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Published on: February 28, 2014
Association of Circulating Cardiomyocyte Cell-Free DNA With Cancer Therapy-Related Cardiac Dysfunction in Patients
Anthony F Yu1,2, Zachary R Moore3, Chaya S Moskowitz4
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Importance:
Cancer therapy-related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD.
Objective:
To determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy.
Design, Setting, And Participants:
A prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/- pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022.
Main Outcomes And Measures:
The outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression.
Results:
Of 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046).
Conclusions And Relevance:
This study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02177175.
Insights
Higher levels of cardiomyocyte cell-free DNA (cfDNA) after anthracycline chemotherapy indicate an increased risk of cancer therapy-related cardiac dysfunction (CTRCD) in ERBB2-positive breast cancer patients. This finding suggests cfDNA may serve as an early predictive biomarker for CTRCD.
Area of Science:
- Cardiology
- Oncology
- Biomarkers
Background:
- Cancer therapy-related cardiac dysfunction (CTRCD) is a significant risk for patients undergoing treatment for ERBB2-positive breast cancer.
- Early identification of cardiotoxicity biomarkers is crucial for personalized cardiac surveillance and intervention.
Purpose of the Study:
- To investigate the association between circulating cardiomyocyte cell-free DNA (cfDNA) and CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy.
Main Methods:
- A prospective cohort of 71 ERBB2-positive breast cancer patients were monitored. Cardiomyocyte cfDNA levels were measured after anthracycline therapy.
- Echocardiography was performed at baseline and during ERBB2-targeted therapy to assess cardiac function.
- Logistic regression was used to analyze the association between post-anthracycline cfDNA levels and the development of CTRCD over 1 year.
Main Results:
- Ten of 71 patients (14%) developed CTRCD.
- Patients who developed CTRCD had significantly higher post-anthracycline cardiomyocyte cfDNA levels compared to those who did not (30.5 vs 7 copies/mL, P=.004).
- Elevated cardiomyocyte cfDNA post-anthracycline therapy was associated with an increased risk of CTRCD (HR, 1.02 per 1-copy/mL increase; P=.046).
Conclusions:
- Higher cardiomyocyte cfDNA levels after anthracycline chemotherapy are associated with an increased risk of CTRCD.
- Cardiomyocyte cfDNA shows promise as a predictive biomarker for stratifying CTRCD risk in breast cancer patients receiving cardiotoxic therapies.
- Further validation of cardiomyocyte cfDNA is warranted for clinical application in predicting cardiotoxicity.
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