In a prospective, longitudinal cohort study published in JACC: CardioOncology by Glen et al, cancer therapy–related cardiac dysfunction and hypertension were found to be common cardiovascular adverse events among patients with melanoma who received BRAF or MEK inhibitor therapy.

Nearly half of the study population developed cancer therapy–related cardiac dysfunction, and although about two in five patients experienced mild dysfunction, it did not appear to worsen during follow-up. As a result, most patients tolerated treatment without unacceptable cardiovascular effects, the investigators explained. However, they noted that the risk of moderate or severe cancer therapy–related cardiac dysfunction remained relevant and was apparent as early as 4 weeks after the initiation of BRAF or MEK inhibitor therapy in those at risk.

“Our findings support the utility of baseline cardiotoxicity risk stratification, including the measurement of NT-proBNP [N-terminal pro–B-type natriuretic peptide, identified as a potential biomarker],” as well as early echocardiographic assessment, the investigators remarked. “Serial blood pressure assessment should be performed routinely, and our findings highlight the value of home measurement.”

Understanding the Heart Risks

According to the investigators, BRAF and MEK inhibitors target the MAPK pathway—a regulator of cell proliferation, differentiation, and apoptosis—to achieve cancer disease control; however, this pathway is also involved in cardiac and vascular cell signaling, and its pharmacologic manipulation can lead to unintended cardiovascular effects. The mechanisms driving these cardiovascular toxicities remain poorly defined, they explained, and expanding clinical indications for these therapies in melanoma and other cancers “further highlights the importance of understanding the mechanisms, incidence, and timing of associated cardiovascular adverse effects to inform risk stratification, surveillance, and treatment.”

The investigators noted that current European Society of Cardiology (ESC) cardio-oncology guidelines recommend risk stratification before the initiation of targeted therapies using the Heart Failure Association (HFA)/International Cardio-Oncology Society (IC-OS) cardiotoxicity risk tool. Routine blood pressure monitoring and electrocardiography are advised for all patients, with echocardiographic assessment of left ventricular ejection fraction tailored to baseline risk. However, they pointed out that these recommendations are not supported by high-quality evidence, and the risk tool has not been rigorously validated in this patient population.

Considering these knowledge gaps, the investigators conducted the present analysis, focusing on 61 patients with melanoma who received BRAF or MEK inhibitor therapy in a regional cancer network (March 2021–March 2023). Baseline cardiotoxicity risk was assessed using the risk stratification tool recommended by the ESC cardio-oncology guidelines. Participants underwent comprehensive cardiovascular evaluations at baseline and at 4, 12, and 24 weeks, which included home and clinic blood pressure monitoring, echocardiography, stress perfusion cardiovascular MRI, and assessment of blood biomarkers. Cancer therapy–related cardiac dysfunction was classified according to the IC-OS definitions.

Incidence, Severity, and Timing

In the present analysis, a total of 28 patients (45.9%) were diagnosed with hypertension; an equal number developed cancer therapy–related cardiac dysfunction: 24 (85.7%) mild, 3 (10.7%) moderate, and 1 (3.6%) severe. All cases of moderate or severe cancer therapy–related cardiac dysfunction were evident by 4 weeks and were at least partially reversible, the investigators wrote. No patients classified as low risk at baseline developed moderate or severe cancer therapy–related cardiac dysfunction.

Biomarkers and Risk Factors

Patients with vs without cancer therapy–related cardiac dysfunction had higher median baseline NT-proBNP levels (109 pg/mL [Q1–Q3: 51–380 pg/mL] vs 54 pg/mL [Q1–Q3: 29–149 pg/mL]; P = .047). The investigators reported that neither hypertension nor cardiovascular MRI–derived myocardial or perfusion characteristics were robustly associated with incident cancer therapy–related cardiac dysfunction.

Reflecting on their findings, the investigators stated that “future cardio-oncology guidelines should consider recommending early echocardiographic assessment [at 4 weeks] for all patients treated with BRAF inhibitors or MEK inhibitors, except those deemed to be in the lowest baseline risk group.” They suggested future research, which might specifically evaluate the appropriateness of lower-intensity cardiac imaging surveillance in patients deemed to be at low baseline risk and potentially also in those with reassuring findings at 4 weeks.

“These efforts to risk-stratify and perform appropriate cardiovascular surveillance in patients treated with BRAF inhibitors or MEK inhibitors should allow patients to receive optimal anticancer therapy while minimizing the risk for associated cardiovascular morbidity,” they concluded.

Ninian N. Lang, MBChB, PhD, of University of Glasgow, Scotland, is the corresponding author of the JACC: CardioOncology article.

Disclosure: For full disclosures of the study authors, including funding information, visit jacc.org.