Clonal hematopoiesis in head and neck carcinomas receiving immunotherapy.

Abstract

6064 Background: Clonal hematopoiesis (CH) is an age-related accumulation of somatic genetic alterations in hematopoietic stem cells. It is implicated in the evolution of myeloid neoplasms and has been associated with poor prognosis in patients with solid tumors. Immunotherapy (ITx) has become the standard of care in the treatment of recurrent/metastatic head and neck cancer (R/M HNSCC), however, response rate corresponds to 20% of total population and relies in a robust innate host immunity. This study aims to identify the presence of CH among ITx-treated R/M HNSCC patients and its potential association with treatment outcomes. Methods: Matched pre-treatment peripheral blood (PB) and tumor tissue samples of 32 ITx-treated R/M HNSCC patients were used for DNA extraction. The ten most commonly mutated CH genes were sequenced using a custom NGS Qiagen panel with unique molecular identifiers. Low confidence and synonymous variants were excluded. Pathogenic, likely pathogenic and conflicting with moderate or high annotation impact variants based on the ClinVar database were investigated for associations with progression-free (PFS) and overall survival (OS) as well as for differences in expression between blood and tissue. The same gene alterations and their correlation with survival in HNSCC were also explored in three public datasets (TCGA, GENIE, MSKCC) as an external validation of our findings. Results: A total of 2,088 variants were detected with 1,222 silent variants. After filtering,105 pathogenic, likely pathogenic and conflicting interpretation variants were retained. Mutations in CH related genes were identified in 18 out of 32 PB samples (56%). In tissue samples, (excluding TP53 ) mutations were identified in 12 out of 32 samples (37%). TP53 mutations were significantly higher in tissue samples versus PB ( P =0.028). PPM1D mutations in PB were correlated with shorter PFS ( P =0.003) and OS ( P =0.0116), while TP53 mutations in tissue showed a trend for decreased OS ( P =0.097). TCGA and MSKCC analysis confirmed a negative association of TP53 mutations in tissue with OS ( P =0.0020, P =0.0001, respectively). Conclusions: CH was frequently detected in PB and tumor tissue of R/M HNSCC patients. CH-related PPM1D mutations in PB and TP53 in tumor tissue, were associated with shorter PFS and OS to ITx, suggesting a potential association between both peripheral and intratumoral immune contexture and clinical outcomes.