Aims Cardiac biomarkers are a mainstay in diagnosis of cardiovascular disease but their role in cardio‐oncology has not yet been systematically evaluated. This meta‐analysis aims to determine whether cardiac troponins and (N‐terminal pro) brain natriuretic peptide (BNP/NT‐proBNP) predict cancer therapy‐related left ventricular (LV) dysfunction. Methods and results Scientific databases were searched for studies that assessed troponins or BNP/NT‐proBNP in adult patients undergoing cancer therapy. Data from 61 trials with 5691 patients were included. Cancer therapy was associated with an increase in troponin levels [odds ratio (OR) 14.3, 95% confidence interval (CI) 6.0–34.1; n = 3049]. Patients with elevated troponins receiving chemotherapy or human epidermal growth factor receptor 2 inhibitor therapy were at higher risk for LV dysfunction (OR 11.9, 95% CI 4.4–32.1; n = 2163). Troponin had a negative predictive value of 93%. Mean BNP/NT‐proBNP levels were increased in patients post‐treatment (standardized mean difference 0.6, 95% CI 0.3–0.9; n = 912), but the available evidence did not consistently indicate prediction of LV dysfunction (OR 1.7, 95% CI 0.7–4.2; n = 197). β‐blocker and angiotensin‐converting enzyme inhibitor therapy to mitigate cardiotoxicity during cancer therapy was associated with a decline in serum troponins (OR 4.1, 95% CI 1.7–9.8; n = 466). Conclusion Elevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may qualify as a screening test to identify patients who require referral to cardio‐oncology units and benefit from preventive strategies. Further evidence is required for both biomarkers.

Background: The monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life‐threatening cardiovascular adverse effects could limit its use and may warrant specific follow‐up strategies. Methods and Results: We systematically searched MEDLINE, Cochrane, EMBASE , and Web of Science for randomized controlled trials published until November 2016 that assessed patients with cancer treated with or without bevacizumab in addition to standard chemotherapy. A total of 20 050 patients with a broad range of cancer types from 22 studies were included in this analysis (10 394 in the bevacizumab group and 9656 in the control group). The risks of arterial and venous adverse events were higher in the bevacizumab groups (relative risk [RR], 1.37; 95% CI , 1.10–1.70 [ P =0.004] and RR , 1.29; 95% CI , 1.12–1.47 [ P <0.001], respectively), and more arterial adverse events occurred in patients taking high‐dose bevacizumab regimens. Bevacizumab treatment was associated with the highest risk of cardiac and cerebral ischemia in the high‐dose bevacizumab groups ( RR , 4.4; 95% CI , 1.59–12.70 [ P =0.004] and RR , 6.67; 95% CI , 2.17–20.66 [ P =0.001], respectively). In addition, the risk of bleeding and arterial hypertension were higher in the bevacizumab groups ( RR , 2.74; 95% CI , 2.38–3.15 [ P <0.001] and RR , 4.73; 95% CI , 4.15–5.39 [ P <0.00001], respectively), with higher values for patiens taking high‐dose regimens. Conclusions: Treatment with bevacizumab increases the risk of arterial adverse events, particularly cardiac and cerebral ischemia, venous adverse events, bleeding, and arterial hypertension. This risk is additionally increased with high doses of bevacizumab. Further studies should determine the appropriate options for cardio‐oncology management. Clinical Trial Registration: URL : https://www.crd.york.ac.uk . Unique identifier: PROSPERO ( CRD 42016054305).

The incidence of melanoma has been increasing, and it now accounts for 55 500 cancer deaths annually worldwide.¹ The most frequent mutations in melanoma occur at the level of BRAF with a subsequent upregulation of the canonical MAPK pathway responsible for tumor growth and proliferation.^2,3 The identification of BRAF mutations prompted the development of a new class of targeted cancer drugs: BRAF inhibitors. Subsequent research showed that treatment with BRAF inhibitors alone causes resistance through a paradoxical signaling cascade mediated by MEK, leading to the development of MEK inhibitor therapies.^1,4,5 The combination of BRAF and MEK inhibitor therapy has emerged as an optimal treatment of metastatic BRAF-mutated melanoma, with improved survival rates compared with monotherapy.^6-10 A 2018 study¹¹ found that the first BRAF and MEK inhibitor combination showed significant improvement in relapse-free survival in treating adjuvant stage III melanoma, which led to global approval. To date, 3 BRAF inhibitors (dabrafenib,¹² vemurafenib,¹³ and encorafenib⁷) and 3 MEK inhibitors (trametinib,¹⁴ cobinimetinib,¹⁵ and binimetinib¹⁶) have received US Food and Drug Administration and European Medicines Agency approval. Common combination therapies are dabrafenib and trametinib,⁹ vemurafenib and cobimetinib,¹⁵ and encorafenib and binimetinib.¹⁷

Immune checkpoint inhibitor (ICI) therapy has greatly improved treatment of various advanced cancers but increasing use of ICI therapy has exposed the risk of ICI-related cardiovascular side effects. Immune checkpoints are inhibitory regulators of T cell activation and mediate T cell effector functions during physiological responses to shield from autoimmune reactions. ICI therapy for advanced cancers promotes immune activity against tumors and is applied within a broad collective of cancer patients. Widespread use of ICI therapy has revealed the burden of immune related adverse events with various organ manifestations and characteristics. Since immune checkpoints are highly relevant for maintaining myocardial homeostasis as emerging evidence implicates, inhibition of immune checkpoint pathways has been associated with various forms of cardiotoxicity in preclinical models and patients. Although ICI-related cardiotoxicity is rare, it has significant relevance due to high mortality rates. This review focuses on current knowledge about cardiac ICI-related toxicity. We summarize the most common forms and delineate incidence, presentation, and treatment. Clinical characteristics are correlated to potential underlying pathomechanisms. We outline epidemiology, risk factors, and course of disease. Recommendations for monitoring and critical diagnostic measures are specified within the context of different forms of cardiac involvement. Different therapeutic implications for suspected ICI-related cardiotoxicity and their limitations are critically summarized. We highlight current gaps of knowledge concerning the underlying pathomechanisms and clinical characteristics of ICI-related cardiotoxicity. Future challenges are depicted for optimum cardio-oncology care of patients receiving ICI therapy.

Progress in cancer therapy over the past decades improved long-term survival but increased cancer therapy-related cardiotoxicity. Many novel treatment options have been implemented with yet incompletely characterized cardiovascular side effects including heart failure, coronary artery disease, arrhythmias, valvular disease, venous thromboembolism and myocarditis. Diagnosis of potential cardiotoxic side effects is essential for an optimal treatment but remains challenging. Cardiac biomarkers troponin and brain natriuretic peptide/N-terminal proBNP (BNP/NT-proBNP) have been extensively studied in heart failure and acute coronary syndromes. Emerging evidence implicates a significant role in the detection of cardiotoxicity and guidance of therapy in cancer patients. Elevated troponin or BNP/NT-proBNP levels were associated with increased all-cause mortality in cancer patients and have been shown to predict manifest heart failure. BNP/NT-proBNP may be useful for the prediction of cancer therapy-related heart failure and response to heart failure therapy in adult and pediatric cancer patients while troponin can indicate acute myocardial infarction in patients with cancer therapy-related risk for coronary artery disease. Furthermore, troponin may be used for the identification of immune checkpoint inhibitor-related myocarditis with very high sensitivity. Finally, even D-dimer levels have been shown to improve risk stratification and diagnosis in cancer-associated venous thromboembolism. This review aims to summarize the current knowledge about biomarkers in cancer therapy-related cardiotoxicity. We also outline possible clinical recommendations for the detection and treatment of subclinical and clinically apparent cardiotoxic effects using biomarkers.

Targeted therapy with tyrosine kinase inhibitors with anti-vascular endothelial growth factor activity improves survival of cancer patients. Cardiovascular complications are critical and it is unknown whether these require specific treatment strategies. We aimed to clarify the associated risk of cardiovascular adverse events in patients treated with tyrosine kinase inhibitors. The design of this study was a meta-analysis of randomised controlled trials. We searched PubMed, Cochrane, EMBASE and Web of Science databases for randomised controlled trials published until January 2017 that assessed patients with different types of cancer treated with or without tyrosine kinase inhibitors in addition to standard chemotherapy. A total of 29,252 patients from 71 randomised controlled trials were included. Tyrosine kinase inhibitor treatment was associated with a higher cardiac ischaemia relative risk (relative risk = 1.69; 95% confidence interval: 1.12–2.57; p = 0.01), with the highest risks observed for sorafenib and patients with renal cancer. Risk of thrombocytopaenia (relative risk = 2.2; 95% confidence interval: 1.73–2.79; p < 0.001) was highest for regorafenib and patients with breast cancer. Left ventricular systolic dysfunction was increased after tyrosine kinase inhibitor therapy (relative risk = 2.53; 95% confidence interval:1.79 – 3.57; p < 0.001), with the highest risks reported for sunitinib and hepatocellular cancer. QT corrected interval prolongation (relative risk = 6.25; 95% confidence interval: 3.44–11.38; p < 0.001) and arterial hypertension (relative risk = 3.78; 95% confidence interval: 3.15-4.54; p < 0.001) were reported. The relative risks of arterial adverse events, cerebral ischaemia, venous adverse events and pulmonary embolism were similar across groups. Tyrosine kinase inhibitors increase the risk of severe cardiovascular and particularly thrombotic adverse events. Specific treatment regimens when prescribing tyrosine kinase inhibitor therapies appear desirable.