Clonal haematopoiesis of indeterminate potential (CHIP) may identify patients with breast cancer at increased risk of developing trastuzumab-related cardiotoxicity, according to a cohort study published in JAMA Oncology.
Trastuzumab has substantially improved outcomes for patients with HER2-positive breast cancer but is associated with a risk of cardiac dysfunction and heart failure. Identifying patients at greatest risk remains an important challenge in cardio-oncology.
CHIP, an age-related condition characterised by the expansion of blood cell clones carrying acquired somatic mutations, has previously been linked to an increased incidence of cardiovascular and malignant diseases. However, its association with trastuzumab-related cardiotoxicity has not been well understood.
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To investigate this question, researchers analysed data from a nationwide population-based cohort from the UK Biobank and an independent cohort of patients with breast cancer treated with trastuzumab at Seoul National University Hospital (SNUH). Complementary animal experiments were also conducted to explore potential biological mechanisms.
Overall, the analysis included 15,729 patients with breast cancer from the UK Biobank and 454 patients with breast cancer treated with trastuzumab at SNUH.
In the SNUH cohort, patients with CHIP experienced significantly higher rates of trastuzumab-related cardiotoxicity than those without CHIP. Using European Society of Cardiology criteria, the 2-year cumulative incidence of cardiotoxicity was 15.7% among patients with CHIP compared with 5.0% among those without CHIP. Similar differences were observed using Canadian Trastuzumab Working Group criteria (19.9% vs 10.8%) and Cardiac Review and Evaluation Committee criteria (20.9% vs 11.3%).
In multivariable analyses, CHIP positivity was independently associated with trastuzumab-related cardiotoxicity (adjusted subdistribution hazard ratio 1.91; 95% CI 1.32–2.76). The investigators also found that trastuzumab treatment was associated with incident heart failure in the UK Biobank cohort, with the risk amplified among individuals with CHIP, particularly those with larger clones.
In complementary animal studies, Tet2-deficient clonal haematopoiesis was associated with greater reductions in left ventricular ejection fraction following trastuzumab exposure, supporting a potential biological link between CHIP and cardiotoxicity.
According to the authors, the findings suggest that CHIP may have potential as a biomarker for identifying patients at increased risk of cardiotoxicity during trastuzumab treatment.
However, the study was observational and cannot establish a causal relationship between CHIP and cardiotoxicity in humans. Further research will be needed to determine whether CHIP testing can improve clinical decision-making or guide surveillance strategies in routine practice.
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Source: Park CS, Ryu G, Ahn H, et al. Clonal Hematopoiesis and Risk of Trastuzumab-Related Cardiotoxic Effects. JAMA Oncol. 2026;12(6):572–580. doi:10.1001/jamaoncol.2026.0455. Access online here.
