Serum REG4 Level Is a Predictive Biomarker for the Response to Preoperative Chemoradiotherapy in Patients With Pancreatic Cancer

Objectives: Preoperative chemoradiotherapy is one of the key strategies for the improvement of survival in pancreatic cancer; however, no method to predict the response has yet been established. The aim of this study was to prospectively evaluate the predictive value of REG4, a new member of the regenerating (REG) islet-derived family of proteins. Methods: Stably REG4-expressing cells were established from a pancreatic cancer cell line and exposed in vitro to gamma-ray or gemcitabine to investigate the relevance of REG4 to the resistance to chemotherapy or radiotherapy. In 23 patients with resectable pancreatic cancer, the serum concentration of REG4 was measured before preoperative chemoradiotherapy, and the histologic response was evaluated after the surgery. Results: A 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and fluorescence activated cell scanning (FACS) revealed that REG4-overexpressing cells were resistant to gamma-radiation but showed a modest resistance to gemcitabine. The patients with a higher REG4 level, but not carcinoembryonic antigen or CA-19-9, showed an unfavorable histologic response to chemoradiotherapy (Spearman, rho = 0.439, P = 0.039). The patients showing a higher REG4 level experienced local recurrence postoperatively. Conclusions: These data demonstrated in vitro and in vivo that REG4 protein overexpression was associated with an unfavorable response to preoperative chemoradiotherapy. REG4 can clinically be used as a predictive biomarker.