Abstract 1884: Pancreatic cyst fluid proteins distinguish dysplasia grade of intraductal papillary mucinous neoplasm

Abstract Pancreatic cancer is the third leading cause of cancer-related death and is projected to be the second by 2030 in the US. The 5-year relative survival rate of pancreatic cancer is only 12.8% as over 80% of patients have a late diagnosis. To improve survival, it is vital to detect early-stage pancreatic cancer and its precursors. One such precursor is intraductal papillary mucinous neoplasm (IPMN), the most common type of pancreatic cyst often incidentally detected in asymptomatic patients. The current consensus guidelines, largely based on imaging features, have high sensitivity but low specificity in differentiating benign from malignant IPMNs, leading to widespread overtreatment of presumed “high-risk” cysts that have a low risk of malignancy on surgical pathology. Therefore, it is highly warranted to discover and validate biomarkers for improving the preoperative risk stratification of IPMN. Pancreatic cyst fluid is proximal to the tumor microenvironment and may thus harbor enhanced tumor-derived predictive biomarkers. Pancreatic cyst fluid samples were obtained from patients with pathologically confirmed low-grade (n=73) or high-grade/invasive (n=18) IPMN resected at Indiana University from 1992 to 2019. Global proteome quantitation was performed using liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) between the two groups were analyzed using Wilcoxon rank-sum test. We discovered 152 upregulated and 74 downregulated DEPs by comparing low-grade IPMN with high-grade/invasive IPMN (all p < 0.05). The enriched upstream regulators of these DEPs included let-7, miR-122, IL15, and FLT1 (p = 2.45 × 10-5 - 5.97 × 10-3). Five discriminatory biomarkers with the largest LASSO coefficients and each with the area under the receiver operating characteristic curve (AUCs) of >0.75 (FAHD2A, TCEAL3, TWF1, MMUT, and NTPCR) were identified. The combined five-protein model achieved an AUC of 0.96 (95% CI: 0.92, 1.00). The AUCs of cyst fluid and serum CA19-9 measured in the same patients (Spearman's rank correlation coefficient: 0.65) were 0.67 and 0.70, respectively, both of which were smaller than the AUCs of each of the top five proteins identified. Combining the five best-performing proteins with cyst fluid or serum CA19-9 yielded a near complete separation of malignant from benign IPMN (AUC: 0.981 for the cyst fluid panel and 0.997 for the serum panel). A combined analysis of TCGA and GTEx databases revealed TWF1 overexpression in pancreatic cancer (p < 0.0001) that was associated with poor prognosis (p = 0.0029). In conclusion, the present study identified a panel of cyst fluid proteins (particularly TWF1) that are predictive of malignant pancreatic cysts. If validated in other patient populations, these biomarkers could increase the accuracy of the preoperative detection of high-risk IPMN and thereby improve patient outcomes. Citation Format: Chunliang Liu, Amber Mosley, Ehsan Irajizad, Michele Yip-Schneider, Huangbing Wu, Whitney R. Smith-Kinnaman, Thoa Tran, James P. Long, Kim-Anh Do, Johannes Fahrmann, John M. DeWitt, Samir Hanash, C. Max Schmidt, Jianjun Zhang. Pancreatic cyst fluid proteins distinguish dysplasia grade of intraductal papillary mucinous neoplasm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1884.