Molecular Profiling and Prognostic Value of KRAS Gene Mutations in Tumor Samples and Liquid Biopsies from Patients with Pancreatic Ductal Adenocarcinoma: A Review

Abstract

KRAS is mutated in the large majority of pancreatic ductal adenocarcinomas, and the same mutation can now be read either from a tumour block or froma tube of blood. The two readings are not interchangeable. Tissue reports which variant a tumour carries; plasma  reports whether the tumour is shedding enough DNA to be seen at all, and that fact carries prognostic weight of its own.
Objectives: To summarise published evidence on the frequency and subtype distribution of KRAS mutations in PDAC tissue, on the rate at which mutant KRAS is detected in plasma across disease settings, on concordance between the two compartments, and on the prognostic value attached to each. Material and Methods: Narrative review of primary cohort studies, trial reports and meta-analyses indexed in PubMed and in the major oncology journals. Studies were eligible if they reported KRAS variant distribution in PDAC tissue, plasma detection rates for mutant KRAS or circulating tumour DNA, tissue-plasma concordance, or survival stratified by KRAS status in either compartment. No new patient data were generated for this review. Every frequency, survival estimate and effect size quoted is one published by the original investigators, and the figures and tables reproduce reported values only. Results: KRAS is mutated in approximately 82 to 92 per cent of PDAC tumours. Among mutant cases the distribution is dominated by G12D (about 39 per
cent), G12V (31 per cent), G12R (14 per cent) and Q61 (6 per cent), with G12C accounting for only 1 to 2 per cent. In the largest single-centre series reporting subtype-level survival (n = 803), median overall survival was 38 months for wild-type tumours, 34 months for G12R, 22 months for G12D (HR 1.7) and 20 months for Q61 (HR 1.9). Plasma detection is strongly stage-dependent, reported at 64.7 per cent in metastatic disease, 16.6 per cent in locally advanced disease and 19 per cent after resection. Detection of mutant KRAS in plasma before treatment was associated with a median overall survival of 10.5 months against 22.6 months when it was undetectable (HR 4.70, p = 0.002). Conclusion: Tissue and plasma answer different questions. Tissue establishes the variant, which produces modest but reproducible prognostic separation. Plasma establishes tumour DNA shedding, which behaves as a stronger and more dynamic prognostic signal but is insensitive in localised disease. The two are complementary rather than substitutable, and the evidence base remains dominated by retrospective single-centre series. Abbreviations: PDAC – Pancreatic Ductal Adenocarcinoma, ctDNA – Circulating Tumour DNA, cfDNA – Cell-Free DNA, ddPCR – Droplet Digital Polymerase Chain Reaction, NGS – Next-Generation Sequencing, OS – Overall Survival, HR – Hazard Ratio, MAF – Mutant Allele Fraction, WT – Wild Type.