Clonal Hematopoiesis of Indeterminate Potential Influences Breast Cancer Outcomes in a Genotype-Specific Manner

Abstract Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with adverse outcomes in some solid tumor settings, but its impact on breast cancer remains unclear. We sought to investigate the genotype-specific effects of CHIP on breast cancer outcomes and the tumor microenvironment. Experimental Design: We examined a retrospective cohort of 125 patients with breast cancer, using targeted sequencing to identify CHIP. Metastatic events were recorded, and distant metastasis–free survival probability was analyzed. In parallel, we developed chimeric mouse models of the two most mutated CHIP genes, DNMT3A and TET2. CHIP and control mice were orthotopically injected with syngeneic breast cancer cells. Tumor growth was measured, and immune infiltrate was profiled via mass cytometry. Results: CHIP was present in 18.4% of patients. High-burden CHIP and non-DNMT3A CHIP were associated with significantly shorter distant metastasis–free survival. In vivo, mice with Tet2-CHIP developed larger primary tumors and were more likely to experience lung metastasis, whereas Dnmt3a-CHIP did not differ from controls. The general immune subsets observed in both CHIP models were similar, but immunophenotyping revealed clonal expansion and immune cell subset skewing specific to the Tet2-CHIP model. Conclusions: Our findings demonstrate a genotype-specific impact of CHIP on breast cancer across human and mouse data. Furthermore, the chimeric mouse models we generated offer a clinically relevant tool to study solid tumors in a CHIP background. This work underscores the need for further functional studies and personalized risk assessment to clearly define the impact of various CHIP genotypes on breast cancer.