Genetic Alterations as Predictors of Radiation-Induced Toxicity in Head and Neck Squamous Cell Carcinoma.

Purpose/Objective(s) Optimizing 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 (OAR). 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 oncologic setting and offers a potentially powerful predictive tool for rtAEs beyond dosimetric data. Materials/Methods Next-generation sequencing data was collected from HNSCC patients who received RT for primary or locally recurrent HNSCC. Early and late toxicity data including mucositis, dysphagia and xerostomia were collected and reported based on common terminology criteria for adverse events (CTCAE) Version 5.0. Dosimetric parameters were collected for pertinent structures including the pharyngeal constrictor muscles (PCM), cricopharyngeus and submandibular glands. Based on dosimetric and toxicity outcomes, two patient subsets were defined as RT supersensitive or RT insensitive. Results A total of 37 patients met inclusion criteria. 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 (32%), early dysphagia (45%), xerostomia (37%) and late dysphagia (5%). Further, patients who exhibited alterations in both BRCA2 and ERBB3 experienced a 2-fold or greater increase in early dysphagia, early xerostomia and late dysphagia compared to ERBB3 alteration alone. Interestingly, several alterations including ATR, ESR1 and FAT1 were associated with improved toxicity outcomes compared to their wild-type counterparts. Within the RT insensitive subset (n = 7), alterations were found in TNFAIP3, HNF1A, SPTA1 and CASP8, all of which were found in no patients in the RT supersensitive subset (n = 6). Conversely, more than 17 genetic alterations were found in the RT supersensitive group that were found in no patients in the RT insensitive group. Conclusion Despite consistent RT dosimetric parameters, patients with HNSCC experience heterogeneous patterns of rtAEs. Identifying additional factors associated with toxicity outcomes offers a new avenue for personalized therapy and prophylactic management. Here, next-generation sequencing in a population of HNSCC patients correlates several genetic alterations including BRCA2, ERBB3, ATR and TNFAIP3 with severity of rtAEs. Further analysis is urgently needed in order to identify both somatic and germline genetic patterns associated with rtAEs so that we may optimize therapeutic regimens and reduce harmful outcomes in this challenging population.