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Cell-Free DNA Shows Promise as Cardiotoxicity Biomarker in HER2-Positive Breast Cancer Patients

NEW YORK — Cell-free DNA (cfDNA) derived from injured or dead cardiomyocytes is a promising biomarker to predict cancer therapy-related cardiac dysfunction (CTRCD) in HER2-positive breast cancer patients who undergo anthracycline chemotherapy, a new study has found.

Previous studies have shown that anthracycline chemotherapy, which works by damaging cancer cell DNA, can lead to irreversible heart damage in some ERBB2 (aka HER2)-positive patients leading to CTRCD risk.

However, clinicians have not had the means to predict which patients are at CTRCD risk following chemotherapy. Circulating cfDNA of cardiomyocyte origin is known to be present during acute cardiac injury but has not been established as a biomarker of CTRCD, the authors noted, leading them to assess whether quantifying it in patients' blood could help understand CTRCD risk in HER2-positive breast cancer cases.

In a prospective study published in JAMA Cardiology on Wednesday, the researchers from Memorial Sloan Kettering (MSK) Cancer Center and Weill Cornell Medical College studied 80 HER2-positive breast cancer patients who were enrolled at the cancer center between July 2014 and April 2016.

Their blood was collected before and at different time points after receiving anthracycline-doxorubicin-based chemotherapy followed by trastuzumab. 

The researchers quantified circulating cardiomyocyte-specific cfDNA in all blood samples by using a methylation-specific droplet digital PCR assay. "The patterns of DNA methylation, a common epigenetic modification, are highly tissue-specific and can be resolved by bisulfite treatment," corresponding authors Adam Schmitt and Anthony Yu from MSK wrote along with their colleagues. The approach has previously been used to identify elevated cardiomyocyte cfDNA after myocardial injury by myocardial infarction or sepsis, they added.

They compared the post-treatment values for cardiomyocyte cfDNA and cardiac muscle protein cardiac troponin in patients who eventually developed CTRCD with patients who did not. Presence of troponin in blood is indicative of heart damage.

The findings showed that cardiomyocyte cfDNA levels after anthracycline treatment was higher in all 10 patients who subsequently developed CTRCD compared to those who didn't develop the condition. This led the authors to conclude that a higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD.

Patients who are found to be at high risk based on the new biomarker could benefit from cardioprotective medications or increased cardiac surveillance, the authors said.

However, they cautioned that their findings need further validation. "Much is still unknown about the mechanisms of cardiotoxicity after cancer therapy, and further study of cardiomyocyte cfDNA could be revealing," they wrote.

They further noted that a small sample size was one of the major limitations of the study. Moreover, there were differences in cardiomyocyte cfDNA from samples collected just hours apart. Potential causes of this include the short half-life of cfDNA, variable sample processing, insufficient sample volume, or the direct effect of trastuzumab, which was delivered between sample collections, they noted.