Abstract
Objective: Postoperative risk stratification in esophageal squamous cell carcinoma (ESCC) remains largely dependent on clinicopathologic stage. Biologically interpretable models derived from public transcriptomic data may refine postoperative surveillance and risk communication after esophagectomy. This study aims to develop and internally validate a biologically interpretable Hallmark pathway-derived risk score for overall survival stratification in patients with ESCC. Methods: This retrospective computational study analyzed publicly available cases from the Cancer Genome Atlas esophageal carcinoma project (TCGA-ESCA) restricted to ESCC. Data retrieval for the analytic files was completed on April 29, 2026. Primary tumor messenger RNA (mRNA) expression data and clinical survival information were integrated. Gene-level expression values were transformed into Hallmark pathway scores using within-cohort standardized gene expression. Survival-associated pathways were screened by univariable Cox regression. The three pathways with the strongest univariable survival signals were entered into a penalized Cox model to generate a continuous pathway-derived risk score. Internal validation was performed using 5-fold cross-validation. Prognostic value was evaluated by Kaplan–Meier analysis, Cox regression, clinical-model comparison, and prespecified subgroup analyses. Results: Ninety-five TCGA-ESCC patients with available survival data were included. The final model included the reactive oxygen species pathway, UV response up, and p53 pathway. The 5-fold cross-validated concordance index was 0.687 (95% CI, 0.516–0.833). Using the median risk score as an exploratory visualization threshold, 48 patients were classified as high risk and 47 as low risk, with significant survival separation (log-rank p < 0.001). Univariable analysis revealed that the pathway-derived risk score was associated with overall survival (HR, 3.29; 95% CI, 1.53–7.04; p = 0.002) and remained an independent prognostic factor after adjustment for age, sex, pathological T stage, and nodal status (HR, 3.80; 95% CI, 1.46–9.90; p = 0.006). Adding the risk score to a clinicopathologic model improved the concordance from 0.710 to 0.762 and reduced the partial Akaike information criterion from 209.40 to 203.94. Conclusion: A three-pathway Hallmark-based score provided internally validated and biologically interpretable prognostic stratification in the TCGA-ESCC. The score remains exploratory, and external validation is necessary before clinical translation or threshold-based use.