Mona Arabzadeh, Yi-Han Tang, Christelle Colin‐Leitzinger, Sadegh Marzban, Daniel Walgenbach, Stefania Morganti, Vaidhyanathan Mahaganapathy, Erika Harper, Mingxiang Teng, Jacob K. Kresovich, Iman Washington, H. A. Parsons, Judy E. Garber, Jeffrey West, Shridar Ganesan, Hossein Khiabanian, Nancy Gillis
Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of patients with breast cancer and show that cytotoxic treatments led to strong therapeutic bottlenecks, resulting in significant reductions in hematopoietic allelic populations and differential clonal selection. Positively selected CH that expanded through dose-dependent therapeutic bottlenecks harbored mutations in TP53, PPM1D, SRCAP, DNMT3A, and YLPM1. Patients with positively selected CH during treatment had the shortest progression-free and overall survival compared with patients with unchanging or negatively selected CH across all therapies. These findings, validated in independent breast cancer and pan-cancer cohorts, provide strong evidence for the clinical relevance of monitoring CH during cancer treatment.