β-catenin plus PROX1 immunostaining stratifies disease progression and patient survival in neoadjuvant-treated pancreatic cancer

Abstract

BACKGROUND: Wnt/β-catenin signaling is a highly conserved signaling pathway that regulates the transcription factor PROX1. The role of β-catenin and PROX1 in pancreatic cancer is ambiguous, as some studies have associated their expression with tumor regression and some with tumor progression. OBJECTIVE: We have investigated their expression in surgically treated pancreatic cancer patients receiving neoadjuvant therapy (NAT), and patients treated upfront with surgery (US). We furthermore compared the expression of β-catenin and PROX1 between patients who had a good or poor response to NAT. METHODS: We evaluated β-catenin and PROX1 expression through immunohistochemistry in 88 neoadjuvant and 144 upfront surgery patients by scoring the intensity of the immunopositivity as 0–3, corresponding to negative, weak, moderate, or strong. We developed a six-tier grading scheme for the neoadjuvant responses by analyzing the remaining tumor cells in surgical specimen histological sections. RESULTS: Strong β-catenin immunopositivity associated with improved survival in the patients with good NAT-response (≤10% residual tumor cells) (Hazard ratio [HR] 0.26 95%, confidence interval [CI] 0.07–0.88 p = 0.030). Additionally, the combined moderate β-catenin and PROX1 expression associated with improved survival (HR 0.20 95% CI 0.05–0–76 p = 0.018) among the good responders. Among the patients with a poor NAT-response (> 10% residual tumor cells), both strong β-catenin immunopositivity and strong combined β-catenin and PROX1 associated with shorter survival (HR 2.03 95% CI 1.16–3.55 p = 0.013, and HR 3.1 95% CI 1.08–8.94 p = 0.03, respectively). PROX1 alone was not associated with survival. CONCLUSIONS: Strong β-catenin immunopositivity and combined strong or moderate β-catenin and PROX1 immunopositivity associated with improved survival among the good NAT-responders and worse survival among the poor NAT-responders.