Characterisation of early-onset pancreatic adenocarcinoma molecular profile compared to average-onset pancreatic adenocarcinoma (CARAPAC): A systematic review and a meta-analysis.

BACKGROUND

Early-onset pancreatic adenocarcinoma (EOPA), defined as the diagnosis of pancreatic adenocarcinoma before the age of 50, is increasingly reported and may differ molecularly from average-onset pancreatic adenocarcinoma (AOPA). Understanding these differences is essential for precision medicine in this poor-prognosis malignancy.

METHODS

A systematic review and meta-analysis were conducted following PRISMA guidelines. Studies published between 2015 and 2025 reporting molecular data on EOPA and/or AOPA were identified. Comparative studies stratified by age group for molecular alterations were included in the meta-analysis. Quality assessment was performed using the JBI checklist. This study aimed at systematically review and meta-analyse existing data comparing the molecular landscape of EOPA and AOPA, and evaluate whether EOPA constitutes a distinct molecular subgroup of pancreatic adenocarcinoma.

RESULTS

Thirty-nine articles were included in the systematic review, of which eight met criteria for meta-analysis. KRAS mutations were significantly less frequent in EOPA than in AOPA (OR = 0.61; 95%CI [0.43-0.86], p = 0.005). No significant differences were observed for TP53, CDKN2A, SMAD4, or BRCA1/2 alterations. Sensitivity analyses confirmed the robustness of the KRAS finding. Study heterogeneity was moderate (I2 = 40%). Quality assessment revealed substantial variability in design, molecular methods, and reporting standards.

CONCLUSIONS

EOPA is enriched in KRAS wild-type tumours. This profile may offer alternative therapeutic opportunities, including RNA-based fusion detection, inclusion in targeted therapy trials, and suggest alternative oncogenic pathways for a proportion of this subpopulation. Standardised definitions, consistent molecular reporting, and exploration of age-specific risk factors are critical to improve understanding and management of EOPA.