Comparative Genomic Profiling and Prognostic Impact in Recurrent and/or Metastatic Hypopharyngeal and Esophageal Squamous Cell Carcinoma

Objective This study aimed to characterize the mutational profile of recurrent and/or metastatic esophageal squamous cell carcinoma (ESCC) and hypopharyngeal squamous cell carcinoma (HPSCC). Methods Data from 1319 consecutive patients with ESCC and 195 patients with HPSCC registered in the Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) at the Japan National Cancer Center between June 2019 and October 2025 were analyzed. Genetic alterations were identified using next‐generation sequencing. Patient survival was analyzed using the log‐rank test and the Cox proportional hazards model. Results TP53 , CDKN2A/B , CCND1 , and FGF family genes were frequently mutated in both ESCC and HPSCC, with a comparable number of mutations per individual. Comparative analysis revealed that only NFE2L2 ( p = 2.9 × 10 −6 ) mutations were significantly more frequent in ESCC after FDR correction. Survival analyses demonstrated that CCND1 ( p = 5.8 × 10 −3 ), FGF3 ( p = 8.66 × 10 −3 ), FGF4 ( p = 3.89 × 10 −3 ), FGF19 ( p = 8.75 × 10 −3 ), and NFE2L2 ( p = 8.75 × 10 −3 ) mutations were significantly associated with poorer overall survival in ESCC, whereas distinct prognostic impacts were observed in HPSCC. Conclusions ESCC and HPSCC shared broadly similar mutational landscapes; however, NFE2L2 mutations were significantly enriched in ESCC. Moreover, alterations in CCND1 and FGF family genes were associated with poor prognosis, highlighting their potential roles as prognostic biomarkers and therapeutic targets in ESCC. Level of Evidence III.