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Clonal Hematopoiesis Dynamics and Evolutionary Fitness During Breast Cancer Treatment Impact Clinical Outcomes

We investigated the impact of cancer therapies on clonal hematopoiesis (CH), the age-associated expansion of somatically mutated hematopoietic stem cells, in patients with breast cancer. We examined 392 serial peripheral blood samples collected before and after treatment using chemotherapy, radiation, and/or hormone therapy from a prospective cohort of 171 patients. Ultra-deep targeted DNA exon sequencing was performed across 81 genes (custom Agilent SureSelectXTHS2 panel, median coverage > 5000x) implicated in hematologic malignancies and CH, enabling precise characterization of the mutational spectrum and longitudinal tracking of clonal dynamics.

The primary objective was to understand how different cancer treatments (i.e., chemotherapy, radiation, and hormone therapy) alter the effective hematopoietic population and select for or against specific CH clones. Our analysis revealed that cytotoxic therapies induced significant reductions in allelic diversity, creating therapeutic bottlenecks that led to selective clonal expansion. These selective dynamics were associated with worse clinical outcomes, where patients with positively selected CH during treatment experienced significantly shorter progression-free and overall survival.

Data generated from this study, including the sequencing data, treatment exposure data, and clinical outcomes will be made available through dbGaP. Mutation calls used for analyses are included in the medRxiv (2025.08.27.25334581) supplement and will be available in the published version of the manuscript.