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Background Anthracycline chemotherapy (AC) is an efficacious (neo) adjuvant treatment for early-stage breast cancer (BCa), but is associated with an increased risk of cardiac dysfunction and functional disability. Observations suggest that regular exercise may be a useful therapy for the prevention of cardiovascular morbidity but it is yet to be interrogated in a large randomised trial. The primary aims of this study are to: 1) determine if 12-months of ET commenced at the onset of AC can reduce the proportion of BCa patients with functional disability (peak VO 2 , < 18 ml/kg/min), and 2) compare current standard-of-care for detecting cardiac dysfunction (resting left-ventricular ejection fraction assessed from 3-dimensional echocardiography) to measures of cardiac reserve (peak exercise cardiac output assessed from exercise cardiac magnetic resonance imaging) for predicting the development of functional disability 12-months following AC. Secondary aims are to assess the effects of ET on VO2peak, left ventricular morphology, vascular stiffness, cardiac biomarkers, body composition, bone mineral density, muscle strength, physical function, habitual physical activity, cognitive function, and multidimensional quality of life. Methods One hundred women with early-stage BCa (40–75 years) scheduled for AC will be randomized to 12-months of structured exercise training ( n  = 50) or a usual care control group ( n  = 50). Participants will be assessed at baseline, 4-weeks following completion of AC (4-months) and at 12-months for all measures. Discussion Women diagnosed with early-stage BCa have increased cardiac mortality. More sensitive strategies for diagnosing and preventing AC-induced cardiovascular impairment are critical for reducing cardiovascular morbidity and improving long-term health outcomes in BCa survivors. Trial registration Australia & New Zealand Clinical Trials Registry (ANZCTR), ID: 12617001408370 . Registered on 5th of October 2017.

Background The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer is a poor prognosis. Trastuzumab improves overall survival but is associated with cardiotoxicity, especially a decline in left ventricular ejection fraction (LVEF). In addition, chemotherapy and radiotherapy increase fatigue and pain, decrease physical capacity and health-related quality of life. To date, no study has evaluated the benefits of physical activity on the side effects of treatment in patients with HER2 positive breast cancer. The aim of this study is to evaluate the impact of 3 months’ exercise intervention on myocardial function and in particular on the rate of cardiotoxicity. Methods This multicenter, randomized clinical trial will include 112 patients treated by adjuvant trastuzumab for HER2 positive breast cancer to investigate the effects of a 3 months’ supervised exercise program (intermittent exercise, combining moderate and high intensities; 55 minutes duration, 3 times per week), on the rate of cardiotoxicity [defined by either a decrease of the LVEF under 50% or an absolute drop of LVEF of 10%] between baseline and at 3 months and on strength, aerobic capacity, metabolic, inflammatory and hormonal parameters. Health-related quality of life, fatigue, pain and level of physical activity will also be assessed. Participants are randomly allocated to one of the two groups (“training group” vs “standard oncological care”). Performance-based and self-reported outcomes are assessed at baseline, at the end of supervised exercise program and at six months follow-up. Discussion Although physical exercise is recommended to reduce the side effects of adjuvant treatments in breast cancer patients, no randomized study has been conducted to assess the benefits of a physical training program in patients with HER2 overexpressing breast cancer. Cardiac toxicity of trastuzumab may be minimized with an exercise program combining high and moderate intensities. This type of program may be safe, feasible and effective but also increase cardiorespiratory fitness and improve health-related quality of life. If these benefits are confirmed, this exercise intervention could be systematically proposed to patients during the course of treatment by trastuzumab in addition to standard oncological care. Trial registration National Clinical Trials Number ( NCT02433067 ); Registration 28 april 2015.

Despite the known cardiotoxic effects of doxorubicin and other anthracyclines, no evidence-based guidelines exist for the surveillance and prevention of chemotherapy-induced cardiotoxicity in adult survivors of breast cancer who have had limited previous doses of anthracyclines (ie, total cumulative dose 240 mg/m2), or limited-dose anthracyclines followed by trastuzumab-based regimens. Nonetheless, some national and international cardio-oncology and cardiac-imaging organisations recommend increased cardiac surveillance during or after treatment, measurement of cardiac biomarkers and other surrogate endpoints, and in some cases initiation of cardioprotective drug therapy in asymptomatic women. However, two unintended potential harms of such approaches are medicalisation (definition and treatment of subclinical heart problems without high-level evidence for a consequent reduction in the incidence of subsequent heart failure or cardiac deaths) and increased health-care costs when the value of providing that care is unknown. Whether existing cardio-oncology or imaging guideline recommendations will provide increased value or cause increased distress and lower health-related quality of life is unknown. Further research is needed to assess the long-term benefits, harms, and value of expanded cardiac surveillance, use of surrogate cardiac biomarkers, and prophylactic cardioprotective therapy in asymptomatic women with limited exposure to anthracyclines.

BackgroundBreast cancer is a leading cause of death for women worldwide, with incidence increasing in lower-income countries. For patients with human epidermal growth factor receptor-2-positive (HER2+) breast cancer, widespread availability of several agents targeting the HER2 receptor has resulted in survival gains over the past decades. However, improved survival has resulted in an increased need for management and mitigation of adverse events associated with anticancer therapy. Cardiac adverse events such as decreased ejection fraction and heart failure have been of particular concern in patients with HER2+ breast cancer. Anti-HER2 agents and chemotherapies (specifically anthracyclines, which are frequently used to treat HER2+ disease) have been associated with cardiotoxicity. As increasing numbers of patients are living longer due to more effective therapy, a better understanding of both monitoring and management of cardiotoxicity is urgently needed.MethodsA comprehensive review of the literature was conducted via PubMed in January 2018 for phase II and phase III trials of “trastuzumab”, “lapatinib”, “pertuzumab”, “T-DM1”, “neratinib”, in “breast cancer”. Literature was evaluated for content related to cardiac adverse events.FindingsWe describe the incidence of and proposed mechanisms for the cardiotoxicity of available HER2-targeted therapies. We summarize current and emerging practices in the management of cardiotoxicity and provide guidance for routine patient care in real-world practice using illustrative patient scenarios.ConclusionsThe future of cardiotoxicity management in patients with HER2+ breast cancer is discussed, with a focus on novel techniques to improve cardiac outcomes, including new imaging modalities, biomarkers, interventional therapies, and ongoing trials.

Purpose of ReviewImmune checkpoint inhibitors (ICIs) have improved the survival of several cancers. However, they may cause a wide range of immune-related adverse events (irAEs). While most irAEs are manageable with temporary cessation of ICI and immunosuppression, cardiovascular toxicity can be associated with high rates of morbidity and mortality. As ICIs evolve to include high-risk patients with preexisting cardiovascular risk factors and disease, the risk and relevance of ICI-associated cardiotoxicity may be even higher.Recent FindingsSeveral cardiovascular toxicities such as myocarditis, stress cardiomyopathy, and pericardial disease have been reported in association with ICIs. Recent findings also suggest an increased risk of atherosclerosis with ICI use. ICI-associated myocarditis usually occurs early after initiation and can be fulminant. A high index of suspicion is required for timely diagnosis. Prompt treatment with high-dose corticosteroids is shown to improve outcomes.SummaryAlthough the overall incidence is rare, ICI cardiotoxicity, particularly myocarditis, is associated with significant morbidity and mortality, making it a major therapy-limiting adverse event. Early recognition and prompt treatment with the cessation of ICI therapy and initiation of high-dose corticosteroids are crucial to improve outcomes. Cardio-oncologists will need to play an important role not just in the management of acute cardiotoxicity but also to reduce the risk of long-term sequelae.

With an ever-expanding repertoire of cancer therapies, cardiologists increasingly encounter patients with cancer therapy–related cardiac dysfunction. This can range from asymptomatic mild left ventricular dysfunction to severe symptomatic congestive heart failure. A multidisciplinary approach involving oncologists and cardiologists is needed in the management of these patients. This case-based review provides a practical guide for clinicians regarding the diagnosis and management of cancer therapy–related cardiac dysfunction associated with commonly used cancer treatments: anthracyclines, human epidermal receptor 2–targeted therapies, and immune checkpoint inhibitors.

Adriamycin (doxorubicin hydrochloride) is a widely used chemotherapeutic agent for treating various malignancies. However, its most significant adverse effect is cardiac toxicity. Early detection of Adriamycin-induced cardiac dysfunction is crucial in preventing heart failure through interventions such as angiotensin-converting enzyme inhibitors and beta-blockers. Adriamycin-induced cardiotoxicity is classified into Type I (irreversible, involving cardiomyocyte necrosis) and Type II (potentially reversible, involving cardiomyocyte dysfunction). Type I toxicity is more common, leading to long-term heart cell necrosis. Monitoring cardiac function in children receiving Adriamycin is essential. Non-invasive imaging techniques like transthoracic echocardiography, cardiac magnetic resonance imaging, and computed tomography are used to evaluate left ventricular (LV) systolic and diastolic functions. However, the role of cardiac Troponin I for early detection of anthracycline-induced cardiomyopathy remains debated. This prospective study included 50 children (26 males, 24 females) with a median age of 8 years (range: 2-14) receiving Adriamycin. Troponin I levels were measured before and 24 hours after Adriamycin administration. Standard Doppler Echocardiography and Tissue Doppler Imaging (TDI) were performed at baseline, one month, and six months' post-treatment to assess LV function. Out of 50 patients, two showed a decrease in left ventricular ejection fraction (LVEF) below the normal range (<55%) one month post-treatment, along with significant increases in Troponin I levels. No significant decline in LVEF was observed at one or six months' post-treatment using Standard Doppler Echocardiography. However, TDI revealed a decrease in LV systolic and diastolic function in all patients one month after Adriamycin administration. TDI is more sensitive than Standard Doppler Echocardiography in detecting Adriamycin-induced cardiotoxicity. Elevated cardiac Troponin I levels correlate with a decline in LVEF, but subclinical cardiac dysfunction is better detected with TDI.

Purpose Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. Methods We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. Results Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [adjusted hazard ratio (aHR) = 1.02, 95% confidence interval (CI) 1.00–1.04; p  = 0.05], metastasis (aHR = 2.66; 95% CI 1.36–5.20; p  < 0.01), and concomitant trastuzumab (aHR = 4.08; 95% CI 2.31–7.21; p  < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. Conclusions Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.

Trastuzumab (Tra)-induced cardiotoxicity (TIC) is a serious side effect of cancer chemotherapy, which can seriously harm the health of cancer patients. However, there is currently a lack of effective and reliable biomarkers for the early diagnosis of TIC in clinical practice. Therefore, we screened the TIC candidate diagnostic gene solute carrier family 6 member 6 (SLC6A6) by combining multi-machine learning algorithm based on bioinformatics. In addition, cross-validation showed that SLC6A6 had a consistent expression trend in multi-data-sets. To further explore the diagnostic capability of SLC6A6 in TIC, we constructed a nomogram diagnostic model based on SLC6A6 expression level, and receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis proved that SLC6A6 had good diagnostic capability. In order to further verify the TIC expression of SLC6A6 in the real world, we have constructed cell and animal models. Animal experiments showed that left ventricular ejection fraction (LVEF) was significantly decreased (from 65.01 ± 3.30% and 351.32 ± 3.51%, p < 0.0001) after Tra injection, and severe cardiac function was impaired. Similarly, RT-QPCR demonstrated that SLC6A6 was significantly downregulated in Tra-treated cardiomyocytes in vitro and in vivo. Our study suggests that the differential expression of SLC6A6 in vitro and in vivo models is associated with TIC, which may be a candidate diagnostic gene for the early occurrence and development of TIC and a potential therapeutic target.

Background Combined anthracycline-trastuzumab chemotherapy has been associated with LV dysfunction. We aimed to assess early changes in left ventricular (LV) and right ventricular (RV) mechanics associated with combined anthracycline-trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)–speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity. Methods Sixty-six patients with breast cancer who received anthracycline-trastuzumab treatment were included (mean [±SD] age, 52 [9] years). Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), first cycle (T1), and second cycle (T2) of combined chemotherapy. All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. Results Cardiotoxicity developed in 13 of the 66 patients (20%). The mean (±SD) LVEF at T0 was 66% (±6); at T1 60% (±7); and at T2, 54% (±6). For the 53 patients without cardiotoxicity, the LVEF was 65% (±4%) at T0, 63% (±5%) at T1, and 62% (±4) at T2. Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, − 14.06; sensitivity, 91%; specificity, 83%; P  = .003). Compared with baseline (T0), left ventricular longitudinal strain, LV circumferential strain, circumferential peak systolic strain rate (SR), circumferential peak early diastolic SR, right ventricular longitudinal strain, and longitudinal peak systolic SR at T1 and T2 were reduced significantly in patients with cardiotoxicity ( P  < .05). Conclusions Anthracycline-trastuzumab treatment leads to early deterioration of LV GLS, circumferential strain, and systolic SR. Right ventricular GLS and SR were also affected. Early changes in GLS are good predictors of subsequent development of anthracycline-trastuzumab–induced cardiotoxicity.