Herceptin for Breast Cancer: Clonal Hematopoiesis Identified as New Cardiotoxicity Risk Factor

Seoul National University Hospital Research Team Conducts Multilayered Analysis Using UK Biobank

"Clue for Identifying High-Risk Groups Before and Early in Treatment"

Clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a new risk factor associated with the cardiotoxicity of Herceptin (ingredient name: trastuzumab), a targeted anticancer drug used in the treatment of HER2-positive breast cancer. This finding is drawing attention as a clue for identifying high-risk groups prior to treatment.

On April 17, Seoul National University Hospital announced that the research team led by Professor Junbin Park of the Department of Cardiology and Professor Youngil Ko of the Department of Hematology and Oncology has confirmed the association between clonal hematopoiesis and trastuzumab-related cardiotoxicity through studies using the UK Biobank, the Seoul National University Hospital patient cohort, and animal experiments. The results of the study were recently published in the international journal JAMA Oncology.

From the left, Professor Go Youngil of Seoul National University Hospital, Professor Park Junbin of Cardiology, and Professor Park Chansun of Cardiology at Asan Medical Center. Seoul National University Hospital

Trastuzumab is a key drug for the treatment of HER2-positive breast cancer, which accounts for about 15–20% of all breast cancer cases; however, some patients experience cardiotoxicity such as decreased left ventricular function or heart failure. Until now, there have been few clear risk prediction indicators aside from the use of anthracyclines in combination therapy.

The research team reported that analysis of 15,729 breast cancer patients in the UK Biobank showed the risk of heart failure was highest in the group with clonal hematopoiesis who were exposed to trastuzumab. The hazard ratio for heart failure in this group was 4.57 compared to the reference group.

A similar trend was observed in the analysis of 454 patients from Seoul National University Hospital. The two-year cumulative incidence of cardiotoxicity in the clonal hematopoiesis-positive group ranged from 15.7% to 20.9%, depending on the evaluation criteria, which was higher than that in the negative group (5.0% to 11.3%). Multivariate analysis also identified clonal hematopoiesis as an independent risk factor. In animal experiments, a significant decrease in left ventricular ejection fraction was observed only in genetic knockout models related to clonal hematopoiesis.

This study is considered significant as it is the first to present the association between clonal hematopoiesis and trastuzumab-induced cardiotoxicity by combining human cohort data and animal experiments. The research team believes that assessing clonal hematopoiesis before or at the early stages of treatment can be utilized to identify high-risk patients and establish monitoring strategies.

Professor Junbin Park stated, "Trastuzumab is an essential medication for HER2-positive breast cancer, but it has not been easy to accurately identify patients at high risk for cardiotoxicity before treatment. This study demonstrates that clonal hematopoiesis can serve as an important clue for predicting patient-specific cardiotoxicity risk, and we expect it will contribute to the development of tailored cardiac monitoring and preventive strategies in the future."

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