Clinical and genomic characterisation of early-onset pancreatic cancer

Background The incidence of early-onset pancreatic cancer (EOPC) has risen dramatically in recent years. We aimed to characterize the clinical and genomic features of EOPC and evaluate their therapeutic implications. Methods We performed a comparative, single-center, retrospective analysis of clinical, germline and genomic features in EOPC (≤50 years) patients and compared them with a control group of average-onset pancreatic cancer patients (AOPC, ≥70 years). Key molecular findings were compared with an external, publicly available cohort. Results We reviewed 336 patients who met all inclusion criteria (EOPC N=139, AOPC N=197). EOPC was associated with smoking status, lower prevalence of diabetes, better performance status, higher CA19.9 levels and higher albumin levels at diagnosis. After adjustment for baseline covariates, we observed no differences in overall survival (OS). Age was associated with an increase in the incidence of KRASMUT both in our cohort and the validation cohort. EOPC were enriched in potentially actionable alterations according to ESCAT tiers I-IIIA when compared with AOPC in discovery and validation cohorts (19% vs 14% and 14% vs 8%, respectively). In the first-line metastatic setting, EOPC had a longer progression-free survival (HR 0.61, 95% CI 0.43-0.87) and OS (HR 0.65, 95% CI 0.45-0.95), although there were no differences in response rate. After adjusting for the number of treatment lines, EOPC patients who did receive targeted therapies exhibited longer OS compared with EOPC who did not (HR 0.34, 95% CI 0.12-0.93). Conclusions EOPC patients have improved outcomes in the metastatic setting when compared to AOPC and are enriched for targetable alterations that open opportunities for precision oncology-based approaches.