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Tarara V, Panteris E, Varlamis S, Andreadou E, Pessach I, Bobos M, Chatzidimitriou M, Mitka S, Papoutsi A, Eleftheriou P, Skepastianos P, Karamitrousis E. Prognostic biomarkers for pancreatic ductal adenocarcinoma: A contemporary systematic review and modelling study. World J Transl Med 2026; 12(4): 126295 [DOI: 10.5528/wjtm.126295]
Vassiliki Tarara, Sotirios Varlamis, Eleni Andreadou, Ilias Pessach, Mattheos Bobos, Maria Chatzidimitriou, Stella Mitka, Androniki Papoutsi, Phaedra Eleftheriou, Petros Skepastianos, Evangelos Karamitrousis, Department of Biomedical Sciences, International Hellenic University, Thessaloniki 57400, Kentrikí Makedonía, Greece
Eleftherios Panteris, School of Medicine, University of Crete, Heraklion 70013, Crete, Greece
Author contributions: Tarara V and Karamitrousis E conceived and designed the research study; Tarara V conducted the literature search, study selection, and data extraction, performed the bioinformatic and statistical analyses, and prepared the Figures and Tables; Tarara V and Karamitrousis E checked the risk-of-bias ratings; Tarara V drafted the manuscript; Panteris E and Karamitrousis E supervised the methodological approach and interpretation of the findings; Varlamis S, Andreadou E, Pessach I, Bobos M, Chatzidimitriou M, Mitka S, Papoutsi A, Eleftheriou P, and Skepastianos P contributed to the interpretation of the findings and critically revised the manuscript for important intellectual content; all authors reviewed and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.
AI contribution statement: Generative AI tools were used to assist with consistency checks of numerical values and R code. No AI tools were used to generate, analyse, or interpret the underlying molecular data; perform statistical analyses; or select studies for inclusion. All literature screening, data extraction, risk-of-bias and certainty judgements, and statistical analyses were performed by the authors. The authors reviewed and verified all AI-assisted text and accept full responsibility for the content and integrity of the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Evangelos Karamitrousis, MD, Assistant Professor, Department of Biomedical Sciences, International Hellenic University, Alexandria Campus, Sindos, Thessaloniki 57400, Kentrikí Makedonía, Greece. karamitrousis@ihu.gr
Received: July 30, 2026 Revised: September 20, 2026 Accepted: October 28, 2026 Published online: November 28, 2026 Processing time: 97 Days and 7.9 Hours
Abstract
BACKGROUND
Despite extensive biomarker discovery efforts in pancreatic ductal adenocarcinoma (PDAC), few biomarkers have been implemented clinically, and outcomes in clinical trials remain modest.
AIM
To evaluate prognostic transcriptomic and proteomic biomarkers in PDAC, assess clinical trial integration, and develop an exploratory molecular prognostic signature.
METHODS
A systematic review of studies published between 1 January 2025 and 6 March 2026 was conducted. Eligible studies evaluated tumor-derived transcriptomic or proteomic biomarkers in multivariable survival analyses or clinical trials. In parallel, Clinical Proteomic Tumor Analysis Consortium PDAC data were analyzed to identify candidate proteins. The corresponding genes were evaluated using least absolute shrinkage and selection operator (LASSO) Cox regression in The Cancer Genome Atlas pancreatic adenocarcinoma cohort to develop a prognostic signature, externally validated in GSE71729.
RESULTS
A total of 71 records met the predefined eligibility criteria, comprising 57 biomarker studies and 14 clinical trials. All 57 biomarker studies reported independent prognostic associations in adjusted multivariable models. None of the 14 clinical trials incorporated molecular biomarkers to determine eligibility, stratify randomization, or define a prespecified endpoint, indicating a substantial translational gap. The resulting 5-gene LASSO signature showed a strong association with overall survival in the derivation cohort but only modest discrimination. Its prespecified continuous risk score failed external validation. Although median-based risk stratification in the validation cohort was nominally significant, the association did not remain significant after correction for threshold selection.
CONCLUSION
The 5-gene signature in this study failed external validation. Contemporary PDAC biomarker discovery has not yet produced clinically reproducible prognostic tools.
Core Tip: This study integrates a contemporary systematic review with exploratory modelling to examine why prognostic biomarker discovery in pancreatic ductal adenocarcinoma has not translated into clinical practice. Although numerous tumor-derived transcriptomic and proteomic biomarkers showed independent survival associations, robust external validation and incorporation into clinical trials remained uncommon. An exploratory 5-gene molecular signature showed a strong survival association but only modest discrimination in the derivation cohort, and its continuous risk score failed external validation. These findings highlight reproducibility, prespecified validation, and biomarker-guided trial design as priorities for clinically useful pancreatic ductal adenocarcinoma risk stratification.
