Abstract / Summary
Neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS) is a conditionally recommended treatment for resectable pancreatic ductal adenocarcinoma (PDAC) in Japan. However, therapeutic efficacy remains limited in a subset of patients who lose surgical opportunities due to tumor progression. This study investigated preoperative biomarkers for prognostic risk stratification in patients undergoing surgical resection. In this prospective multicenter study of patients with resectable PDAC, podocalyxin-like protein (PODXL) and integrin β1 (ITGB1) expression was evaluated in preoperative endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens using novel monoclonal antibodies and an automated detection system. The primary study cohort was restricted to patients with resectable PDAC ( n = 55), including 37 who received NAC-GS and 18 who underwent upfront surgery. A small cohort with borderline resectable PDAC ( n = 7) was analyzed strictly as an exploratory subset. In the resectable cohort ( n = 55), the Both-high group ( n = 24, 43.6%) displayed significantly worse overall survival than the Others group ( n = 31, 56.4%) (median OS: 1.99 vs. not reached [3.71–NA] years; hazard ratio [HR] = 3.77, 95% confidence interval [CI] = 1.74–8.18, log-rank p = 0.0003). In the subgroup receiving NAC-GS followed by surgery ( n = 37), the Both-high group ( n = 14) also showed significantly worse OS than the Others group ( n = 23) (median OS: 2.59 vs. not reached years; HR = 5.56, 95% CI = 2.03–15.21, log-rank p = 0.0002). In multivariate analysis, Both-high status remained an independent prognostic factor for patients with resectable PDAC (HR = 4.41, 95% CI = 1.91–10.17, p = 0.0005). Survival classification and regression tree (CART) analysis suggested that Both-high status was the primary explanatory factor for prognostic discrimination. Exploratory model evaluation suggested a modest incremental prognostic value of combining ITGB1 with PODXL, as demonstrated by decision curve analysis (DCA) and time-dependent AUC (Supplementary Material). Preoperative immunohistochemical evaluation of Both-high PODXL/ITGB1 expression in EUS-FNAB specimens is a potential method for prognostic stratification of patients with resectable PDAC undergoing surgery. Because this study evaluated only patients reaching surgical resection, these biomarkers serve as prognostic stratifiers rather than definitive predictive markers for neoadjuvant treatment efficacy or loss of surgical opportunity. Future prospective interventional trials including non-resected patients are required to establish whether biomarker-guided treatment modification improves patient outcomes.