Plasma Extracellular Vesicle Characteristics as Biomarkers of Resectability and Radicality of Surgical Resection in Pancreatic Cancer—A Prospective Cohort Study

SIMPLE SUMMARY: Despite diagnostic workup, unresectable or metastatic disease is still often found in PDAC patients at surgery, leading to unnecessary laparotomy and delay in systemic treatment. Liquid biopsy with sEV from plasma provides a direct insight into tumor characteristics and biology and has been shown to be valuable for diagnosis and treatment surveillance in different types of cancer. In patients with PDAC, deemed resectable upon diagnostic workup, preoperative concentrations of plasma sEV differ between patients who will undergo tumor resection and those who will solely have exploration without resection. Furthermore, among patients with resection, preoperative sEV concentrations differ between patients who will undergo radical (R0) resection and those with microscopic or macroscopic tumor remnant. In the future, liquid biopsy with sEV concentrations could provide important complementary information for better stratification of patients with presumably resectable PDAC and could assist in the decision to postpone surgery for neoadjuvant therapy or avoid surgery with possible complications altogether. ABSTRACT: Due to possible diagnostic misjudgment of tumor resectability, patients with pancreatic ductal adenocarcinoma (PDAC) might be exposed to non-radical resection or unnecessary laparotomy. With small extracellular vesicles (sEV) obtained by liquid biopsy, we aimed to evaluate their potential as biomarkers of tumor resectability, radicality of resection and overall survival (OS). Our prospective study included 83 PDAC patients undergoing surgery with curative intent followed-up longitudinally. sEV were isolated from plasma, and their concentration and size were determined. Fifty patients underwent PDAC resection, and thirty-three had no resection. Preoperatively, patients undergoing resection had higher sEV concentrations than those without resection (p = 0.023). Resection was predicted at the cutoff value of 1.88 × 10(9)/mL for preoperative sEV concentration (p = 0.023) and the cutoff value of 194.8 nm for preoperative mean diameter (p = 0.057). Furthermore, patients with R0 resection demonstrated higher preoperative plasma sEV concentrations than patients with R1/R2 resection (p = 0.014). If sEV concentration was above 1.88 × 10(9)/mL or if the mean diameter was below 194.8 nm, patients had significantly longer OS (p = 0.018 and p = 0.030, respectively). Our proof-of-principle study identified preoperative sEV characteristics as putative biomarkers of feasibility and radicality of PDAC resection that also enable discrimination of patients with worse OS. Liquid biopsy with sEV could aid in PDAC patient stratification and treatment optimization in the future.