Impact of Genomic Alterations on Response to Treatment and Prognosis in Head and Neck Squamous Cell Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 900,000 cases worldwide annually and approximately 3% percent of malignancies in the US with 14,600 deaths. Approximately 75% of HNSCC patients will receive radiation therapy (RT) as part of their treatment. The toxicity associated with treatment can cause delays or early cessation which has been associated with worse outcomes. In a previously published study, we found that patients who had an increased rate of adverse events (AEs) during treatment, controlling for dose and other factors, also had an increased prevalence of multiple germline genetic alterations. Here we sought to evaluate if this presumed increase in sensitivity to radiation was also associated with differences in outcomes. <h3>Materials/Methods</h3> Patients with HNSCC who had undergone genomic testing for germline alterations were included for evaluation. Records were analyzed for age, site of disease, stage, HPV status, pre-RT surgical resection and RT dose as well as date of locoregional recurrence, metastasis and last follow up or death. Patients were grouped into "supersensitive" or "insensitive" groups based on rates of mucositis, dysphagia and xerostomia controlling for dose. Differences in patient characteristics were compared using Fisher's exact test; overall survival (OS), locoregional recurrence (LRR) and metastasis free survival (MFS) were compared by Kaplan-Meier survival analysis. <h3>Results</h3> 34 patients were included with RT dates ranging from January 2009 to January 2021. There were 14 (41.2%) treated in the post-operative setting. RT dose was available for 31 (91.2%) of patients, median 70 Gy, range 60-70 Gy. 27 patients (79.4%) received concurrent systemic therapy, most frequently cisplatin (70.4%). Median age at treatment was 62.5 years (range 37-85). Median follow up 42.5 months (range 7-205). 16 patients were categorized in the RT supersensitive subset (Group A) and 18 in the RT insensitive subset (Group B). There was no significant difference in age, stage, site of origin, HPV status or pre-RT surgery between the groups. Kaplan Meier survival analysis showed significant differences in OS between groups A and B (p = 0.017). There were also significant differences in LRR (p = 0.041) and MFS (p = 0.010). Alterations in TSC2 were associated with lower LRR (p = 0.018) and HLA-A V91M approached significance (p = 0.058), both more prevalent in Group A. HLA-DMB/DMA variants which were more common in Group B were associated with increased risk of LRR (p = 0.041). <h3>Conclusion</h3> This patient group that has previously been shown to have increased sensitivity to RT related AEs has also displayed significantly different outcomes after treatment with specific germline alterations (e.g., TSC2) being associated with reduced LRR. While this is a small, heterogenous group the data suggests that genomic analysis may play an important role in treatment planning and prognosis in HNSCC.