Impact of Clonal Hematopoiesis of Indeterminate Potential on Treatment Response and Tumor Microenvironment in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with systemic inflammation and solid tumor progression, but its impact on breast cancer therapy remains unclear. This study investigated whether CHIP influences neoadjuvant chemotherapy (NAC) response and shapes the tumor microenvironment (TME) in breast cancer. We analyzed tumor sequencing data from The Cancer Genome Atlas (TCGA), focusing on mutations in CHIP-driver genes within a variant allele frequency range of 2–33.3%, a signature indicative of tumor-infiltrating clonal hematopoiesis (TI-CH). Patients harboring these TI-CH-associated mutations exhibited significantly worse overall and disease-free survival. In a retrospective cohort of 44 NAC-treated patients, CHIP mutations were detected in 15.9% of patients, most frequently in DNMT3A and NOTCH3. CHIP positivity was significantly associated with extensive residual disease (residual cancer burden, RCB III; P = 0.027) and chemotherapy resistance. CHIP-positive patients also showed elevated post-treatment markers of renal stress (creatinine) and hypercoagulability (D-dimer). Transcriptomic analysis revealed an immunosuppressive TME in CHIP-positive tumors after NAC, characterized by reduced CD8 + T cell infiltration and dysregulation of immune pathways including antigen processing and presentation, T cell receptor signaling, and primary immunodeficiency. Notably, CHIP-positive tumors also carried a higher tumor mutational burden, suggesting a state of “immune ignorance” where defective myeloid-driven immunity overrides neoantigen abundance. Collectively, these findings demonstrate that CHIP promotes an immunosuppressive TME and systemic inflammation, both linked to chemotherapy resistance and poor outcomes in breast cancer. Our results identify CHIP as a potential biomarker for risk stratification and a therapeutic target to overcome therapy resistance.