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.

Immune checkpoint inhibitor (ICI) use may be associated with diverse cardiovascular (CV) adverse events (AEs), but their baseline prevalence and incidence after ICI initiation are poorly known. We aimed to describe CV events using real-world hospital data from Belgian cancer patients. Electronic health records (EHRs) from patients receiving at least one ICI between March 2017 and August 2022 at three Belgian hospitals were processed into an Observational Medical Outcomes Partnership Common Data Model warehouse. Structured data were enriched with unstructured data that were processed using a natural language processing (NLP) pipeline. We analyzed CV events from first ICI administration until last follow-up, identifying and validating the first detection of a CV event at the patient level. We included 1571 patients (66% male, median age 67 years); CV events were detected in 196 (12.5%) patients [median (min-max) follow-up: 8 (0-63) months]. The CV AEs detected were heart failure (5.3%), atrial fibrillation (4.6%), myocardial infarction (2.0%), atrioventricular block (1.9%), myocarditis (1.2%), vasculitis (0.8%), pericarditis (0.4%), and Takotsubo cardiomyopathy (<0.3%). Median time (min-max) to onset ranged from 109 days (17-849 days) for myocarditis to 529 days (91-967 days) for Takotsubo cardiomyopathy. To our knowledge, this is the first study using a dataset enriched with NLP-processed EHRs that describes the frequency and onset time of CV events. CV event frequencies were higher than those reported in clinical trials, but similar to other real-world studies. However, we observed a later time to onset. Hence, clinicians should note that CV AEs can present in various ways and at any time during or after treatment.

Background: Myocarditis in patients treated with immune checkpoint inhibitors has previously been reported to be rare, though it has most likely been underreported owing to misdiagnosis in the absence of overt clinical presentation. Early detection and characterization of this potentially life-threatening immune-related adverse event is of major importance. Herein we report a case of early-onset myocarditis in an asymptomatic patient treated with dual checkpoint inhibition for metastatic cholangiocarcinoma. Case presentation: A 69-year-old male Caucasian patient with metastatic cholangiocarcinoma presented with mild epigastric pain and troponinemia prior to the third dose of dual checkpoint inhibition (ipilimumab 1 mg/kg body weight and nivolumab 3 mg/kg body weight). Initial workup showed no significant abnormalities (physical/neurological examination, electrocardiogram, 72-hour Holter monitoring, and a transthoracic echocardiogram). However, cardiac magnetic resonance imaging revealed a zone of contrast enhancement in the inferior segment of the left ventricular wall indicating a recent episode of myocarditis. Despite steroid initiation (0.5 mg/kg oral prednisolone per day), troponin levels kept increasing, in the absence of coronary disease, for which steroids were increased to 1.5 mg/kg/day. Fluorodeoxyglucose positron emission tomography/computed tomography, 28 days after detecting elevated troponin levels, depicted multiple zones of active myocardial inflammation (basal septal, mid-anterior, and apical inferior). The patient is currently stable, and troponinemia is slowly decreasing while steroids are steadily being tapered. Conclusion: As the number of cancers treated with immune checkpoint inhibitors is expanding, the incidence of immune checkpoint inhibitor-induced myocarditis is likely to increase. Moreover, the emerging combination of immune checkpoint inhibitors with non-immune checkpoint inhibitor therapies with potential synergistic cardiotoxic side effects (for example, tyrosine kinase inhibitors) will further complicate the diagnosis of immune-related cardiotoxicity. This case highlights the urgent need for predictive biomarkers to stratify patients at risk and to develop a standardized and multidisciplinary management approach for early diagnosis and treatment of this severe immune-related adverse event.

Enfortumab vedotin (EV), an antibody–drug conjugate directed against Nectin-4, significantly prolonged survival compared to standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who previously received platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. The overall response rate in the phase 3 EV301 trial leading to approval was 40.6%. However, no data have been published yet regarding the effect of EV on brain metastases. Here, we present three patients from different centers with brain metastases receiving EV. A 58-year-old white male patient, who had been heavily pretreated for urothelial carcinoma with visceral metastases and a solitary clinically active brain metastasis, started on EV 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle. After three cycles, the first evaluation showed a partial remission by RECIST v1.1, with a near complete response on the brain metastasis and disappearance of neurological symptoms. The patient is currently still receiving EV. A second, 74-year-old male patient started on the same regimen, after previous progression on platinum-based chemotherapy and avelumab in maintenance. The patient achieved a complete response and received therapy for five months. Nevertheless, therapy was discontinued at the patient’s request. Shortly after, he developed new leptomeningeal metastases. Upon rechallenge with EV, there was a significant reduction in the diffuse meningeal infiltration. A third, 50-year-old white male patient also received EV after previous progression on cisplatin–gemcitabine and atezolizumab maintenance, followed by palliative whole-brain radiotherapy and two cycles of vinflunine. After three cycles of EV, there was a significant reduction in the brain metastases. The patient is currently still receiving EV. These are the first reports on the efficacy of EV in patients with urothelial carcinoma and active brain metastases.