Impact of clonal hematopoiesis on tumor control following radiation therapy.
Authors: Tao Jacqueline , Setton Jeremy , Sanchez Vela Pablo , Safonov Anton Mikhailovich , Comen Elizabeth Anne , Braunstein Lior Zvi , Reis-Filho Jorge S. , Riaz Nadeem , Powell Simon N. , Levine Ross L. , Norton Larry , Khan Atif J. , Razavi Pedram 
Published: June 2022

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Background: Clonal hematopoiesis (CH) has well established associations with adverse clinical outcomes including all-cause mortality, cardiovascular disease, and progression to hematologic malignancy. The presence of CH has also been demonstrated to adversely impact survival from non-hematologic cancers, however whether CH may modulate response to radiation therapy (RT) in solid tumors is not known. Here we investigate the potential impact of CH mutations on radiation outcomes. Methods: We analyzed data from two previously well annotated cohorts of patients with tumors harboring somatic ATM mutations (n = 358) and FAT1 mutations (n = 365) who received RT and underwent prospective tumor and matched WBC sequencing utilizing the MSK-IMPACT assay. CH variants were detected in the blood samples utilizing a well-validated variant detection and filtration pipeline. Given that pathogenic mutations in ATM have been shown to be strongly associated with improved response to RT, these patients were excluded to avoid confounding. Additionally, patients with blood sampling for CH assessment that occurred more than 6 months after RT were excluded to address the possibility of therapy-related CH. We compared outcomes including irradiated tumor progression in patients with and without CH. Results: The final analysis consisted of 412 patients who underwent 811 total courses of radiation. A wide spectrum of solid tumor types were represented, most commonly non-small cell lung cancer (32.5%) and breast cancer (11.9%). A total of 161 patients (39.0%) had CH, with the most commonly mutated genes being DNMT3A (25.6%), PPM1D (6.2%), TET2 (5.8%), and TP53 (5.0%), consistent with prior studies of CH. Patients with CH were older at blood sample collection (67.6 vs 60.2 years, p < 0.001), reflecting an expected increase in CH burden with age. Fine Gray competing risks analysis, with death treated as a competing event and with clustering around patient identifier, showed no difference in irradiated tumor progression between patients with and without CH (HR 1.03, 95% CI 0.69 – 1.53, p = 0.896). Similarly, subanalyses by CH variant allele frequency and putative CH-driver mutations did not reveal an association between CH and response to RT. A hypothesis generating subgroup analysis by common cancer types, however, suggested that CH was associated with increased risk of progression post-radiation in prostate (HR 4.68, 1.14 – 19.1) and thyroid (HR 3.13, 1.55 – 6.34) cancer cohorts, warranting further investigation. Conclusions: We found no difference in irradiated tumor progression among patients who did and did not have CH. There may be an association between CH and poor radiation outcomes in certain cancer types, and further studies are needed to clarify the specific clinical and genomic factors that may influence radiation response.