Characterization of the ctDNA mutational landscape in HER2-positive metastatic breast cancer patients who developed cancer therapy-related cardiac dysfunction.

e24026 Background: Cancer therapy-related cardiac dysfunction (CTRCD) remains a major challenge in managing HER2+ breast cancer due to therapy-induced cardiotoxicity. While prior studies have identified genetic polymorphisms associated with the development of cardiac toxicity in this population, the role of plasma circulating tumor DNA (ctDNA) as a predictive biomarker in this context remains unclear. This study aimed to characterize the ctDNA mutational profiles of patients with HER2+ metastatic breast cancer (MBC) who developed CTRCD. Methods: This retrospective study analyzed 65 patients with HER2+ MBC who underwent plasma ctDNA testing between 2016–2024 under an IRB-approved protocol (NU16B06) at Northwestern University Robert H. Lurie Cancer Center. All patients received HER2-directed therapy as part of an anthracycline-based or non-anthracycline-based regimen. Genetic alterations in ctDNA were identified using next-generation sequencing via Guardant360. Mutational profiles were constructed by aggregating ctDNA results obtained throughout treatment. CTRCD was defined in accordance with the 2022 European Society of Cardiology Guidelines on Cardio-Oncology. Results: 36 patients with HER2+ MBC were identified as having developed CTRCD. The most common mutations in these patients were TP53 (79%, n = 28), PIK3CA (39%, n = 14), ERBB2 (36%, n = 13), ESR1 (17%, n = 6), and FGFR1 (17%, n = 6). There was no significant difference in mutational profiles between patients who developed CTRCD and those who did not, nor between those treated with anthracycline-based versus non-anthracycline regimens. Baseline clinical characteristics, including body mass index (27.4 vs 27.4, p = 0.3), age at metastatic diagnosis (56 vs 52 years, p = 0.6), baseline ejection fraction (62.3% vs. 63%, p = 0.8), de novo metastatic presentation (11 vs 9, p > 0.9), and anthracycline use (19 vs 16, p = 0.8), were not significantly different between patients with and without CTRCD. Among CTRCD patients, 25 experienced mild, 10 moderate, and 1 severe cardiotoxicity, with no significant difference in severity between anthracycline-based and non-anthracycline regimens. Overall survival also did not differ significantly between the two groups (HR: 2.104, 95% CI: 0.735–6.021; p = 0.2). Conclusions: Our findings reveal that the ctDNA mutational landscape in patients with HER2+ MBC undergoing HER2-directed therapy who develop CTRCD is largely similar to those who do not, regardless of anthracycline use. This raises the possibility that ctDNA may not fully capture clinical or genetic factors, including known polymorphisms, contributing to CTRCD risk in HER2+ MBC. Further research analyzing ctDNA at specific time points during management and integrating it with other biomarkers is needed to assess its potential as an early, non-invasive method to identify at-risk patients.