72 Clonal Hematopoiesis and Anthracycline Cardiotoxicity in Breast Cancer: A Missed Opportunity in Cardio-Oncology Risk Stratification?

Background

Clonal hematopoiesis of indeterminate potential (CHIP), defined by somatic mutations in hematopoietic stem or progenitor cells without cytopenias, dysplasia, or overt hematologic malignancy, is a common age-related phenomenon. Its prevalence increases with age, affecting 10% to 20% of individuals over age 70 and up to 40% of older women with breast cancer. CHIP is enriched in patients exposed to cytotoxic therapies, particularly anthracyclines and alkylating agents, which may drive the selection and expansion of clones harboring high-risk mutations, notably in TP53 and PPM1D, genes involved in DNA damage response. While initially described in hematologic contexts, CHIP has emerged as a potent risk factor for cardiovascular disease (CVD), including coronary artery disease, myocardial infarction, and heart failure. Independent of traditional cardiovascular risk factors like hypertension, diabetes, and hyperlipidemia, CHIP confers a 2- to 4-fold increase in CVD risk. Despite these associations, CHIP remains unaccounted for in current cardio-oncology guidelines from the American Heart Association and American College of Cardiology.

Materials and Methods

We conducted a comprehensive literature review using PubMed, Scopus, and Embase through June 2025. Peer-reviewed studies were included if they assessed CHIP prevalence, gene mutation profiles, CVD outcomes, or anthracycline-induced cardiotoxicity (AIC) in patients with breast cancer. Key data extracted included mutation frequencies, clonal evolution post chemotherapy, HRs for cardiovascular events, and left ventricular ejection fraction (LVEF) changes.

Results

CHIP mutations particularly in DNMT3A, TET2, ASXL1, TP53, and PPM1D are found in 15% to 40% of patients with breast cancer, often detectable prior to chemotherapy. TP53 and PPM1D mutations frequently expand post anthracycline exposure. Population studies report a 25% to 100% increase in risk for heart failure and myocardial infarction in individuals with CHIP, with TET2 and ASXL1 mutations showing the strongest associations. Mechanistically, CHIP promotes chronic inflammation via IL-1β and NLRP3 inflammasome activation, leading to myocardial injury and fibrotic remodeling. One prospective cohort study found CHIP to be independently associated with an 8-fold increased risk of symptomatic heart failure or LVEF decline after anthracycline therapy, even after adjusting for age, cumulative dose, and baseline risk factors. However, data remain limited by small sample sizes, heterogeneous cancer types, and inconsistent CHIP definitions.

Conclusion

CHIP is a common, age-related genomic alteration with significant cardiovascular implications in patients with breast cancer, especially those treated with anthracyclines. Despite emerging evidence linking CHIP to AIC, it remains absent from current risk stratification models. Prospective, breast cancer–specific studies are needed to validate CHIP as a predictive biomarker and inform its integration into personalized cardio-oncology management strategies.