Predictive Biomarkers for Early Diagnosis of Pancreatic Ductal Adenocarcinoma (PDAC) (B-PDAC)

Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the poorest prognosis and is often diagnosed at an advanced stage, resulting in very low 5-year survival rates. Many PDACs arise from non-invasive precursor lesions that develop over years, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN). Only a minority of pancreatic cystic lesions progress to invasive carcinoma, and current clinical and radiologic criteria have limited accuracy in predicting which patients are at high risk. This observational translational study will enroll adult patients undergoing pancreatic surgical resection for suspected pancreatic neoplasm (IPMN, PanIN, or PDAC) at IRCCS "Saverio de Bellis". Residual tumor tissue not required for diagnostic purposes, and when available adjacent non-neoplastic tissue, will be collected, coded, and pseudonymized for molecular analyses. Tumor cells will be used to generate three-dimensional cultures (tumorspheres and organoids) and will undergo genomic characterization by next-generation sequencing, RNA-sequencing-based transcriptomic profiling, protein expression analyses, advanced imaging, and in-vitro drug response assays. The main goal is to identify and validate molecular biomarkers predictive of progression to PDAC, improve risk stratification of patients with pancreatic precursor lesions, and support the development of innovative precision medicine strategies.

Study Overview

• Status: Not yet recruiting
• Conditions: Pancreatic Ductal Adenocarcinoma (PDAC); Intraductal Papillary Mucinous Neoplasm of Pancreas; Pancreatic Intraepithelial Neoplasia

Detailed Description

Pancreatic ductal adenocarcinoma (PDAC) is currently one of the leading causes of cancer-related mortality worldwide and is characterized by late diagnosis, high biological aggressiveness, and marked resistance to systemic therapies. Epidemiologic projections indicate that, by 2030, PDAC will become the second most common cause of cancer death in Western countries, highlighting the need for improved early-diagnosis strategies and therapeutic interventions. Most PDACs arise from non-invasive precursor lesions through a multistep neoplastic transformation process. Key precursor entities include pancreatic intraepithelial neoplasia (PanIN) and mucinous cystic lesions, particularly intraductal papillary mucinous neoplasms (IPMN), which are clinically detectable by imaging, biologically heterogeneous, and associated with variable malignant potential. The widespread use of high-resolution imaging has increased incidental detection of pancreatic cysts, but only a subset of these lesions will progress to invasive carcinoma, making clinical management challenging.

In this context, the identification of reliable molecular biomarkers capable of predicting progression to invasive carcinoma is a clinical and scientific priority. This single-center, prospective observational translational study will include three arms: patients with IPMN, patients with PanIN, and patients with PDAC confirmed by histopathologic examination after pancreatic resection. Residual tissue not needed for diagnostic histopathology will be processed following standardized procedures to ensure high-quality biospecimens and full traceability. Fresh samples will be used for isolation of tumor stem-like cells and establishment of three-dimensional cultures (tumorspheres and organoids); additional material will be fixed in formalin and embedded in paraffin (FFPE) for histopathologic and immunohistochemical analyses.

Molecular analyses will comprise next-generation sequencing (NGS) to identify somatic mutations, genomic instability, tumor mutational burden (TMB), and alterations in key oncogenic genes and pathways; RNA-sequencing (RNA-seq) to characterize transcriptional programs associated with neoplastic transformation; protein expression studies by immunofluorescence, immunohistochemistry, and Western blot focusing on proliferation, apoptosis, and tumor stemness markers; advanced cellular imaging to study proliferation, survival, invasiveness, and metabolic adaptation under stress; and in-vitro pharmacologic assays to assess sensitivity of patient-derived models to inhibitors targeting the identified biomarkers. Statistical analyses will include Monte Carlo-based sample-size estimation, group comparisons using parametric and non-parametric tests, logistic regression models, ROC curve analyses, and high-dimensional bioinformatic pipelines for differential expression, clustering, and multivariate pattern recognition. The ultimate aim is to define and validate molecular signatures predictive of progression toward PDAC, correlate them with clinical and pathological features, and generate organoid models for preclinical studies in precision oncology.

• Study Type: Observational
• Enrollment (Estimated): 180

Contacts and Locations

• Study Contact: Name: Raffaele Armentano, MD; Phone Number: +390804994185; Email: raffaele.armentano@irccsdebellis.it
• Study Contact Backup: Name: Martina Lepore Signorile, Biologist; Email: martina.lepore@irccsdebellis.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study population consists of adult patients (≥18 years) referred to the IRCCS "Saverio de Bellis" for pancreatic surgical resection due to suspected pancreatic neoplasm. Eligible participants are those with a histopathologic diagnosis of intraductal papillary mucinous neoplasm (IPMN), pancreatic intraepithelial neoplasia (PanIN), or pancreatic ductal adenocarcinoma (PDAC), with availability of residual tumor tissue not required for routine diagnostics and who have provided written informed consent for use of biological samples in translational research.

Description

Inclusion Criteria:

• Age ≥ 18 years.
• Patients undergoing pancreatic surgical resection for suspected pancreatic neoplasm.
• Histopathologic diagnosis of intraductal papillary mucinous neoplasm (IPMN), pancreatic intraepithelial neoplasia (PanIN), or pancreatic ductal adenocarcinoma (PDAC).
• Availability of residual tumor tissue from the surgical procedure not required for diagnostic purposes.
• Signed written informed consent for the use of biological samples for research purposes

Exclusion Criteria:

• Age < 18 years.
• Surgical procedure performed for neoplasms other than IPMN, PanIN, or PDAC.
• Absence of written informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
IPMN Cohort; Adult patients undergoing pancreatic resection with histopathologic diagnosis of intraductal papillary mucinous neoplasm (IPMN); residual tumor tissue and, when available, adjacent non neoplastic tissue will be collected for molecular analyses and organoid generation
PanIN Cohort; Adult patients undergoing pancreatic resection with histopathologic diagnosis of pancreatic intraepithelial neoplasia (PanIN); residual tissue will be used for genomic, transcriptomic, proteomic, and functional studies in patient derived models
PDAC Cohort; Adult patients undergoing pancreatic resection with histopathologic diagnosis of pancreatic ductal adenocarcinoma (PDAC); biospecimens will be processed for comprehensive molecular characterization and comparison with precursor lesions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular biomarkers predictive of progression to pancreatic ductal adenocarcinoma (PDAC	Identification of genomic, transcriptomic, and proteomic biomarkers associated with progression from pancreatic precursor lesions (IPMN, PanIN) to PDAC, based on NGS, RNA seq, protein expression assays, and advanced imaging in patient derived tumorspheres and organoids.	Up to 36 months from surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Protein level validation of candidate biomarkers	Validation of selected predictive biomarkers at the protein level by immunohistochemistry, immunofluorescence, and Western blot in tissue and organoid samples from IPMN, PanIN, and PDAC patients.	Up to 36 months from surgery
Association between biomarker profiles and tumor progression	Evaluation of correlations between biomarker expression profiles and clinical, histopathologic, and imaging indicators of tumor progression, using logistic regression and ROC curve analyses.	Up to 36 months
Establishment of patient derived organoid models for preclinical studies	Generation and characterization of stable patient derived tumorsphere and organoid models from IPMN, PanIN, and PDAC samples suitable for preclinical drug testing and precision medicine applications	Up to 36 months

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis
• Investigators: Principal Investigator: Raffaele Armentano, MD, IRCCS "Saverio de Bellis"

Publications and helpful links

General Publications

• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12.
• Rahib L, Coffin T, Kenner B. Factors Driving Pancreatic Cancer Survival Rates. Pancreas. 2025 Jul 1;54(6):e530-e536. doi: 10.1097/MPA.0000000000002489.
• Marsoner K, Haybaeck J, Csengeri D, Waha JE, Schagerl J, Langeder R, Mischinger HJ, Kornprat P. Pancreatic resection for intraductal papillary mucinous neoplasm- a thirteen-year single center experience. BMC Cancer. 2016 Nov 4;16(1):844. doi: 10.1186/s12885-016-2887-8.
• Muraki T, Jang KT, Reid MD, Pehlivanoglu B, Memis B, Basturk O, Mittal P, Kooby D, Maithel SK, Sarmiento JM, Christians K, Tsai S, Evans D, Adsay V. Pancreatic ductal adenocarcinomas associated with intraductal papillary mucinous neoplasms (IPMNs) versus pseudo-IPMNs: relative frequency, clinicopathologic characteristics and differential diagnosis. Mod Pathol. 2022 Jan;35(1):96-105. doi: 10.1038/s41379-021-00902-x. Epub 2021 Sep 13.
• Taherian M, Wang H, Wang H. Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers. Cells. 2022 Sep 29;11(19):3068. doi: 10.3390/cells11193068.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: July 13, 2026
• First Submitted That Met QC Criteria: July 13, 2026
• First Posted (Actual): July 16, 2026

Study Record Updates

• Last Update Posted (Actual): July 16, 2026
• Last Update Submitted That Met QC Criteria: July 13, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: PDAC; IPMN; PanIN
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Pancreatic Neoplasms; Pancreatic Intraductal Neoplasms
• Other Study ID Numbers: RC 2025 - PDAC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No