| Summary: | About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, <i>TP53</i> (62%), <i>CCND1</i> (51%), <i>CDKN2A</i> (30%) and <i>PIK3CA</i> (21%), were not associated with PFS. However, co-occurring <i>CCND1</i> and <i>CDKN2A</i> mutations were associated with short PFS (HR 2.24, <i>p</i> = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, <i>p</i> = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, <i>p</i> = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring <i>CCND1</i> and <i>CDKN2A</i> mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.
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