From heterogeneity to molecular stratification: A multiplex genomic panel for tailored therapy of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy with notable high rates of therapeutic failure. Diversity in prognostication reflects the interplay between differential environmental exposures-tobacco, alcohol, human papillomavirus (HPV) infection-and the intrinsic genomic heterogeneity of HNSCC. The present Perspective elaborates upon a multiplex genomic panel targeting key disrupted pathways and clinically relevant genes, including cell-cycle regulators (tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A)), lineage-determining pathways (NOTCH1-3, FAT atypical cadherin 1 (FAT1)), HPV-associated oncogenic drivers (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3), and targetable receptor tyrosine kinase (RTK) alterations. Mapping the multilayered genetic nature enhances stratification by identifying prognostic subtypes and therapeutic vulnerabilities. To advocate the broad adoption of multi-gene panels in diagnostic algorithms, a pre-screening based on HPV-status and anatomic site of carcinoma is merited, to ensure the optimal selection of biomarkers. Nevertheless, the prognostic value of selected genes should be established in wide genomic clinical trials, regarding drug response and overall survival rate (OSR). This article aims to elucidate the clinical utility of several genetic alterations towards a genetically informed prognostication and rationalized combination of novel targeted therapeutic tools.