Rational and design of SATRACD study: detecting subclinical anthracycline therapy related cardiac dysfunction in low income country

Background: Anthracycline therapy-related cardiac dysfunction (ATRCD) is the most notorious adverse side-effect of chemotherapy. It has become a significant cardiovascular health concern for long-term cancer survivors. With the emerging concept of subclinical ATRCD and newer diagnostictools (Speckle Tracking Echocardiography (STE) and biomarkers), detecting anthracycline cardiac toxicity at an early stage has become an important step to prevent severe cardiac dysfunction and improve the cardiovascular outcome in cancer survivors. Despite the increasing population at risk in sub-Saharan Africa (SSA), there is no contemporary data in Uganda to address the burden, pathogenesis and risk factors of subclinical ATRCD. This big gap in knowledge has led to a lack of local guidelines for monitoring and management of ATRCD. Methods: SATRACD (Detecting Subclinical Anthracycline Therapy Related Cardiac Dysfunction In Low Income Country) study is an observational prospective cohort study. Three hundred and fifty-three anthracycline naïve cancer patients will be recruited at baseline. Patients are followed up on completion of anthracycline-based chemotherapy and at 6 months after completion of anthracycline therapy. Data on demographics, cancer profile and clinical presentation will be collected at baseline. Comprehensive cardiac assessment will be performed at each visit, including electrocardiogram, conventional echo- cardiography, STE, cardiac and oxidative stress markers. We will be able to determine the incidence of subclinical and clinical ATRCD at 6 months after completion of anthracycline therapy, determine whether hypertension is a major risk factor for ATRCD, evaluate the role of conventional echocardiography parameters, and biomarkers for detecting subclinical ATRCD. Conclusion: This SATRACD study will provide contemporary data on Ugandan cancer patients who have subclinical and clinical ATRCD, help in the development of local strategies to prevent and manage ATRCD, and improve cardiovascular outcome for Ugandan cancer survivors. Keywords: SATRACD study; subclinical anthracycline therapy; cardiac dysfunction; low income country.

Polymorphisms rs4673 and rs28714259 as predictors of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12005 Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to study the frequency of rs4673 and rs28714259 and possible associations with the risk of cardiovascular changes in patients with breast cancer during anthracycline therapy (anthracycline-mediated cardiotoxicity — AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular changes, who were treated with anthracyclines at the National Medical Research Center of Oncology in 2019-2020. For genotyping of rs4673 and rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphisms was confirmed by Sanger sequencing on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients were diagnosed with signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AOC the allelic frequency of rs4673 (c.214T > C CYBA) was 0.38, the frequency of genotypes C/C – 0.4, C/T – 0.43, and T/T – 0.17. In the same group, the frequency of the A allele rs28714259 was 0.07, the frequency of the G/G genotypes – 0.87, G/A – 0.13, and A/A – 0. The prevalence of genotypes T/T rs4673 and allele G rs28714259 in a cohort of Russian patients differed from the European population (p = 0.014 and p = 0.05, respectively). The risk of cardiovascular changes on the background of anthracycline therapy increased in the presence of the rs4673 polymorphic allele by 6.49 times, in the case of the G/A and A/A rs28714259 genotypes - by 3.27 times. The results of the ROC-analysis suggested high quality of the tests based on the dominant models rs4673 and rs28714259 (AUC was 71.9% and 76.3% correspondingly). Conclusions: In this study the prognostic efficiency of the genetic markers rs4673 and rs28714259 was shown for the prompt detection of the risks of AMC development in the management of cancer patients. However, population characteristics should be taken into consideration for risk assessment.

IGNYTE-ESO: A master protocol to assess safety and activity of letetresgene autoleucel (lete-cel; GSK3377794) in HLA-A*02+ patients with synovial sarcoma or myxoid/round cell liposarcoma (Substudies 1 and 2).

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

Cardiac Surveillance for Early Detection of Late Subclinical Cardiac Dysfunction in Childhood Cancer Survivors After Anthracycline Therapy

BackgroundIn childhood cancer survivors (CCSs) anthracycline-related cardiotoxicity is an important cause of morbidity and late mortality, but the optimal modality of cardiac surveillance still remains to be defined. The aim of this study was to assess whether non-invasive echocardiography-based functional cardiac measures can detect early subclinical myocardial changes in long-term pediatric cancer survivors who received anthracycline therapy.MethodsTwenty anthracycline-treated long-term CCSs and 20 age, sex, and body surface area matched healthy controls were enrolled in this study. Among cancer survivors, mean age at diagnosis was 6.5 ± 4.4 years, and the mean cumulative anthracycline dose was 234.5 ± 87.4 mg/m2. All subjects underwent a comprehensive functional echocardiographic protocol study including two-dimensional echocardiography (2D Echo), tissue Doppler imaging (TDI), speckle tracking (STE) and three-dimensional echocardiography (3D Echo). Patients were studied at a mean follow-up time of 6.5 ± 2.8 years from the end of therapy.ResultsNo significant differences in two-dimensional left ventricle ejection fraction (LVEF), diastolic parameters and speckle tracking (STE)-derived myocardial strain were observed between patients treated with anthracyclines and controls. Myocardial performance index was significantly prolonged (p = 0.005) and three-dimensional LVEF was significantly reduced (p = 0.002) in CCSs compared to controls, even though most values were within the normal range. There were no significant correlations between 2D, STE, and 3D echocardiographic parameters and age at diagnosis or duration of follow-up. No significant differences in echocardiographic parameters were found when stratifying cancer patients according to established risk factors for anthracycline cardiomyopathy.ConclusionsThis study found significantly reduced three-dimensional LVEF in CCSs compared with controls, despite no significant differences in two-dimensional LVEF and longitudinal strain values. These findings suggest that long-term CCSs who had received anthracycline therapy may be found to have subclinical features of myocardial dysfunction. However, further studies are needed to demonstrate the validity of new imaging techniques, including STE and 3D Echo, to identify patients at risk for cardiomyopathy in the long-term follow-up of CCSs.

Early surveillance of anthracycline induced cardiotoxicity in children using echocardiography and biomarkers: A prospective study

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CIHR Background Anthracyclines, which are commonly used in cancer treatment can induce myocardial damage, result in heart failure during treatment and have cardiac effects even decades after treatment. Monitoring of cardiotoxicity during treatment is largely based on the use of echocardiographic functional markers like ejection fraction and more recently myocardial strain imaging. Some studies have also looked at the utility of biomarkers like troponin and BNP. The utility of this surveillance strategy remains controversial as larger prospective studies are lacking. Purpose The aim of this study was to prospectively describe the impact of anthracycline treatment on echocardiographic functional parameters and cardiac biomarkers (high sensitivity troponin T and NT-Pro BNP) during the treatment period and twelve months after completion of treatment. In the current study we wanted to look at whether monitoring parameters during treatment were predictive of left ventricular function 12 months after treatment. Methods This was a prospective multi-centre nested case-control study of 256 children diagnosed with cancer requiring anthracycline therapy. Baseline functional echocardiographic parameters and cardiac biomarkers were obtained prior to starting anthracycline therapy, during the treatment protocol, and 12 months after treatment completion. Patients were assigned to one of two comparison groups based on the fractional shortening at the12-month echocardiogram: patients in group 1 had normal fractional shortening, (FS ³ 28%) while patients in group 2 had reduced fractional shortening (FS < 28%). Results A total of 917 echoes were performed, 376 of these occurred during the treatment period. FS was reduced in 27 (7%) of echoes obtained during the treatment period with 22 patients developing new onset dysfunction. Twelve months after treatment completion 232 patients had normal FS (Group 1), while 24 patients showed reduced FS (Group 2). Both groups had normal systolic function and cardiac biomarkers at baseline, however patients in group 2 were older at diagnosis (13.2 years (11.8-16) vs 6.5 years (3.4-13.2), p = 0.003) and received a higher cumulative anthracycline dose (200 mg/m2 (143-318) vs 125 mg/m2 (75-200), p= 0.005). One third (8/24) of patients in group 2 had at least 1 abnormal echo during the treatment period compared to 7% (16/232) in the normal group P < 0.001. The proportion of patients with at least one abnormal biomarker during this period however, was similar between groups. Conclusion(s) Patients receiving higher accumulative anthracycline doses and those with abnormal FS during the treatment period are at higher risk of having reduced cardiac function 12 months after treatment. High sensitivity troponin and NT-Pro BNP levels during the treatment period fail to discriminate patients at risk of developing early reduced systolic function. The relationship of these early results to long term cardiac function remains to be demonstrated.

Abstract 17007: Cardiac Magnetic Resonance Assessment of Right Ventricular Remodeling After Anthracycline Therapy

Introduction: There are limited data characterizing the effect of anthracyclines on right ventricular (RV) structure and function. Hypothesis: The goal of this study was to test the effect of anthracyclines on RV myocardial remodeling using cardiac magnetic resonance (CMR). Methods: This was a prospective CMR and serum biomarker study of 27 women with breast cancer (BC) (51.8±8.9 years) who underwent a CMR prior, and up to 3-times after anthracycline therapy (240 mg/m 2 ). The primary measure of interest was the RV extracellular volume (ECV) and cardiomyocyte mass index (1-ECV). Additional measures of interest were the left ventricular (LV) ECV, and the LV and RV mass. Biomarkers included high-sensitive troponin T, and creatinine-kinase MB isoenzyme (CKMB). Results: Before anthracyclines, all subjects had normal LV ejection fraction (EF) (69.4±3.6%) and RVEF (55.6±9%). At 351-700 days after anthracyclines, the LVEF and LV mass index declined to 58±6% (P<0.001) and 36±6g/m 2 (P<0.001). Similarly, the RVEF and RV mass index also decreased, reaching 46.3±6.8% at (222-350] days (P<0.001) and 8.13±2g/m 2 at (350-700] days (P<0.001) after anthracycline, respectively (Figure 1). At (350-700] days after anthracycline, both LV and RV ECV increased by 0.037 to 0.36±0.04 (P=0.004) and by 0.12 to 0.40±0.07 (P<0.001), respectively (Figure 2). In parallel, both the LV and RV cardiomyocyte mass also decreased after anthracyclines (Figure 2). Conclusions: In a prospective observational study among women with breast cancer, anthracyclines were associated with a decrease in the RV EF, an increase in the RV ECV and a decrease in the RV cardiomyocyte mass.