Symptomatic Cardiac Dysfunction Research Articles

Pathological complete response and survival of HER2-positive invasive breast cancer following docetaxel, carboplatin, and trastuzumab neoadjuvant therapy: a Vietnamese experience

Introduction. Neoadjuvant chemotherapy for HER2-positive breast cancer consists of a chemotherapy regimen plus trastuzumab with or without pertuzumab. The use of trastuzumab has been shown to improve pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Purposes: To evaluate the efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in the treatment of HER2-positive breast cancer in Vietnamese patients. Material and methods. This retrospective study reviewed stage II–III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) at the Vietnamese National Cancer Hospital. The primary endpoint was the pCR rate which was defined as the absence of invasive tumor in the breast and axillary nodes (ypT0/is, ypN0). The secondary endpoints were DFS, OS, and toxicities. Results. The complete and partial clinical response of 51 patients were 33.3% and 58.8%, respectively. The pCR rate was 41.2%; there was a significantly higher response in cT1-2 patients compared to cT3-4 ones (61.1% vs. 39.3%, p = 0.033). Three-year estimated DFS and OS rates were 81.3% and 93.0%, respectively. Treatment was generally well tolerated. Grade 3/4 neutropenia and anemia were uncommon (21.6% and 7.8%). No symptomatic cardiac dysfunction occurred. Conclusions. Neoadjuvant TCH, non-anthracycline chemotherapy with single anti-HER2 regimen achieved high efficacy, with a good pCR rate and favorable tolerability in stage II or III HER2-positive breast cancer patients.

Association between insulin resistance and cardiac remodeling in HER2-positive breast cancer patients: a real-world study

BackgroundInsulin resistance is an overlapping risk factor for both heart and breast cancer, while its interaction with cardiotoxicity in breast cancer (BC) patients is not clear. This study investigated the impact of insulin resistance on cardiac remodeling in patients with human epidermal growth factor receptor 2 (HER2)-positive BC during and after trastuzumab therapy in real-world clinical practice.MethodsHER2-positive BC patients who received trastuzumab treatment between December 2012 and December 2017 were reviewed and 441 patients with baseline metabolic indices and serial echocardiographic measurements (baseline, 6, 12, and 18 months) after trastuzumab therapy initiation were included. Repeated measurement analysis of variance was used to evaluate temporal trends in multiparameter echocardiography. Linear mixed model was applied to further evaluate the role of insulin resistance in forementioned changes. Correlation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) levels to changes in echocardiography parameters was explored.ResultsOf 441 patients (mean age 54 ± 10 [SD] years), 61.8% received anthracycline-based chemotherapy, 33.5% received left-sided radiotherapy, 46% received endocrine therapy. No symptomatic cardiac dysfunction was observed over the therapy course. A total of 19 (4.3%) participants experienced asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), and the peak onset time was 12 months after the initiation of trastuzumab. Albeit relatively low CTRCD incidence, cardiac geometry remodeling, especially left atrial (LA) dilation over therapy was notable and was more severe in high HOMA-IR and TyG level groups (P < 0.01). Noteworthy, a partial reversibility of cardiac remodeling was observed with treatment cessation. Additionally, HOMA-IR level positively correlated to changes in LA diameter from baseline to 12 months (r = 0.178, P = 0.003). No significant association (all P > 0.10) was detected between HOMA-IR or TyG level and dynamic left ventricular parameter evaluation. Multivariate linear regression analysis demonstrated that higher HOMA-IR level was an independent determinant for LA enlargement in BC patients during anti-HER2 targeted therapy course after adjusting for confounding risk factors (P = 0.006).ConclusionInsulin resistance was associated with left atrial adverse remodeling (LAAR) in HER2-positive BC patients that received standard trastuzumab therapy, indicating that insulin resistance could be a supplementation to baseline cardiovascular risk stratification proforma for HER2-targeted antitumor therapies.

Feature tracking cardiac magnetic resonance imaging to assess cardiac manifestations of systemic diseases.

Feature-tracking cardiac magnetic resonance (FT-CMR), with the ability to quantify myocardial deformation, has a unique role in the evaluation of subclinical myocardial abnormalities. This review aimed to evaluate the clinical use of cardiac FT-CMR-based myocardial strain in patients with various systemic diseases with cardiac involvement, such as hypertension, diabetes, cancer-therapy-related toxicities, amyloidosis, systemic scleroderma, myopathies, rheumatoid arthritis, thalassemia major, and coronavirus disease 2019 (COVID-19). We concluded that FT-CMR-derived strain can improve the accuracy of risk stratification and predict cardiac outcomes in patients with systemic diseases prior to symptomatic cardiac dysfunction. Furthermore, FT-CMR is particularly useful for patients with diseases or conditions which are associated with subtle myocardial dysfunction that may not be accurately detected with traditional methods. Compared to patients with cardiovascular diseases, patients with systemic diseases are less likely to undergo regular cardiovascular imaging to detect cardiac defects, whereas cardiac involvement in these patients can lead to major adverse outcomes; hence, the importance of cardiac imaging modalities might be underestimated in this group of patients. In this review, we gathered currently available data on the newly introduced role of FT-CMR in the diagnosis and prognosis of various systemic conditions. Further research is needed to define reference values and establish the role of this sensitive imaging modality, as a robust marker in predicting outcomes across a wide spectrum of patients.

Echocardiographic predictors of symptomatic cardiotoxicity among patients undergoing chemotherapy: A systematic review and meta-analysis.

Chemotherapeutic agents have been associated with cardiotoxicity; thus, they require close monitoring. Several echocardiographic variables have been investigated as early predictors of symptomatic cardiotoxicity in patients undergoing chemotherapy. To identify if global longitudinal strain (GLS) is a better predictor of symptomatic cardiotoxicity compared to left ventricular ejection fraction (LVEF) in patients receiving chemotherapy. MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials were searched from inception through December 2020. Adults who developed symptomatic cardiotoxicity (New York Heart Association [NYHA] Class III-IV heart failure, cardiac arrest, or cardiac death) after undergoing chemotherapy with pre- and postchemotherapy echocardiographic measures of cardiac function were included. The primary focus was on the prediction of symptomatic cardiotoxicity. Estimates were reported as random effects hazard ratios (HR) with 95% confidence intervals (CI). Four studies met inclusion criteria. The most common malignancy identified in the included studies was breast cancer, and the most common chemotherapeutic agent utilized was anthracyclines. Most studies utilized the Simpson biplane method to measure echocardiographic parameters. Pooled results demonstrated no significant association between LVEF and the prediction of symptomatic cardiotoxicity (HR 1.48; 95% CI, 0.96-2.27; P = 0.07). However, 2 studies that analyzed GLS found it to be a strong predictor of symptomatic cardiotoxicity (HR 1.46; 95% CI, 1.34-1.58; P < .001). There was no significant association between symptomatic cardiotoxicity and baseline left ventricular end diastolic volume, end systolic volume, or end diastolic volume index. GLS may predict symptomatic cardiotoxicity and be used to monitor patients on chemotherapy for symptomatic cardiac dysfunction. While the pooled results for baseline LVEF identified that it is not a predictor of symptomatic cardiotoxicity, this differs from the findings of the only randomized trial included in this meta-analysis. The data for baseline GLS as a predictor of symptomatic cardiotoxicity is encouraging, but definite evidence that GLS may be superior to LVEF is lacking. Prospective randomized, blinded trials are required to identify if 1 echocardiographic parameter may be superior to the other.

Altered spatio-specific CaMKII activation in autophagy deficient mice

Abstract Background Autophagy is linked to preventing the development of cardiac hypertrophy and failure. While aberrant activation of Ca2+/calmodulin-dependent kinase II (CaMKII) promotes myocardial remodeling, the role of autophagy in maintaining cardiac Ca2+ homeostasis and regulating CaMKII signaling is unknown. Objective To test whether loss of autophagy promotes subcellular alterations in CaMKII activation in early myocardial remodelling, and whether compromised in vivo cardiac function parallels those changes. Methods Young (10–15 weeks) cardiomyocyte-specific autophagy protein 5-deficient mice (Atg5−/−) mice and their littermate controls (Atg5+/+) underwent comprehensive in vivo phenotyping using echocardiography, exercise tolerance and hemodynamic stress testing. In vitro assessment included gravimetry, qPCR of hypertrophy marker genes and cellular and nuclear dimensions of isolated ventricular myocytes. CaMKII activation was studied by immunocytochemistry in cardiomyocytes upon exposure to basal (1Hz) or high (4Hz) pacing frequency. Autophosphorylated CaMKII (pT286) signal was evaluated in different subcellular spaces (i.e. cytoplasm, nucleoplasm and nuclear envelope). Results Before symptomatic cardiac dysfunction occurred, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation (dp/dt max: 9475±126 vs 7364±496 mmHg/s, N=4–5; p=0.041), despite similar maximum heart rate. Consequently, effort intolerance (distance run: 251±22 vs 152±13 m, N=8; p=0.03) and maximal oxygen consumption (2093±66 vs 1763±131 ml/h/kg, N=8; p=0.04) were reduced during treadmill exercise tolerance testing. Increased heart-to-body weight ratio (8.1±0.5 vs 10.2±0.8 N=9; p=0.017) was associated with elevated mRNA expression of hypertrophy marker NppB (278% of Atg5+/+, N=5; p=0.016) in Atg5−/− mice, which showed enlarged cardiomyocytes and nuclei, as width-to-length ratio. Because Atg5−/− cardiomyocytes exhibit elevated nuclear Ca2+ levels at high pacing frequency, we now measured subcellular CaMKII activation under the same experimental conditions. Interestingly, at 1Hz, p-CaMKII was increased specifically at the nuclear envelope (154% of Atg5+/+, N=5 mice, 153–159 cells; p=0.029), but not in the cytoplasm or nucleoplasm. Increasing pacing frequency to 4Hz did not alter p-CaMKII levels in Atg5+/+ cells. However, p-CaMKII was increased by ∼30% and ∼20% in the cytoplasm and nucleoplasm of Atg5−/− cells respectively (N=5 mice, 153–155 cells). Conclusion Loss of ATG5-dependent autophagy causes cardiac hypertrophy and impaired cardiac reserve upon acute stress, which involves CaMKII activation, likely through the imbalance of nuclear Ca2+ load. Although, selective increase in p-CaMKII at the nuclear envelope in Atg5−/− mice may temporarily protect from nuclear Ca2+ overload, excessive CaMKII activation in the cytoplasm and the nucleoplasm upon increased workload, likely drives hypertrophic signalling toward heart failure in autophagy-defective mice. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund (FWF)

Perinatal outcomes and factors affecting the survival rate of fetuses with twin-to-twin transfusion syndrome treated with fetoscopic laser coagulation: a single-center seven-year experience

Objectives This single-center study aimed to assess the perinatal outcomes and its associated factors in fetuses with twin-to-twin transfusion syndrome (TTTS) treated by fetoscopic laser coagulation (FLC). Methods In this retrospective study, we included fetuses prenatally diagnosed with TTTS at Asan Medical Center, Seoul, Korea, between October 2011 and December 2018. All patients with TTTS stage II or higher and those with stage I TTTS coupled with symptomatic polyhydramnios or cardiac dysfunction were eligible for FLC. Results A total of 172 cases of monochorionic diamniotic twins and one case of dichorionic triamniotic triplets were prenatally diagnosed with TTTS and treated with FLC. The median gestational ages (GAs) at diagnosis and FLC were 20.3 and 20.5 weeks, respectively. The median GA of survivors at delivery was 32.5 weeks. The overall at least one twin- and double-survival rates within 28 days after birth were 82.1% and 55.5%, respectively. The GAs at diagnosis and FLC, Quintero stage, inter-twin weight discordance, associated selective intrauterine growth restriction (sIUGR), procedure time, volume of amnioreduction, preterm prelabor rupture of membranes (PPROM) within one week after FLC, intraoperative intrauterine bleeding, and chorioamnionitis were significant predictive factors of perinatal death. Associated sIUGR, absent end-diastolic flow of umbilical artery, and abnormal cord insertion were significantly associated with donor demise in utero, whereas lower GA at diagnosis and FLC, smaller twins at FLC, pulsatile umbilical vein, and presence of mitral regurgitation were significantly associated with recipient demise in utero. Since the application of the Solomon technique, the survival rate has improved from 75.4% to 88.8%. The FLC before 17 weeks was associated with PPROM within one week after FLC and lower survival rate, whereas that after 24 weeks was associated with twin anemia-polycythemia sequence and higher survival rate. We reached a survival rate of 82% for at least one survival with only 12 procedures. Conclusions FLC is an effective treatment for TTTS. The learning curve reached the acceptable target faster than in previous studies. Several prenatal parameters are identified as predictive factors of fetal survival in TTTS treated with FLC.

Vigilance for carcinoid heart disease is still required in the era of somatostatin analogues: Lessons from a case series.

Carcinoid heart disease (CHD) is a well-documented complication of neuroendocrine tumors (NETs) due to secreted hormones causing fibrosis. Somatostatin analogues (SSAs) can decrease hormonal secretion and inhibit tumor growth. The reported incidence of CHD has decreased as SSA use has increased. We describe a series of patients who have developed CHD even though they were treated with SSA therapy. Nine patients were seen in four centers in Australia and New Zealand. The average duration of follow-up from diagnosis was 39 months. Three patients had Grade 1 and six Grade 2 disease by World Health Organization 2010 criteria. All patients had no CHD symptoms at baseline and started SSA therapy soon after diagnosis, yet developed significant, symptomatic cardiac dysfunction in their disease course. The median time from NET diagnosis to SSA initiation was 1 month, and median time from NET diagnosis to CHD diagnosis was 23 months (range 4-52). All patients who were tested had persistently increased hormonal levels (chromogranin A, urinary 5-hydroxyindolacetic acid). The good symptomatic control afforded by SSAs should not lead to reduced vigilance in screening for CHD, especially in patients with persistently elevated hormonal assays. Clinicians should consider regular echocardiographic screening in patients with a secretory syndrome.

1671O - Assessment of cardiotoxicity (CT) associated with doxorubicin (dox) in patients (pts) with advanced soft tissue sarcoma (STS) in a phase III randomized trial

BackgroundThe ANNOUNCE trial evaluated the efficacy of the anti-PDGFR alpha antibody olaratumab + dox versus placebo + dox in adults with STS. CT was a secondary safety objective. MethodsTreatment included dox 75mg/m2 on Day 1 of a 21-day cycle for up to 8 cycles, with olaratumab/placebo on Days 1, 8 until progression. Use of the cardioprotectant dexrazoxane was allowed with any cycle and recommended with Cycle 5 and beyond. Pts were monitored for left ventricular ejection fraction (LVEF) decreases after 4, 6, 8 cycles and electrocardiogram (ECG) changes in cycles 1 to 9; both were then monitored every 3 months for 1 year, every 6 months for 1 year, then annually. Eligible pts had a LVEF of≥50% at baseline, and were without QTc prolongation, active symptoms of cardiac arrhythmia/dysfunction, and prior anthracycline exposure or mediastinal/pericardial radiation. ResultsMedian age was 57 years. Medical history included cardiac disorders (n=33; 6.5%) and ECG abnormalities (n=1; 0.2%). Of the 506 treated pts from both arms, 504 (99.6%) had at least 1 dox dose, of which, 64.0% received at least 1 dose of dexrazoxane, with 61.0% of these pts starting before Cycle 6. Median dox exposure was 6 cycles/450mg/m2; median duration of CT evaluation was 28 weeks. One pt died due to acute cardiac failure after a cumulative dox dose of 441mg/m2. Adverse events (AEs) of cardiac dysfunction/decreased LVEF are summarized (Table). ECG abnormalities considered AEs occurred in 15 (3.0%) pts. ConclusionsThe ANNOUNCE trial prospectively evaluated CT in a large cohort of dox-treated adults with STS, most of whom received dexrazoxane for cardioprotection. Although LVEF decreases were common with routine monitoring, symptomatic cardiac dysfunction was reported infrequently. Frequency of CT was similar in both arms. Longer safety follow-up may be warranted to determine the true rate of CT with higher cumulative doses of dox.Table1671OTableCumulative Dox Dose (Pooled)Overall<300mg/m2 (n=181)300 to≤500mg/m2 (n=114)>500mg/m2 (n=211)Dox-Olaratumab (n=257)Dox-Placebo (n=249)Any≥G3Any≥G3Any≥G3Any≥G3Any≥G3Cardiac dysfunctiona0018 (15.8)9 (7.9)8 (3.8)2 (0.9)12 (4.7)5 (1.9)14 (5.6)6 (2.4)Number of Dox Cycles (Pooled)Lowest Post-baseline4 Cycles (n=201)6 Cycles (n=153)8 Cycles (n=158)Dox-Olaratumab (n=200)Dox-Placebo (n=201)Decreased LVEFb44 (21.9)36 (23.5)49 (31.0)96 (48.0)98 (48.8)Data are presented as n (%). Abbreviations: Dox, doxorubicin; G, grade; LVEF, left ventricular ejection fraction.aCardiac dysfunction was defined by pre-selected terms from Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query “cardiac failure,” omitting non-specific terms “edema” and “peripheral edema.”bLVEF decrease by<50% and/or >10% from baseline. Clinical trial identificationNCT02451943. Editorial acknowledgementKaren Paulsrud, RPh, with Eli Lilly and Company, provided medical writing support. Legal entity responsible for the studyEli Lilly and Company. FundingEli Lilly and Company. DisclosureR.L. Jones: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Epizyme; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Merck; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Tracon. A.J. Wagner: Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy: Nanocarrier; Honoraria (self): Novartis; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Aadi Bioscience; Research grant / Funding (institution): Karyopharm. A. Kawai: Honoraria (self), Advisory / Consultancy: Eli Lilly and Company. A. Shahir: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. V. Soldatenkova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. J. Wright: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. W.D. Tap: Shareholder / Stockholder / Stock options: Certis Oncology Solutions; Shareholder / Stockholder / Stock options: Atropos Therapeutics; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Immune Design; Honoraria (self), Advisory / Consultancy: Adaptimmune; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Blueprint; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Agios Pharmaceuticals; Honoraria (self), Advisory / Consultancy: NannoCarrier; Advisory / Consultancy: Plexxikon Pharmaceuticals; Licensing / Royalties: Companion Diagnostic for CDK4 inhibitors; Officer / Board of Directors, Editor in Chief: Sarcoma Journal; Officer / Board of Directors, Treasurer: Connective Tissue Oncology Society.

Immune response proteins as predictive biomarkers of doxorubicin-induced cardiotoxicity in breast cancer patients.

Cancer treatment with doxorubicin (DOX) can induce cumulative dose-dependent cardiotoxicity. Currently, there are no specific biomarkers that can identify patients at risk during the initial doses of chemotherapy. The aim of this study was to examine plasma cytokines/chemokines and potential cardiovascular biomarkers for the prediction of DOX-induced cardiotoxicity. Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-based chemotherapy of 27 breast cancer patients, including five patients who presented with >10% decline of left ventricular ejection fraction (LVEF), five patients with LVEF decline of 5-10%, and 17 patients who maintained normal LVEF at the end of chemotherapy (240mg/m2 cumulative dose of DOX from four cycles of treatment). Multiplex immunoassays were used to screen plasma samples for 40 distinct chemokines, nine matrix metalloproteinases, 33 potential markers of cardiovascular diseases, and the fourth-generation cardiac troponin T assay. The results showed that the patients with abnormal decline of LVEF (>10%) had lower levels of CXCL6 and sICAM-1 and higher levels of CCL23 and CCL27 at T0; higher levels of CCL23 and lower levels of CXCL5, CCL26, CXCL6, GM-CSF, CXCL1, IFN-γ, IL-2, IL-8, CXCL11, CXCL9, CCL17, and CCL25 at T1; and higher levels of MIF and CCL23 at T2 than the patients who maintained normal LVEF. Patients with LVEF decline of 5-10% had lower plasma levels of CXCL1, CCL3, GDF-15, and haptoglobin at T0; lower levels of IL-16, FABP3, and myoglobin at T1; and lower levels of myoglobin and CCL23 at T2 as compared to the patients who maintained normal LVEF. This pilot study identified potential biomarkers that may help predict which patients are vulnerable to DOX-induced cardiotoxicity although further validation is needed in a larger cohort of patients. Impact statement Drug-induced cardiotoxicity is one of the major concerns in drug development and clinical practice. It is critical to detect potential cardiotoxicity early before onset of symptomatic cardiac dysfunction or heart failure. Currently there are no qualified clinical biomarkers for the prediction of cardiotoxicity caused by cancer treatment such as doxorubicin (DOX). By using multiplex immunoassays, we identified proteins with significantly changed plasma levels in a group of breast cancer patients who were treated with DOX-based chemotherapy and produced cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment or at early doses of treatment, thus they could be potential predictive biomarkers of cardiotoxicity although further validation is required to warrant their clinical values.

Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups. Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity

Cardiotoxicity is a well-known complication following treatment with anthracyclines. However, they are still widely used in chemotherapy for breast cancer, lymphoma, leukemia, and sarcoma, among others. Patient clinical characteristics, such as age, sex, comorbidities, anthracycline dose and infusion schedule, and the combined anti-cancer agents used, are diverse among cancer types. It is difficult to recommend guidelines for the prevention or management of anthracycline-induced cardiotoxicity applicable to all cancer types. Therefore, anthracycline-induced cardiotoxicity remains a major limitation in the proper management of cancer patients treated with an anthracycline-combined regimen. Efforts have been extensive to determine the mechanism and treatment of anthracycline-induced cardiotoxicity. Because cardiotoxicity causes irreversible damage to the myocardium, prevention is a more effective approach than treatment of cardiotoxicity after symptomatic or asymptomatic cardiac dysfunction develops. This article will review the pathophysiological mechanisms of anthracycline-induced cardiotoxicity and strategies for protecting the myocardium from anthracycline.

Abstract P4-14-07: Outcome with use of 12 weeks of adjuvant or neoadjuvant trastuzumab in a resource constrained setting

Abstract Background: Adjuvant trastuzumab has improved overall survival in women with HER2 receptor positive breast cancer. However, only a small fraction (4%) of eligible patients in resource constrained settings have access to this drug. A patient assistance program of 12 weeks of adjuvant or neoadjuvant trastuzumab was thus started for those who did not have any access to trastuzumab due to financial constraints. We undertook a retrospective analysis of outcomes in women who were enrolled between January 2011 to December 2012 in this patient assistance program. Methods: Patients received four cycles of anthracycline based chemotherapy (AC/CAF/ EC/CEF) and 12 doses of weekly paclitaxel (80mg/m2) with trastuzumab (4mg/kg loading followed by 2mg/kg) in the neoadjuvant or adjuvant setting in either sequence (anthracycline followed by taxane trastuzumab or taxane trastuzumab followed by anthracycline). Patients received adjuvant hormonal therapy depending on the hormone receptor status. The primary endpoint of this analysis was disease free survival (DFS). Results: A total of 103 patients with HER2 receptor positive breast cancer were analysed. The median age was 46 (24-65) years, 50% were premenopausal, 60.7% had stage III disease (86.8% had node positive disease) and 37% patients had ER and or PR positive disease. Forty patients (38.8%) had breast conserving surgery while the rest had modified radical mastectomy. At a median follow-up of 34 (7-46) months the 3-year DFS and overall survival was 77.2% and 82.7% respectively. Among patients who developed recurrence one had only local recurrence, 4 had both local and distant recurrence and 11 had distant metastasis alone. Of the 15 patients who developed distant metastasis 7 had brain involvement . Symptomatic cardiac dysfunction developed in four patients, two of whom died while in the other 2 ejection fraction recovered. The results are summarised in the table. Patient Characteristic and outcome with 12 weks of adjuvant or neoadjuvant TrastuzumabNumber of PatientsNode Positive (%)Hormone Positive (%)DFS at 3 yearsOS at 3 yearsBrain Mets(%)Grade 3/4 Cardiac Toxicity(%)10386.83777.282.76.83.9 Conclusions: These results suggest that 12 weeks of neoadjuvant or adjuvant trastuzumab is an acceptable alternative in patients who lack access to full 1 year of trastuzumab. Citation Format: Ghosh J, Joy Phillip DS, Ghosh J, Gupta S, Bajpai J, Gulia S, Parmar V, Nair N, Budrukkar AN, Jalali R, Desai SB, Sawant S, Dhir AA, Kembhavi S, Hawaldar R, Banavali SD, Badwe RA. Outcome with use of 12 weeks of adjuvant or neoadjuvant trastuzumab in a resource constrained setting. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-07.

The Importance of Fragmented QRS in Systemic Sclerosis Patient's Early Diagnosis of Cardiac Involvement

PP-179 Systemic sclerosis (SSc) is autoimmune connective tissue disease that characterized with fibrosis and diffuse vascular lesions. Even though cardiac involvement is rarely in clinical, myocardial fibrosis is to be expressed in proportion of %50-80. When clinical symptomatic cardiac dysfunction

Abstract 156: Prognostic significance of distance travelled to the cancer center in women treated with adjuvant trastuzumab.

Abstract Background: Adjuvant trastuzumab therapy (ATT) in women with HER2 positive breast cancer has significantly improved survival. The current standard duration of ATT is one year. In order to prevent symptomatic cardiac dysfunction, periodic cardiac monitoring is recommended during ATT. Rural residents have to travel in excess of several hundred kilometers both for cardiac monitoring and treatment. The study aims to determine relationship between distance travelled to the cancer center and disease free survival (DFS) and overall survival (OS) in women with HER2 positive breast cancer. Methods: Retrospective cohort study of women with early stage HER2 positive breast cancer treated in the province of Saskatchewan from 2005 to 2009. The study cohort was divided into two groups: group I (distance travelled &amp;lt;100 km) and group II (distance travelled 100 km). Kaplan-Meier methods were used for survival estimation and Log Rank testing was done for survival comparison. Cox proportional hazard models were performed and various clinico-pathological variables were examined for their prognostic significance. Results: A total of 211 eligible women with median age of 54 yrs (range: 27-80) were identified. 70% were postmenopausal, 52% had node positive disease and 60% had ER or PR positive disease. 57% women were rural residents. A statistically significant difference was noted between the 2 groups with respect to age, rural residence, comorbid illness and delay in start of therapy. All women received adjuvant chemotherapy and ATT. 97% women completed adjuvant chemotherapy and 83% completed planned ATT. During the median follow-up period of 37.1 months, 30 women developed recurrent disease and 26 died. Median DFS of Group II was 63.09 months and has not reached in Group I (p=0.5). Median OS of both groups has not reached. 5 years estimated DFS of group I was 77% compared with 57% in Group II (p=0.5). ER/PR negative disease, hazard ratio (HR) 2.53 (95% CI: 1.14-5.64) and discontinuation of ATT, HR 2.3 (95% CI: 1.06-5.00) were significantly correlated with an increased risk of recurrence. With respect to survival younger age, HR 5.33 (95% CI: 1.72-16.52); ER/PR negative tumors, HR 6.6 (95% CI: 2.23-19.37); and premenopausal status, HR 8.18 (95% CI: 2.27-29.51) were correlated with an increased mortality. Conclusions: Although there was a trend toward increased risk of recurrence in women travelled longer distance, it was not statistically significant. Younger age, premenopausal status, ER/PR - tumors and discontinuation of ATT were correlated with inferior outcomes. Citation Format: Sarah Roberts, Sabuj Sarker, Richard Lee-Ying, Charanpreeti Ubhi, Shahid Ahmed. Prognostic significance of distance travelled to the cancer center in women treated with adjuvant trastuzumab. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 156. doi:10.1158/1538-7445.AM2013-156

ARRHYTHMIA ASSOCIATED WITH ACUTE CORONARY SYNDROME: OCCURRENCE, RISK FACTORS, THERAPY AND PROGNOSIS: A SINGLE-CENTRE STUDY

ObjectivesArrhythmia associated with acute coronary syndrome is a common phenomenon. Careful investigation on its occurrence and risk factors in this progressed clinical scenery may lead to further standardisation of therapy...

Long Term Follow-Up of National Surgical Adjuvant Breast and Bowel Project Trial B-31: How Well Can We Predict Cardiac Toxicity With Trastuzumab?

Theintroductionofadjuvant trastuzumabhasdramaticallyreduced recurrence rates and improved survival among women with stage I to III human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Although the majority of trials have evaluated the use of trastuzumab administered sequentially after an anthracycline-based regimen, other regimens have also been evaluated, including the regimen of docetaxel, carboplatin, and trastuzumab (TCH). The motivation for testing a nonanthracycline-based regimen was founded largely on concerns about both shortand long-term cardiotoxicity. Indeed, in the pivotal trial that was conducted in the first-line metastatic setting, 27% of patients receiving concurrent doxorubicin, cyclophosphamide, and trastuzumab developed either symptomatic or asymptomatic cardiac dysfunction, compared with 13% of patients who received paclitaxel with trastuzumab. Fortunately, rates of early cardiac dysfunction in the large adjuvant trastuzumab trials have been substantially lower than might have been predicted from the metastatic data. In the Herceptin Adjuvant (HERA) study that evaluated a sequential regimen of trastuzumab monotherapy after completion of chemotherapy, the rate of severe congestive heart failure (CHF) was 0.8%, and 3.6% of individuals experienced a significant decrease in left ventricular ejection fraction (LVEF) at a median follow-up of 3.6 years. In the North Central Cancer Treatment Group (NCCTG) N9831 study, among patients who received doxorubicin and cyclophosphamide followed by concurrent trastuzumab-paclitaxel (ACTH), the cumulative incidence of cardiac events was 3.3% at 3 years. In two phase II trials that explored dose-dense doxorubicin and cyclophosphamide preceding trastuzumab-based regimens, the rates of cardiac toxicity were also low at short-term follow-up. However, there remain valid concerns about the impact of trastuzumab on longer term cardiac outcomes. As highlighted in a recent editorial, the long-term sequelae of trastuzumab-associated CHF and the clinical meaning of the asymptomatic drops in LVEF are still incompletely characterized. If the superiority of TCH compared with ACTH were unquestioned, then there would be little debate. However, the Breast Cancer International Research Group (BCIRG) 006 trial was neither designed nor adequately powered to directly compare these two regimens, and the 3% absolute difference in disease-free survival favoring ACTH raises the possibility that the two regimens may not have equivalent efficacy. Given these issues, how can oncologists provide the most balanced recommendations, and how can patients make the most informed decisions, taking into account both efficacy and toxicity on an individual patient-by-patient basis? Although the role of anthracyclines in the treatment of HER2positive breast cancer continues to be debated, rightly or wrongly, clinicians and patients are voting with their feet. Nationally, the use of anthracycline-based trastuzumab regimens has declined precipitously in recent years. In 2008, among the Medicare population, taxane-based trastuzumab regimens were administered five times more frequently than anthracycline-based regimens. Even among patients younger than age 65 years in an insurance claims database (64% younger than age 55 years), taxane-based trastuzumab regimens were employed approximately twice as often as anthracycline-based regimens (S. Giordano, personal communication, June 2012). Although we are not aware of large-scale studies examining the factors underlying this shift, it is reasonable to postulate that concerns about toxicity, and in particular, cardiac toxicity, are likely a major driver. In the article that accompanies this editorial, Romond et al present results of a 7-year follow-up of cardiac function in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 clinical trial. The trial randomly assigned patients with node-positive, HER2-positive primary breast cancer to receive either anthracyclineand taxane-based chemotherapy alone or with trastuzumab, with the trastuzumab initiated concurrently with commencement of the taxane. A cardiac event was defined as cardiac death or symptomatic CHF with concomitant decline in LVEF. The cumulative incidence of cardiac event at 7 years was 4.0% in the trastuzumab arm and 1.3% in the nontrastuzumab arm, a 2.7% absolute difference. Notably, only two of the 37 cardiac events in the trastuzumab arm occurred beyond 2 years of follow-up; overall, LVEF recovered to 50% or greater in more than half of patients (58%). Only one cardiac death has been observed to date in either arm of the trial. The authors also report the outcomes of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 31 NOVEMBER 1 2012

A modified juvenile arthritis damage index to improve articular damage assessment in juvenile idiopathic arthritis—enthesitis-related arthritis (JIA-ERA)

Juvenile arthritis damage index (JADI) consists of two parts which measure articular (JADI-A) and extra-articular (JADI-E) damage in patients with juvenile idiopathic arthritis (JIA). It does not include assessment of cardiac dysfunction and joint areas commonly affected in enthesitis-related arthritis (ERA) category of JIA. We have tried to study if modification of JADI will improve its performance in JIA-ERA. We studied 101 consecutive patients of JIA-ERA. JADI-A was modified (JADI-AM) to include damage assessment of tarsal joints and lumbar spine. JADI-E was modified (JADI-EM) to include assessment of symptomatic cardiac dysfunction. The performances of the modified and standard JADI were compared. Ninety-seven patients were male. The median age was 18 years (9-36). At a median disease duration of 6 years (1-24), joint damage was observed in 47 as assessed by JADI-A. JADI-AM could identify 11 more patients (N = 58) with articular damage. JADI-AM had good correlation with number of joints with limitation of movement (Spearman's [rS] = 0.9) and low to moderate correlation (rS < 0.7) with measures of disease activity and functional status. JADI-AM discriminated well among patients with different disability levels. Extra-articular damage was observed in 35, and modification of JADI-E with inclusion of cardiac dysfunction did not identify any additional patient. Thus, we propose a modification of the JADI-A (JADI-AM). In JIA-ERA, modification of JADI-A improves its ability to identify articular damage. Modification of the JADI-E may not be needed as symptomatic cardiac involvement is rare.

Radiosensitization of Chemotherapy-Refractory, Locally Advanced or Locally Recurrent Breast Cancer With Trastuzumab: A Phase II Trial

Trastuzumab (Herceptin), an anti-human epidermal growth factor receptor 2 (HER2) antibody, has been shown to be an effective radiosensitizer in preclinical studies. The present Phase II trial evaluated trastuzumab plus radiotherapy in patients with HER2-positive, chemotherapy-refractory, locally advanced or locoregionally recurrent breast cancer. Eligible patients had measurable disease, normal cardiac function, and biopsy-confirmed residual HER2-positive disease. Patients received weekly trastuzumab (2 mg/kg intravenously), concurrent with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks. If feasible, surgery followed radiotherapy. The primary endpoint was safety, and the secondary endpoint was efficacy (pathologic response and interval to symptomatic local progression). Of the 19 patients enrolled, 7 were ineligible and received radiotherapy alone and 12 received therapy per protocol. Of these 12 patients, 11 had a Stage T4 diagnosis. Grade 3 toxicities included skin (n = 2) and lymphopenia (n = 1). One patient experienced delayed wound healing after surgery. No patients developed symptomatic cardiac dysfunction. Of the 7 patients who had undergone mastectomy, 3 (43%) had a substantial pathologic response (complete response or microscopic residual disease), significantly more than a comparison cohort (2 of 38 or 5%, p = .02). The median interval to symptomatic local progression was not reached. The median overall survival was 39 months. This is the first prospective trial providing evidence for a radiosensitizing effect of trastuzumab in breast cancer. The combination of trastuzumab and radiotherapy was well tolerated.

111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: A clue to uncover the mechanisms of trastuzumab-related cardiotoxicity

Aim Trastuzumab can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial human epidermal growth factor receptor 2 (HER2) expression may be transiently upregulated by a compensatory mechanism following cardiac stress. 111In-DTPA-trastuzumab, scintigraphy can detect HER2 positive tumour lesions, however previously, we found myocardial uptake in only 1 of the 15 anthracycline-pre-treated patients with a median of 11 months after the last anthracycline administration. To evaluate whether myocardial HER2 expression is upregulated by anthracycline-induced cardiac stress or in case of heart failure by chronic pressure or volume overload, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracyclines and with non-anthracycline-related heart failure. Methods Patients within 3 weeks after undergoing 4–6 cycles first-line anthracycline-based chemotherapy and patients with heart failure due to cardiac disease underwent gammacamera imaging 48 and 96 h after 111In-DTPA-trastuzumab intravenously. Results Myocardial 111In-DTPA-trastuzumab uptake was observed in 5 out of 10 anthracycline-treated patients, who all were without symptomatic cardiac dysfunction. None of the 10 heart failure patients showed myocardial uptake. Conclusion Shortly after completion of anthracycline treatment, myocardial HER2 over-expression was detectable in 50% of the patients. 111In-DTPA-trastuzumab scintigraphy after anthracyclines prior to adjuvant trastuzumab potentially identifies patients susceptible for trastuzumab-related cardiotoxicity and thus may facilitate the optimal timing of trastuzumab therapy.

Multicenter Phase II Trial of Neoadjuvant Therapy With Trastuzumab, Docetaxel, and Carboplatin for Human Epidermal Growth Factor Receptor-2–Overexpressing Stage II or III Breast Cancer: Results of the GETN(A)-1 Trial

Trastuzumab plus chemotherapy has become the standard of care for human epidermal growth factor receptor-2 (HER-2) -positive breast cancer. Trastuzumab-based preoperative systemic therapy (PST; neoadjuvant therapy) also appears promising, warranting further investigation. Patients with HER-2-positive, stage II/III, noninflammatory, operable breast cancer requiring a mastectomy (but who wanted to conserve the breast) received trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, plus docetaxel 75 mg/m2 every 3 weeks, and carboplatin (area under curve, 6) for six cycles before surgery. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens. Seventy patients were enrolled. Most patients had clinical T2/T3 tumors (100%) or clinical N1/2 nodes (53%). Sixty-seven patients (96%) completed six cycles of therapy, one patient withdrew due to progressive disease, and two patients withdrew for toxicity. A complete or partial objective clinical response occurred in 95% of patients (85% and 10%, respectively). Surgery was breast conservative in 45 (64%) of 70 patients. In an intent-to-treat analysis, tumor and nodal pCR were seen in 27 (39%) of 70 patients. Centralized retrospective analysis of HER-2 status demonstrated a 43% pCR rate in the 24 of 56 confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization-positive tumors. Treatment was generally well tolerated. Grade 3/4 neutropenia and febrile neutropenia were uncommon (2%). Two patients withdrew prematurely due to a transient, asymptomatic decrease in left ventricular ejection fraction. No symptomatic cardiac dysfunction occurred. PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.