Early-onset enriches the identification of actionable alterations in patients with KRAS wild-type pancreatic ductal adenocarcinoma

Background

Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) cases are KRAS wild-type (KRAS-wt). Among these, only a small subgroup harbors druggable genomic alterations, raising the question of when to apply broader next-generation DNA sequencing testing. Early-onset (EO) PDAC is increasing globally, with recent evidence suggesting an enrichment of KRAS-wt cases in younger patients.

Patients and methods

This retrospective observational study analyzed secondary data from a predefined database. Genomic alterations were identified using FoundationOne CDx or Liquid gene panels in patients who had failed standard treatments. Cases were classified by KRAS status, and KRAS-wt patients were stratified into EO (≤52.5 years) and late-onset (LO) (>52.5 years) groups. Alterations were evaluated according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESMO ESCAT).

Results

Next-generation sequencing was carried out on 224 PDAC and 10 pancreatic acinar cell carcinoma (PACC) patients. Within PDAC patients, 23.2% (52/224) were KRAS-wt. Actionable TIER I-III alterations were more frequent in KRAS-wt cases (23.1% versus 11.6%, P = 0.04), with gene fusion events exclusively found in KRAS-wt (9.6% versus 0%, P = 0.0006). Among KRAS-wt PDACs, significantly higher frequencies of druggable TIER I-III were identified across EO-PDAC (6 versus 6, or 54.5% versus 14.6%, P = 0.006). Notably, actionable gene fusions were found to be significantly enriched in KRAS-wt EO-PDACs compared with LO counterparts (4 versus 1, or 36.4% versus 2.4%, P = 0.005).

Conclusions

KRAS-wt PDAC diagnosed at a younger age more frequently harbors actionable mutations, highlighting the importance of comprehensive genomic profiling to guide targeted therapeutic interventions in this patient population.