Prognostic impact of tumor suppressor and DNA damage repair gene mutations in oral cavity squamous cell carcinoma: A clinico-genomic analysis from a real-world database.

Abstract

6065 Background: Oral cavity squamous cell carcinoma (OCSCC) has unique genomic features, yet molecular biomarkers predicting prognosis remain poorly defined. Prior surgical series and TCGA analyses demonstrated TP53 and TERT promoter mutations associate with worse outcomes, while DDR pathways may influence immunotherapy response. However, no study has systematically evaluated these mutations with linked treatment and survival data. This is the first real-world clinico-genomic analysis addressing this gap in OCSCC. Methods: Using a pre-specified protocol with IRB approval, we analyzed 381 OCSCC patients from the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Inclusion required confirmed OCSCC, genomic profiling (~300 genes), and survival data. We evaluated tumor suppressors (TP53, CDKN2A), TERT promoter, PIK3CA, and DDR genes (BRCA1/BRCA2/PRKDC). IPTW adjusted for age, sex, stage, smoking, advanced disease, and TMB. A 90-day landmark eliminated immortal time bias. Complete case analysis handled missing data. IO cohort (n=213, 56%) received checkpoint inhibitors. Primary endpoint: OS from diagnosis; secondary: OS from IO initiation. Results: Stage IV was the strongest clinical prognostic factor (HR 1.64, 95%CI 1.29-2.08, p<0.0001). In IO-treated patients, TMB-high showed improved survival (HR 0.54, p=0.035). DDR pathway mutations were associated with markedly inferior outcomes from IO initiation (HR 2.34, 95%CI 1.00-5.49, p=0.049; median OS 5.7 vs 13.8 months; 12-month OS 17.4% vs 50.4%). TP53+CDKN2A co-mutation showed a trend toward worse survival versus TP53 alone (HR 1.50, 95%CI 0.99-2.27, p=0.056; median OS 9.8 vs 12.8 months; 12-month OS 34.7% vs 51.5%). Conclusions: In this first real-world clinico-genomic analysis of OCSCC, TP53 mutation was associated with worse OS, and TP53+CDKN2A co-mutation identified an even higher-risk subset with nearly halved median survival (20.9 vs 44.5 months) compared to wild-type. CDKN2A co-occurred with TP53 in 95% of cases. TERT promoter mutations confirmed their adverse prognostic role. Notably, PIK3CA mutation showed favorable prognosis (HR 0.59), potentially relevant for targeted therapeutics. DDR pathway mutations predicted particularly poor outcomes following immunotherapy. These findings provide a molecular framework for risk stratification in OCSCC and warrant prospective validation. Prognostic impact of gene mutations on overall survival in oral cavity cancer. Genes HR (95%CI) p-value Median OS (MT vs WT) 12-mo OS (from diagnosis) TP53+CDKN2A co-mutation 1.83 (1.23-2.72) 0.003 20.9 vs 44.5 mo 76.5% vs 83.9% TP53 1.72 (1.20-2.47) 0.003 26.0 vs 44.5 mo 80.6% vs 85.1% CDKN2A 1.34 (1.04-1.73) 0.024 20.9 vs 34.2 mo 77.3% vs 83.6% TERT promoter 1.35 (1.01-1.80) 0.041 24.4 vs 38.0 mo 77.6% vs 88.8% PIK3CA 0.59 (0.42-0.85) 0.004 51.3 vs 25.7 mo 83.5% vs 81.0%