Abstract
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, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A 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.
Highlights
Advanced stage head and neck squamous cell carcinoma (HNSCC) has a poor prognosis.Chemoradiotherapy cures about half of all patients with advanced HNSCC
Disrupting mutations were found in multiple genes of this pathway in both patient tumors and cell lines. We found that such mutations are associated with a poor outcome in HNSCC patients treated with chemoradiotherapy [16]
We found that patients with tumors harboring co-occurring CCND1 mutations and CDKN2A mutations (SPMs and deletions) had shorter progression free survival (PFS) than the rest (Supplementary Materials: Figure S3C)
Summary
Advanced stage head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Chemoradiotherapy cures about half of all patients with advanced HNSCC. Allowing the preservation of organ function, it has become the preferred treatment option for these cancers [1]. Patients with a poor prognosis under such standard treatment may be eligible for increased surveillance and/or alternative treatments if they could be identified upfront. The current TNM staging [2] based prognosis is very limited in this regard and novel prognostic biomarkers are urgently needed. Tumor growth and treatment responses are largely determined by tumor intrinsic genetics
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