Abstract 1913: Cystic fluid acetylated polyamines predict risk of malignancy of intraductal papillary mucinous neoplasms of the pancreas

Abstract Background: Intraductal papillary mucinous neoplasms are recognized precursor lesions to pancreatic ductal adenocarcinoma (PDAC). There remains an unmet need to establish biomarkers for identifying IPMN at high-risk of malignant progression for early interception. Previously, we reported that acetylated polyamines inform upon presence of PDAC. Here, we assessed to what extent cystic fluid polyamines predict risk of malignancy for patients with IPMN. Methods: Using mass spectrometry, we screened for polyamines in cystic fluid from 19 patients with either high-grade dysplasia (HG; N=12) or HG with a concurrent PDAC (IPMN/PDAC; N=7) and 70 patients with low-grade (LG) dysplasia). A total of 8 polyamines were detected and quantified, consisting of six that are host derived (spermidine, spermine, N-acetylputrescine (NAcPut), acetylspermidine (AcSpmd), diacetylspermidine (DiAcSpmd), and diacetylspermine (DAS) and two of microbial origin (acetycadaverine (AcCad) and diacetylcadaverine (DiAcCad). Predictive performance of individual polyamines for identifying HG or PDAC/IPMN was determined and complementarity with cystic fluid CA19-9 assessed. Findings were compared to metabolic profiles generated on 9 IPMN tumors (N= 3 LG; 3 HG, and 3 IPMN/PDAC) as well as cell lysates and conditioned medium from doxycycline-activated mutant Kras;Gnas IPMN cell lines. Publicly available spatial and single cell transcriptomic datasets of IPMN tumors were used to evaluate for spatial and cell-type specific differences in transcript levels of cognate enzymes involved in polyamine metabolism. Results: Of the 8 quantified polyamines, spermine, AcSpmd, DAS, and DiAcCad were statistically significantly elevated in cystic fluid of patients with HG or PDAC/IPMN compared to those with LG IPMN. DAS had the highest predictive performance for HG or PDAC/IPMN with an overall AUC of 0.73 (95% CI: 0.58-0.88). An OR-rule based on CA19-9, DAS, and AcSpmd achieved sensitivity of 52.6% and specificity of 91% for detecting HG and PDAC/IPMN. Polyamines were elevated in PDAC/IPMN tissues compared to LG IPMN tissues and polyamine levels accumulated in condition medium of mutant Kras;Gnas IPMN cells. Spatial and single cell transcriptomic data revealed transcript levels of polyamine-metabolizing enzymes to be preferentially elevated in neoplastic epithelium and in tumor-associated macrophages. Conclusion: Cystic fluid polyamines offer potential utility for determining risk of malignancy of IPMN, capable of complementing CA19-9. The polyamine signature may aid clinical management of patients with IPMN. Citation Format: Ricardo A. Leon Letelier, Riccardo Ballaro, Yihui Chen, Rongzhang Dou, Ehsan Irajizad, Michele Yip-Schneider, Ranran Wu, Rahmah Ejaz, Jody Vykoukal, Mark Hurd, Anirban Maitra, Jennifer Dennison, Kim-Anh Do, Jianjun Zhang, Samir Hanash, C. Max Smith, Johannes F. Fahrmann. Cystic fluid acetylated polyamines predict risk of malignancy of intraductal papillary mucinous neoplasms of the pancreas. [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 1913.