Clinical relevance of next-generation sequencing in patients aged 60 years or younger with pancreatic cancer: A Nationwide prospective cohort study.

[BACKGROUND AND AIMS] Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and frequent resistance to standard treatments. This study evaluates the feasibility and clinical impact of comprehensive tumor molecular profiling in PDAC patients aged ≤ 60 years.

[METHODS] Nationwide prospective cohort study across 13 Dutch hospitals from April 2021 to June 2024. PDAC patients aged ≤ 60 at any disease stage were included regardless of treatment status. DNA and RNA from tumor samples were isolated from representative, formalin-fixed paraffin-embedded (FFPE) slides for whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS). A multidisciplinary molecular tumor board reviewed results monthly.

[RESULTS] Among 318 patients, 88.7 % (282/318) had tumor samples suitable for sequencing. WES and WTS were completed in 175 patients (55.0 %), with WTS alone in 88 (27.7 %). Complete molecular analysis was more often successful in resection specimens than in biopsy samples (79 % vs 33 %; P < .001). Unknown germline mutations in cancer predisposition genes were identified in 4 % (13/318) of patients. Actionable alterations were detected in 13.2 % (42/318), rising to 22.3 % (39/175) among patients with WES and WTS. Actionable targets were found in 92.3 % (12/13) KRAS-wildtype tumors. Only 11 of 42 (26.2 %) patients received tailored therapies.

[CONCLUSIONS] Complete molecular profiling in PDAC patients ≤ 60 years showed moderate success (55 %) and limited clinical impact, with actionable findings in 13 % and therapy implementation in 3.5 %. Prioritizing KRAS testing and deeper sequencing in KRAS-wildtype tumors, alongside broader access to targeted therapies, may improve outcomes.