1106 - Impact of Cancer Therapy on Clonal Hematopoiesis Mutations and Subsequent Clinical Outcomes

K. T. Nead¹, T. Kim², T. McDowell², J. Wong², I. Chan³, E. Brock⁴, C. L. Lee⁵, J. I. Abe⁶, K. Bolton³, P. Scheet², and S. H. Lin⁷; ¹Department of Breast Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ²UT MD Anderson Cancer Center, Houston, TX, ³Washington University School of Medicine, St. Louis, MO, ⁴Harvard College, Boston, MA, ⁵Duke University Medical Center, Durham, NC, ⁶Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, ⁷Department of Thoracic Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Purpose/Objective(s): Cancers frequently arise from a multi-stage successive acquisition of somatic (i.e. acquired) mutations. A limited number of these mutations may lead to a clonal expansion of the mutated cell population, without malignant transformation. Clonal hematopoiesis (CH) refers to somatic mutations leading to clonal expansion in the hematopoietic. Individuals with CH, including those with cancer, have a large increased risk of hematologic malignancy and worse overall survival. Additionally, CH is associated with an increased risk of numerous non-cancer adverse health outcomes including cardiovascular, cerebrovascular, pulmonary, endocrine, renal, and liver disease. There are limited prospective studies investigating the genesis and evolution of CH following cancer treatments using serial samples. We hypothesize that chemoradiation therapy is associated with increased CH mutations and these changes are associated with clinical outcomes. Materials/

Methods: We undertook error-corrected duplex sequencing in DNA from blood collected prior to, and two timepoints following, chemoradiation for thoracic malignancies in 29 patients (n=87 samples). We applied a customized workflow to identify and examine the earliest changes in CH mutation count, clone size, and their association with clinical outcomes.

Results: Median participant age was 67 years, 76% (n=22) were male, and median follow-up was 3.9 years. The most mutated genes were DNMT3A, TET2, TP53, and ASXL1. We observed a two-fold increase in the number of mutations from pre-treatment to post-treatment in TP53, which differed from all other genes examined (p<0.001), and was driven by post-therapy selection for missense mutations. Mutational signature analysis demonstrated immunosuppression and defective DNA mismatch repair patterns. Among mutations detected pre- and post-treatment, we observed an increased clone size in 38% and a decreased clone size in 5% of TP53 mutations (odds ratio, 3.7; 95% CI, 1.75-7.84; p<0.001). Changes in mutation count and clone size were not observed in other genes. Individuals with an increase in the number of TP53 mutations following chemoradiation experienced worse overall survival (hazard ratio, 7.07; 95% CI, 1.50-33.46; p=0.014).

Conclusion: Here we show an increase in the number of CH mutations and size of clones following chemoradiation therapy in patients with solid malignancy, specifically in DDR genes. Additionally, we found an association between increased TP53 mutations following therapy and worse survival. Future studies are needed to better understand which patients are most at risk for therapy associated CH and the mechanisms by which these acquired changes may impact clinical outcomes.