The landscape of clonal hematopoiesis of indeterminate potential in long-term breast cancer survivors.

Abstract

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) can confound blood-based genomics and may be shaped by cytotoxic therapy; clarifying its persistence after breast-cancer chemotherapy is relevant for long-term survivorship follow-up. PATIENTS AND METHODS: Buffy-coat whole-exome sequencing was performed in 189 stage I-III breast-cancer survivors with blood collected a median 136.5 months after diagnosis. CHIP was assessed using a prespecified 100-gene hematopoietic-driver compendium and exome-wide interrogation. Clinical associations were assessed with univariable tests and multivariable logistic regression including chemotherapy, radiotherapy, age, smoking and obesity. RESULTS: Within the 100-gene compendium, 54/189 (28.6%) patients harbored ≥1 variant, predominantly missense, with DNMT3A and TET2 predominating and multi-hit cases rare. In multivariable models, chemotherapy was not associated with panel-defined CHIP (OR 0.77; 95% CI 0.40-1.48; p = 0.432). Similarly, age, adjuvant radiotherapy, obesity and smoking status were not significantly associated with panel-defined CHIP. Gene-level comparisons showed no differences by chemotherapy exposure. Exome-wide, 67/189 (35.4%) patients carried ≥1 variant; chemotherapy was not associated with exome-wide variant positivity (OR 0.89; 95% CI 0.48-1.67; p = 0.721), and no locus differed between chemotherapy-exposed and never-exposed women. CONCLUSION: Buffy-coat WES performed in long-term breast cancer survivors shows no cohort-level association between prior chemotherapy and increased CHIP.