Molecular analysis of aggressive disease and treatment response in recurrent/metastatic head and neck squamous cell carcinoma.

Abstract

e18033 Background: Immunotherapy (IO), alone or with chemotherapy, is standard first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Here, we evaluated molecular features associated with disease patterns and treatment response in HNSCC. Methods: Molecular profiling data were retrospectively reviewed for 80 patients with recurrent/metastatic HNSCC treated with systemic therapy. Clinically obtained next-generation sequencing reports (FoundationOne, Tempus, Caris, and institutional OncoPanel) were included. Genomic features were compared by metastatic pattern (bony vs non-bony) and clinical outcome (early failure ≤6 months vs sustained response ≥1 year). Non bony disease was defined as local-regional or visceral disease. Tumor mutational burden (TMB), somatic alterations, copy number changes, and mutational signatures were analyzed. Results: Among sequenced patients, 15 had bony metastases and 65 had non-bony metastatic disease. Patients with bony metastases were slightly older (mean 68.9 vs 64.6 years; p=0.11). Mean TMB was numerically higher in bony metastases (26.0 vs 5.8 mut/Mb), driven by high-TMB outliers, but was not statistically significant (p=0.28). Median overall survival was numerically longer in the TMB-high group (62.7 vs 48.3 months), (HR 1.47; 95% CI 0.72–3.01; p=0.29). Distinct genomic patterns were observed: non-bony metastases frequently demonstrated chromosome 11q13.3 amplifications ( CCND1, FGF3, FGF4, and FGF19 ) and tumor suppressor alterations ( TP53, CDKN2A, FAT1, and LRP1B ), while PTEN alterations were significantly enriched in bony metastatic disease by seven-fold (p<0.05). Clinical outcome analysis included 25 patients with early failure and 6 with sustained response. Mean TMB did not differ by outcome group (4.8 vs 5.1 mut/Mb; p=0.92). Early failure tumors demonstrated higher mutation frequencies in TP53 and CDKN2A , frequent co-occurring alterations, and greater mutational heterogeneity with increased transversions, including C>A substitutions. In contrast, sustained responders exhibited transition-dominant mutational patterns with low transversion rates and infrequent alterations, with occasional mutations in EP300, KMT2C, and FGFR3 observed in a small subset. Conclusions: Distinct molecular features characterize aggressive disease and treatment resistance in recurrent/metastatic HNSCC. Bony metastatic disease is enriched for PTEN alterations while early treatment failure is associated with TP53 and CDKN2A mutations, greater genomic complexity and heterogeneous mutational processes. These findings highlight biologic heterogeneity underlying metastatic behavior and treatment response and warrant validation in larger, uniformly characterized cohorts. Identifying mutational signatures in patients with metastatic HNSCC may guide treatment.