Comparative Proteomic Analysis of HPV(+) Oropharyngeal Squamous Cell Carcinoma Recurrence

Deintensification therapy for human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV­(+) OPSCC) is under active investigation. An adaptive treatment approach based on molecular stratification could identify high-risk patients predisposed to recurrence and better select for appropriate treatment regimens. Collectively, 40 HPV­(+) OPSCC FFPE samples (20 disease-free, 20 recurrent) were surveyed using mass spectrometry-based proteomic analysis via data-independent acquisition to obtain fold change and false discovery differences. Ten-year overall survival was 100.0 and 27.7% for HPV­(+) disease-free and recurrent cohorts, respectively. Of 1414 quantified proteins, 77 demonstrated significant differential expression. Top enriched functional pathways included those involved in programmed cell death (73 proteins, p = 7.43 × 10^–30), apoptosis (73 proteins, p = 5.56 × 10^–9), β-catenin independent WNT signaling (47 proteins, p = 1.45 × 10^–15), and Rho GTPase signaling (69 proteins, p = 1.09 × 10^–5). PFN1 (p = 1.0 × 10^–3), RAD23B (p = 2.9 × 10^–4), LDHB (p = 1.0 × 10^–3), and HINT1 (p = 3.8 × 10^–3) pathways were significantly downregulated in the recurrent cohort. On functional validation via immunohistochemistry (IHC) staining, 46.9% (PFN1), 71.9% (RAD23B), 59.4% (LDHB), and 84.4% (HINT1) of cases were corroborated with mass spectrometry findings. Development of a multilateral molecular signature incorporating these targets may characterize high-risk disease, predict treatment response, and augment current management paradigms in head and neck cancer.