Molecular profiling of head and neck cancers (HNCs): Genetic heterogeneity, immune landscape, and therapeutic targets.

Abstract

e18058 Background: HNCs are a diverse group of malignancies characterized by genetic, epigenetic, and proteomic alterations that drive tumor progression, treatment resistance, and poor outcomes. Methods: Molecular profiling of 273 HNC samples was conducted using a semiconductor-based next-generation sequencing (NGS) platform at Datar Cancer Genetics. A subset of 106 cases underwent targeted transcriptomic analysis of 20,802 genes. Additionally, PD-L1 (22C3) IHC, microsatellite instability (MSI), and tumor mutational burden (TMB) were analyzed in selected samples. Results: Transcriptomic analysis highlighted significant alterations in critical cellular pathways, including cell cycle control, apoptosis, DNA repair mechanisms, and transcription regulation. Among the most dysregulated genes were DLGAP5 , CASP14 , BCL2 , and JUN . Copy number profiling in a subset (N=74) revealed significant chromosomal instability, with 34% of cases showing losses on specific chromosome arms and 9% exhibiting gains, notably in regions such as 4p, 19p and 1p. Mutations were predominantly observed in tumor suppressor genes, with a lower frequency in oncogenes. Frequently altered genes include TP53 (63%), CDKN2A (19%), PIK3CA (12%), TERT (15%), HRAS (6%) and EGFR (1%). HRAS mutations offer potential for targeted therapy with tipifarnib, a farnesyltransferase inhibitor. EGFR alterations, though rare, have proven challenging to effectively target with EGFR -specific therapies such as cetuximab or tyrosine kinase inhibitors, underscoring the critical need for innovative strategies to exploit this target. Amplifications were observed in MYC (9%), CCND1 (8%), FGF19 (6%), FGF3 (4%) and FGF4 (4%). Targetable amplifications were seen in EGFR (6%), ERBB2 (2%) and MET (1%), offering potential opportunities for personalized therapies. MET amplifications are also linked to aggressive tumor behavior. Fusion was a relatively less common event, observed in 9.5% cases, including one case each of targetable BRAF-MRPS33 and FGFR1-PLAG1 fusion. High TMB (≥10 muts/mb) was seen in 21% cases (Median 12, range 0-28). None of the tumors showed MSI-high status (n=63). Higher PD-L1 positivity was observed in TMB high samples (76% vs 59%), with PD-L1 22-C3 CPS ≥1 in 66% (50/ 76) and PD-L1 28-8 TPS ≥1 in 46% (36/ 78). Conclusions: This study underscores the genetic heterogeneity of HNCs, pointing to deregulated pathways involved in cell cycle control, apoptosis, and DNA repair as promising targets for future therapeutic development and personalized treatment strategies. Also this study points towards a subset of patients who may derive a greater benefit with immunotherapy, based on TMB/PDL1. ESCAT TIER distribution of the molecular alterations detected in head and neck cohort (N=273). TIERs Total Cases % occurrence IC 6 2% IIA 21 8% IIIA 85 31% IIIA 1 0% IIIB 57 21% IVA 180 66% IVB 71 26% X 142 52%