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BackgroundOptimizing the therapeutic ratio for radiation therapy (RT) in head and neck squamous cell carcinoma (HNSCC) is uniquely challenging owing to high rates of early and late toxicity involving nearby organs at risk. These toxicities have a profound impact on treatment compliance and quality of life. Emerging evidence suggests that RT dose alone cannot fully account for the variable severity of RT-related adverse events (rtAEs) observed in HNSCC patients. Next-generation sequencing has become an increasingly valuable tool with widespread use in the oncology field and is being robustly explored for predicting rtAEs beyond dosimetric data.MethodsPatients who had Foundation Medicine sequencing data and received RT for primary or locally recurrent HNSCC were selected for this study. Early and late toxicity data were collected and reported based on Common Terminology Criteria for Adverse Events version 5.0. Dosimetric parameters were collected for pertinent structures.ResultsA total of HNSCC 37 patients were analyzed in this study. Genetic alterations in BRCA2, ERBB3, NOTCH1 and CCND1 were all associated with higher mean grade of toxicity with BRCA2 alteration implicated in all toxicity parameters evaluated including mucositis, early dysphagia, xerostomia and to a lesser extent, late dysphagia. Interestingly, patients who exhibited alterations in both BRCA2 and ERBB3 experienced a twofold or greater increase in early dysphagia, early xerostomia and late dysphagia compared to ERBB3 alteration alone. Furthermore, several gene alterations were associated with improved toxicity outcomes. Within an RT supersensitive patient subset, alterations were found in TNFAIP3, HNF1A, SPTA1 and CASP8. All of these alterations were not found in the RT insensitive patient subset. We found 17 gene alterations in the RT insensitive patient subset that were not found in the RT supersensitive patient subset.ConclusionDespite consistent RT dosimetric parameters, patients with HNSCC experience heterogeneous patterns of rtAEs. Identifying factors associated with toxicity outcomes offers a new avenue for personalized precision RT therapy and prophylactic management. Here, next-generation sequencing in a population of HNSCC patients correlates several genetic alterations with severity of rtAEs. Further analysis is urgently needed to identify genetic patterns associated with rtAEs in order to reduce harmful outcomes in this challenging population.