Impact of Neoadjuvant Approach and Tumor Response on Survival in Pancreatic Adenocarcinoma.

INTRODUCTION: Neoadjuvant therapy for pancreatic adenocarcinoma (PDAC) has evolved from single-agent to multi-agent approaches, largely informed by metastatic disease studies demonstrating improved survival; albeit at the price of increased toxicity. It remains unclear how response to varied neoadjuvant regimens impact survival. We hypothesized that tumor response to different neoadjuvant approaches reflects underlying tumor biology, and achieving a pathologic complete response (pCR) with single-agent neoadjuvant may signal favorable biology. METHODS: Adult PDAC patients (2010-2021) who received neoadjuvant therapy were identified in the National Cancer Database. Tumor response was categorized as pCR (pT0N0), moderate (≥ 2 T-stage reduction), or minimal/no response (≤ 1 T-stage reduction). Patients with stage IV disease, margin positive, or nodal involvement on final pathology were excluded; sensitivity analyses including these patients were performed. Neoadjuvant regimens were classified as single-agent, multi-agent, or multi-agent therapy plus adjuvant chemotherapy. RESULTS: Of 1923 patients, 9.8% achieved pCR, 19.1% had moderate response and 71.1% had minimal/no response. The 3-year overall survival (OS) was 74% [68-81] for pCR, 56% [51-62] for moderate, and 50% [47-52] for minimal/no response. Notably, 11% of pCR patients received single-agent therapy and had a 3-year OS comparable to those who received more intensive regimens, even after adjusting for confounders. Conversely, single-agent therapy in moderate or minimal/no responders was associated with significantly worse survival. Sensitivity analyses including patients with nodal metastasis and positive margins demonstrated consistent trends. CONCLUSIONS: Most PDAC patients benefit from multi-agent neoadjuvant, although a small subset achieve pCR with single-agent therapy and experience excellent outcomes. Response to varied neoadjuvant approaches merits further investigation in biomarker-driven studies and may inform opportunities for therapy personalization in appropriately selected PDAC patients.