Cardiovascular adverse events induced by immune checkpoint inhibitors (ICIs) have gained significant interest over the past decade due to their impact on short-and long-term outcomes. They were initially thought to be rare, but the increasing use of ICIs in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in their incidence. Different guidelines have proposed screening measures for ICI-induced myocarditis by incorporating troponin measurements at baseline and during the first few weeks of treatment. However, no specific guidelines have been developed yet regarding the interpretation of an asymptomatic rise in troponins. This state-of-the art review aims to provide an overview of the clinical relevance of elevated troponins during checkpoint inhibition and recommendations on how to manage elevated troponin levels during ICI therapy.

Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10−5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of POLRMT in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.

Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based on anecdotal evidence and expert opinions, due to a lack of solid data and prospective studies. As many questions remain unanswered, cardiac monitoring, in patients receiving ICIs, is not always implemented by oncologists. Hence, an urgent need to investigate the possible short- and long-term CV effects of ICIs, as ICI approval is continuing to expand to the (neo)adjuvant setting. Methods: We have initiated a prospective, multicenter study, i.e., the CAVACI trial, in which a minimum of 276 patients with a solid tumor, eligible for ICI treatment, will be enrolled. The study consists of routine investigations of blood parameters (troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, in particular) and a thorough CV follow-up (electrocardiograms, transthoracic echocardiograms, and coronary calcium scoring) at fixed time points for a total period of two years. The primary endpoint is the cumulative incidence of troponin elevation in the first three months of ICI treatment, compared to baseline levels. Furthermore, secondary endpoints include incidence above the upper limit of normal of both troponin and NT-proBNP levels, evolution in troponin and NT-proBNP levels, the incidence of CV abnormalities/major adverse cardiac events, evaluation of associations between patient characteristics/biochemical parameters and CV events, transthoracic echocardiography parameters, electrocardiography parameters, and progression of coronary atherosclerosis. Recruitment of patients started in January 2022. Enrolment is ongoing in AZ Maria Middelares, Antwerp University Hospital, AZ Sint-Vincentius Deinze, and AZ Sint-Elisabeth Zottegem. Trial registration: ClinicalTrials.gov Identifier: NCT05699915, registered 26 January 2023.