cardiogenic shock. Both patients had 2 CV risk factors and were African American. Only 24% (n = 12) had surveillance echocardiograms completed one year post treatment. Conclusions: Our study results showed that cardiotoxicity risk was lower compared to that in the Keynote-522 trial. The outcomes are limited as a majority (76%) of the patients did not have surveillance echos completed. While the risk of cardiotoxicity with ICI and AC have been studied independently, there have been mouse models that showed that AC therapy may make heart vulnerable to toxicity from ICI therapy. To our knowledge, this is the first study to evaluate cardiotoxicity in patients who received concomitant AC and ICI treatment. Our study highlights the importance of prospective studies and long term follow up to monitor cardiotoxicity in these patients as early detection is key to prevent future morbidity. [Table: see text]

7+3 versus decitabine + venetoclax: A global, propensity-matched study comparing outcomes for both regimens in AML.

6537 Background: In the treatment of AML, 7+3 (seven days of standard-dose cytarabine and three days of anthracycline therapy) has long been the standard for attempted remission induction. Recently published studies have explored the efficacy and tolerability of decitabine and venetoclax as a favorable alternative regimen in older adults with AML. However, there has not yet been a head-to-head study in the literature comparing real world outcomes for both regimens. Here we present a retrospective database analysis comparing remission status and mortality among elderly patients treated with 7+3 versus decitabine and venetoclax. Methods: The TriNetX research network was used for this study. Two patient cohorts were created by utilizing International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX platform. Both cohorts had patients age 65 and up with a diagnosis of AML (C92.0) and who started treatment within six weeks of diagnosis. The 7+3 cohort received cytarabine and either idarubicin or daunorubicin, while the other cohort received decitabine and venetoclax. Each cohort was excluded from the other treatment to remove crossover as a confounding factor. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm. This resulted in 519 patients in each arm. They were then evaluated for the outcome of AML in remission (C92.01) and for death within 12 months. Results: Patients treated with 7+3 were more likely to obtain remission status (54.5% vs 34.7%, RR 1.57, 95% CI (1.36,1.81), P value &lt; 0.0001). The 7+3 cohort also had a lower rate of mortality at 12 months (37% vs 54%, RR 0.69, 95% CI (0.60,0.79), P value &lt; 0.0001). Conclusions: These results show that among elderly patients with AML, treatment with 7+3 is associated with statistically higher remission rates and lower mortality when compared with decitabine and venetoclax therapy. One limitation of our study was that we were not able to determine the cytogenetics in either arm. These results should be taken into consideration when choosing an induction regimen in this population.

Examining the risk factors for trastuzumab-related cardiotoxicity in a predominantly Hispanic South Texas population: A descriptive study.

e24000 Background: Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), stands as first line treatment for HER2 positive breast cancer. Despite its efficacy, trastuzumab’s association with cardiotoxicity requires monitoring via serial transthoracic echocardiograms (TTEs). We aimed to evaluate the risk factors for trastuzumab related cardiotoxicity in a South Texas population that is uniquely a majority-minority Hispanic population. Methods: A retrospective chart review study was conducted of all female patients with HER2-positive breast cancer who received trastuzumab treatment from 2015-2021. A total of 180 patients were identified. Patients without baseline TTE or a baseline left ventricle ejection fraction (LVEF) less than 53% were excluded. The final sample size included 132 patients. Cardiotoxicity was defined as a decrease in LVEF of more than 10% during the 1-year study period. Results: The mean age at the time of diagnosis in the study population was 54.2 years. The average BMI of the study participants was 30.89. The incidence of cardiotoxicity in this study population was 6%. Among those who developed cardiotoxicity, 50% had hypertension, 25% had hyperlipidemia, 12.5% had type 2 diabetes mellitus, and 12.5% had previous coronary artery bypass surgery (CABG). In terms of cancer treatment, 12.5% of patients had a history of radiation, 25% had a history of anthracycline therapy, and 12.5% had their trastuzumab treatment ended prematurely. Of the cardiotoxicity population, 37.5% patients were former smokers and 25% were former alcohol users. Hispanic/Latino patients composed 58% of the study population and represented 50% of patients who experienced cardiotoxicity. Conclusions: The incidence of trastuzumab-related cardiotoxicity in this Hispanic/Latino majority-minority population was 6%, lower than the 9% observed in a predominantly white population in our previous study. However, further studies are needed to determine the factors contributing to this reduced cardiotoxicity rate in this population.

Long-term outcomes of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) and docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) for HER2-positive primary breast cancer: results of the randomized phase 2 JBCRG20 study (Neo-peaks)

PurposeThe randomized phase 2 Neo-peaks study examined usefulness of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) following docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) as compared with the standard TCbHP regimen. We previously reported that pCR rate after neoadjuvant therapy tended to be higher with TCbHP followed by T-DM1 + P. We conducted an exploratory analysis of prognosis 5 years after surgery.MethodsNeoadjuvant treatment with TCbHP (6 cycles; group A), TCbHP (4 cycles) followed by T-DM1 + P (4 cycles; group B), and T-DM1 + P (4 cycles; group C, + 2 cycles in responders) were compared. Group C non-responders after 4 cycles were switched to an anthracycline-based regimen. We evaluated 5-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS).ResultsData from 203 patients (50, 52, and 101 in groups A–C, respectively) were analyzed. No significant intergroup differences were found for DFS, DDFS, or OS. The 5-year DFS rates (95% CI) were 91.8% (79.6–96.8%), 92.3% (80.8–97.0%), and 88.0% (79.9–93.0%) in groups A–C, respectively. TCbHP followed by T-DM1 + P and T-DM1 + P with response-guided addition of anthracycline therapy resulted in similar long-term prognosis to that of TCbHP.ConclusionsIn patients who achieved pCR after neoadjuvant therapy with T-DM1 + P, omission of adjuvant anthracycline may be considered, whereas treatment should be adjusted for non-pCR patients with residual disease. T-DM1 + P with response-guided treatment adjustment may be useful for minimizing toxicity.Trial registration number and date of registrationUMIN-CTR, UMIN000014649, prospectively registered July 25, 2014. Some of the study results were presented as a Mini Oral session at the ESMO Breast Cancer 2023 (Berlin, Germany, 11–13 May 2023).

Abstract PO4-01-03: Dual anti-HER2 Therapy with Pertuzumab and Trastuzumab versus Trastuzumab Alone in Addition to Anthracycline and Taxane-Based Neoadjuvant Therapy in Patients with HER2-Positive Early-Stage Breast Cancer; Real-World Data

Abstract Background: When use in the neoadjuvant setting, anti-HER2 targeted therapy had improved pathologic complete response rate (pCR) in patients with HER2-positive early-stage breast cancer (EBC). Here we present real-world data on the use trastuzumab with or without pertuzumab on the backbone of anthracycline and taxanes-based NSAPB-B27 chemotherapy regimen. Methods: We retrospectively reviewed records of patients with HER2-positive EBC who received neoadjuvant therapy using the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B27 protocol (4 cycles of adriamycin and cyclophosphamide, followed by 4 more cycles of docetaxel; all given every 3 weeks) with anti-HER2 therapy from Jan 2014 to September 2021, treated at a tertiary care cancer center. The clinicopathological features, treatment received, and outcome were collected from patients’ electronic medical records. We estimated 3-year disease-free survival (DFS), a validated endpoint in HER2-positive EBC, using Kaplan-Meier with recurrence and/or death as events. Outcomes were reported in subgroups based on known prognostic factors. Results: The study comprised 528 patients with a median follow-up of 36 months. Median age was 48 (21-80) years. Hormone receptors (HR) were positive in 379 (71.8%), lymph node-involvement prior to neoadjuvant therapy was reported in 402 (76.1%) patients and 319 (60,4%) had grade-3 disease. Majority (n= 482, 91.3%) were labeled HER2-positive based on immunohistochemistry staining (IHC+3) and the rest were based on IHC+2 with positive FISH/ISH. Dual anti-HER2 therapy (trastuzumab and pertuzumab) was used in 316 (59.8%) patients, single agent trastuzumab in 173 (32.8 %) patients, while 39 (7.4%) others did not receive any anti-HER2 therapy. Except for 9 (1.7%) patients who progressed while on treatment, all patients underwent surgery. Among the whole group, 225 (43.4%) achieved pCR; significantly higher (n=80, 53.7%) in HR-negative compared to 38.3% among those with HR-positive disease, p=0.002. Additionally, pCR was higher in patients who received dual anti-HER2 (46.2%) compared to 39.3% for those treated with trastuzumab and 28.2% for those who did not receive anti-HER2 therapy. Following surgery, 463 (89.4%) of the patients received adjuvant trastuzumab, however, none of them received pertuzumab or TDM1 in adjuvant sitting. Estimated 3-year DFS was 86.1% with dual anti-HER2 and 83.0% with trastuzumab alone, p=0.19. However, DFS was better among those with node-negative disease; 96.5% compared to 80.9% in node-positive disease, p= &amp;lt; 0.001. Patients who achieved pCR had significantly better 3-year DFS; 89.3% compared to 80.2% in patients with residual disease, p= 0.006. Conclusions: Even with the wide use of pertuzumab in the neoadjuvant setting, the DFS was not improved compared to trastuzumab alone, and this highlights the importance of switching trastuzumab to TDM1, or to continue with pertuzumab in the adjuvant setting in patient with residual disease. Citation Format: Baha' Sharaf, Faris Tamimi, Osama Salama, Anas Zayed, Osama El Khatib, Suhaib Khater, Malek Horani, Suhaib Al-Sawajneh, Yosra AL-Masri, Hikmat Abdel-Razeq. Dual anti-HER2 Therapy with Pertuzumab and Trastuzumab versus Trastuzumab Alone in Addition to Anthracycline and Taxane-Based Neoadjuvant Therapy in Patients with HER2-Positive Early-Stage Breast Cancer; Real-World Data [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-03.

Abstract PO4-12-07: INSTITUTIONAL EXPERIENCE IN PATIENTS WITH EARLY BREAST CANCER WHO RECEIVED CARDIOTOXIC THERAPY IN CARDIONCOLOGY UNIT

Abstract Introduction: Early breast cancer (eBC) is the most frequent malignancy diagnosed in women worldwide; fortunately, survival is increasing related to early diagnosis and the incorporation of new drugs. In this scenario, preventing long-term toxicities become essential. Cardiac adverse events related to anthracyclines or trastuzumab such as reduction in left ventricular (LV) systolic function and clinical heart failure (HF), are well known and are the leading cause of morbidity in breast cancer survivors. Cardioprotective strategies and early diagnoses of asymptomatic cardiac dysfunction are essential to optimized management and prevention of overt cardiovascular (CV) disease. We made a specific cardiac assessment within an Oncocardiology multidisciplinary Unit in patients receiving anticancer therapies. We present the experience in patients with eBC treated with anthracyclines, trastuzumab or both in the past five years. Materials and Methods: We conducted an institutional, interventional, prospective study in patients who received anthracyclines, trastuzumab or both according to the standard of care (SoC) in eBC. Basal CV risk stratification included lipid profile, glycated haemoglobin, high-sensitive troponin T (hs-TnT) and N-terminal ProB-type natriuretic peptide (NT-ProBNP) was done. Image assessment was done by echocardiogram (echo), including myocardial deformation assessed by speckle tracking (STRAIN). Follow-up was done according to anthracycline or trastuzumab therapy with echo and cardiac biomarkers during the systemic therapy and at the end of anticancer treatment, 1, 2 and 5 years after. Patients with uncontrolled CV risks factors according to local protocol, asymptomatic cardiac dysfunction defined as decreased strain (&amp;gt;15% compared with baseline) or increased cardiac biomarkers (Hs-TnT &amp;gt;14 at baseline or x3 basal value during the follow-up; NT-ProBNP &amp;gt; 300 in patients with &amp;lt; 50y; &amp;gt; 600 in patients between 50-75-y or &amp;gt;900 in patients &amp;gt; 75 years or older) or patients who develop heart failure during the treatment or follow-up were referred to cardiologist. Results: between 2018 and 2022, 1125 patients were diagnosed with eBC in our institution, and 435 patients received systemic treatment with anthracyclines, trastuzumab or both. During the study period, 165 of these patients were referred to the cardio-oncologist. 60% received treatment with anthracyclines, 36% with trastuzumab and 4.1% with both. The median age was 58(±23.2), 60% had previous CV risk factors. The main reason to refer patients to the cardio-oncologist was asymptomatic cardiac dysfunction and uncontrolled CV risk factors. (Table 1). 60% of patients initiated angiotensin-converting-enzyme inhibitors or Beta-blockers, and only two patients stopped anticancer therapy due to severe cardiac dysfunction. The period of high risk of developing cardiotoxicity was the first year after the end of treatment. Conclusion: multidisciplinary evaluation within a cardio-oncology unit is useful to optimize CV risk factors and to detect asymptomatic cardiac dysfunction in patients receiving cardiotoxic drugs. Table 1. Main reasons to refer patients to cardiologist. Citation Format: Tamara Martos, Laia Carla Belarte-Tornero, Mireia Ble, Eva Gimeno, Laura Sanhauja, Felicidad Martines-Medina, Maria Martinez-García, Maria Castro-Henriques, Joan Albanell, Sonia Servitja. INSTITUTIONAL EXPERIENCE IN PATIENTS WITH EARLY BREAST CANCER WHO RECEIVED CARDIOTOXIC THERAPY IN CARDIONCOLOGY UNIT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-07.

Abstract 1079: Pre-treatment Circulating Vascular Biomarker Signatures Predict Cancer-therapy Related Cardiac Dysfunction During Breast Cancer Treatment

Aim: Breast cancer treatment with anthracycline and trastuzumab can result in cancer therapy-related cardiac dysfunction (CTRCD). It is not currently possible to accurately identify patients at risk of CTRCD from clinical and demographic information alone. We sought to identify circulating biomarkers that can be used to identify individuals at risk of CTRCD before or early during cancer treatment. Methods: Multi-omic analysis of circulating biomarkers of cardiac damage, inflammation, and endothelial activation, together with profiling of plasma microRNAs was performed before and early during cancer treatment in 136 women ≥ 18 years of age with HER2+ breast cancer (Stages I-III) undergoing treatment with sequential anthracycline and trastuzumab therapy. Results: We identified three endothelial-centric biomarkers (i.e., Angiopoeitin-2, Endothelin-1 and Endoglin) that were elevated prior to and during cancer treatment, and one marker (i.e., E-Selectin) that was elevated during treatment in patients that went on to develop CTRCD. Additionally, there were significant elevations in inflammatory biomarkers (including Myeloperoxidase, Interferon gamma-induced protein-10 and Interferon-α2) before treatment in patients that developed CTRCD. No appreciable differences were observed in cardiac damage biomarkers (Troponin I, BNP, GDF-15) between groups. Assessment of plasma microRNAs prior to treatment revealed distinct microRNA signatures and predicted disease-relevant pathways in patients who went on to develop CTRCD. A Random Forest machine learning approach using all available baseline clinical, cardiac imaging and biomarker data revealed that pre-treatment Angiopoietin-2, Myeloperoxidase and Endoglin levels were the best predictors of CTRCD risk, and the model was further validated in an independent cohort. Conclusion: A combination of endothelial-centric and inflammatory biomarkers measured before treatment can accurately predict CTRCD during breast cancer therapy. Our findings suggest that sub-clinical vascular activation may predispose to cardiac dysfunction during cancer treatment, and that the vasculature may serve as a potential therapeutic target.