The molecular landscape of immunotherapy treatment and advanced disease in head and neck squamous carcinoma (HNSCC).

Abstract

6032 Background: Advanced head and neck squamous cell carcinoma (HNSCC) exhibits variable responses to immunotherapy, highlighting the need to understand its complex molecular landscape. While immune checkpoint inhibitors show promise, optimizing treatment and predicting outcomes requires deeper molecular insights. Here, we leverage the cBioPortal for Cancer Genomics, analyzing ~800 HNSCC genomic and transcriptomic profiles, to investigate the molecular landscape influencing immunotherapy response in advanced disease. Methods: In this retrospective study, we analyzed publicly available data from 825 HNSCC patients treated with immunotherapy, enrolled in participating institutions between 2017 and 2022, sourced from the cBioPortal for Cancer Genomics. We investigated the frequency of most common mutations, copy number alterations, and mRNA expression levels, along with clinicopathological factors and overall survival (OS). Results: Genomic analysis of 809 HNSCC samples revealed TP53 as the most frequently mutated gene (63.5%, 514/809), followed by TTN (37.4%), FRG1BP (20.7%), FAT1 (19.3%), and CDKN2A (19.0%). Other genes were mutated at frequencies between 18.7% and 15.2%. Copy number alterations analysis (n=673) showed frequent homozygous deletions in 9p21.3, affecting CDKN2A-AS1 (30.3%, 158/673) and CDKN2A (26.0%, 175/673), and amplifications in 11q13.3, including PPFIA1 (25.7%), FADD (25.3%), CTTN (25.1%), and ANO1 (25.1%). Notably, TP53 mutations and CDKN2A-AS1 deletions were associated with inferior OS (log-rank P < 0.001; mOS mutated vs wild-type 45.93 vs 156.37 months and P = 0.006; mOS altered vs non-altered 35.45 vs 65.77 months, respectively). Transcriptomic and GSEA profiling linked these alterations to dysregulation of oncogenic pathways, including DNA replication stress, p21 activation, apoptosis, and immune evasion. Conclusions: This study of immunotherapy-treated advanced HNSCC provides a valuable resource for understanding the complex genomic landscape of this disease. We identified frequent mutations and copy number alterations which were associated with inferior OS and linked to dysregulation of key oncogenic pathways. These findings underscore the potential of this to facilitate biomarker discovery and the development of personalized medicine approaches to improve outcomes in advanced HNSCC.