Clonal Hematopoiesis in Young Women Treated for Breast Cancer

Purpose: Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy com-prise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping. Experimental Design: We performed targeted sequencing on longitudinal blood samples to characterize the clonal hemato-poietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study. Results: We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free sur-vival) or non-breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM. Conclusions: Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.

Automated summary

This study aimed to investigate the presence of clonal hematopoiesis of indeterminate potential (CHIP) in young women treated for breast cancer and its impact on prognosis. The results showed that only a small number of patients had clones large enough to be diagnosed as CHIP, and there was no significant association between their prognosis and non-breast cancer-related outcomes.