Assessing Response and Outcomes to Modern Multiagent Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly used for resectable and borderline-resectable pancreatic ductal adenocarcinoma (PDAC), yet interpretation of treatment response remains challenging. PATIENTS AND METHODS: A single-center retrospective review was conducted of patients with resectable or borderline-resectable PDAC treated with multiagent NAT between 2008 and 2024. Radiographic response was assessed using RECIST 1.1 criteria, biochemical response by serum CA 19-9 reduction, and histopathologic response by College of American Pathologists (CAP) score. Primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: Among 166 patients, 148 (89%) completed NAT and 121 (73%) underwent resection. After NAT, radiographic response was uncommon: 27% had tumor regression, 66% stable disease, and 7% progressive disease. By contrast, 83% achieved ≥ 45% CA 19-9 reduction after NAT, and 74% demonstrated histopathologic response after resection, including 8% complete pathologic response. Among resected patients with radiographically stable/progressive disease, 88% had biochemical response and 68% at least partial histopathologic response. Neither radiographic nor biochemical response were significantly associated with improved PFS or OS. Histopathologic response (CAP 0-2) was associated with improved PFS/OS on univariable analysis as well as improved PFS on multivariable analysis [adjusted hazard ratio (aHR) 0.57, 95% confidence interval (CI) 0.34-0.96; p = 0.034]. Isolated unresectable local progression during NAT was rare (n = 2). CONCLUSIONS: While imaging response and downstaging can occur with NAT, histopathologic response is more predictive of long-term survival and often occurs despite stable or progressive disease on imaging. Isolated unresectable local progression after NAT is rare, though broader treatment-related attrition remains a consideration in neoadjuvant sequencing.