Prognostic biomarkers for pancreatic ductal adenocarcinoma: A contemporary systematic review and modelling study

Table 1 Population, intervention, comparison, outcome, and study design framework for study eligibility

Criteria	Review stage	Inclusion	Exclusion
Study design	Abstract/full article review	Original human studies evaluating the prognostic significance of tumor-derived transcriptomic and/or proteomic biomarkers in PDAC. Eligible designs include prospective or retrospective cohort studies, nested biomarker studies, translational correlative studies embedded within clinical trials, and secondary analyses of publicly available human molecular datasets (e.g., TCGA, ICGC, CPTAC). Eligible only if the study demonstrated an independent prognostic biomarker, i.e. the tumor transcriptomic/proteomic biomarker remained significantly associated with the survival outcome in an adjusted multivariable time-to-event model including clinicopathological covariates	In vitro studies, cell line studies, animal studies, narrative reviews, systematic reviews, meta-analyses, editorials, letters, commentaries, protocols, case reports, case series with insufficient outcome data, and conference abstracts without full-text data
Population	Abstract/full article review	Adults (≥ 18 years) with histologically confirmed PDAC, including resectable, locally advanced unresectable, and metastatic disease, provided that survival or other prognostic outcome data were available	Studies focused exclusively on non-PDAC malignancies, including pancreatic neuroendocrine neoplasms, periampullary cancers, ampullary cancers, cholangiocarcinoma, acinar cell carcinoma, or mixed pancreatic tumor populations where PDAC-specific results cannot be disaggregated
Treatment/intervention	Abstract/full article review	Tumor molecular profiling using transcriptomic or proteomic methods, including RNA sequencing, gene expression microarrays, qPCR-based tumor expression profiling, mass spectrometry-based proteomics, RPPA, or molecular signatures derived from transcriptomic/proteomic datasets	Studies based solely on clinical variables, histopathology without molecular profiling, circulating biomarkers only, imaging biomarkers only, radiomics without molecular tumor data, genomic/DNA-only biomarkers without transcriptomic or proteomic readout, or studies lacking explicit biomarker assessment
Comparator	Abstract/full article review	Comparisons across biomarker-defined strata, such as high vs low expression, biomarker-positive vs biomarker-negative status, molecular subtype classification, or low- vs high-risk prognostic groups derived from transcriptomic/proteomic signatures	Studies with no biomarker-based stratification or no analysable comparison across molecular groups
Outcomes	Abstract/full article review	Primary outcome: OS. Secondary outcomes: PFS, DFS, RFS, CSS, PFI, and other clinically relevant time-to-event prognostic outcomes	Studies not reporting survival, recurrence, or other prognostic time-to-event outcomes; studies reporting only treatment response without survival correlation
Biomarker modality and sample type	Abstract/full article review	Eligible only if the biomarker was a transcriptomic (RNA) or proteomic readout measured in PDAC tumor tissue (resection specimen, biopsy, or FFPE/fresh-frozen archival tissue), including tumor tissue profiled by RNA-seq, microarray, qPCR, NanoString, mass spectrometry, RPPA, or IHC-validated protein expression where the protein readout was the tested prognostic marker. Multimodal studies are eligible if tumor transcriptomic/proteomic results are reported separately and can be disaggregated	Not eligible: (1) Liquid biopsy/circulating analytes as the sole readout (ctDNA, cfDNA, CTCs, circulating or exosomal miRNA/mRNA, plasma or serum proteomics, CA19-9 and other serum markers); (2) Histopathology alone (grade, stage, margin status, lymphovascular or perineural invasion, tumor budding, stroma scoring) without a molecular readout; (3) Genomic/DNA-only markers (KRAS, TP53, SMAD4, or CDKN2A mutations; copy number; methylation; TMB; MSI) with no transcript- or protein-level measurement; (4) Imaging/radiomics markers; and (5) Germline variants. These modalities were recorded at screening but excluded from data extraction unless accompanied by a tumor transcriptomic or proteomic result

PDAC: Pancreatic ductal adenocarcinoma; TCGA: The Cancer Genome Atlas; ICGC: International Cancer Genome Consortium; CPTAC: Clinical Proteomic Tumor Analysis Consortium; RPPA: Reverse-phase protein array; qPCR: Quantitative polymerase chain reaction; OS: Overall survival; PFS: Progression-free survival; RFS: Recurrence-free survival; DFS: Disease-free survival; CSS: Cancer-specific survival; PFI: Progression-free interval; FFPE: Formalin-fixed paraffin-embedded; RNA-seq: RNA sequencing; IHC: Immunohistochemistry; ctDNA: Circulating tumor DNA; cfDNA: Cell-free DNA; miRNA: MicroRNA; mRNA: Messenger RNA; CTC: Circulating tumor cell; CA19-9: Carbohydrate antigen 19-9; MSI: Microsatellite instability; TMB: Tumor mutational burden.