Neoadjuvant Chemotherapy Diminishes Ki-67 Overexpression and Persistent Overexpression is a Poor Prognostic Factor in Pancreatic Ductal Adenocarcinoma After Pancreatectomy

OBJECTIVES: This study aimed to investigate the clinical and biological significance of neoadjuvant chemotherapy (NAC) by assessing Ki-67 expression in pancreatic ductal adenocarcinoma (PDAC). METHODS: This single-center retrospective study enrolled 213 patients who had curative pancreatic resection with or without NAC between January 2004 and December 2022. Surgical specimens, evaluated via immunohistochemical staining for Ki-67, were divided into the high (≥ 20%) (n = 97) and low (< 20%) (n = 116) expression groups. RESULTS: Of the 213 patients, 118 underwent upfront surgery (US), while 95 were treated with NAC followed by surgery. In the entire cohort, high Ki-67 expression was an independent poor prognostic factor for overall survival (OS) (hazard ratio [HR]: 1.709, P = 0.005) by multivariate Cox regression analyses. The NAC group showed significantly less high Ki-67 expressions than the US group (31.4% and 57.6%, respectively) (P < 0.0001). Furthermore, in the NAC group, the persistently high Ki-67 expressions showed poorer OS relative to the low Ki-67 expressions (3-year OS: 24.1% vs. 53.0%, P = 0.005) and was an independent poor prognostic factor for OS (HR: 2.120, P = 0.006). The high Ki-67 expression was also robustly associated with low SMAD4 and high c-Myc expressions via immunostaining (P = 0.035 and 0.0002, respectively). CONCLUSION: NAC diminishes Ki-67 overexpression, and persistent overexpression even after NAC is an independent poor prognostic factor of PDAC after pancreatectomy. The Ki-67 overexpression may mirror a high malignant state due to the low SMAD4 and high c-Myc expression.