Sex-based differences in metastasis among patients with early-onset pancreatic ductal adenocarcinoma.

e16423 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination and a strong predilection for liver metastasis. The incidence of early-onset PDAC is rising, yet sex-specific patterns of metastasis remain poorly characterized. Preclinical evidence demonstrates that sex hormones, immune composition, and stromal signaling shape PDAC tumor biology and the hepatic metastatic niche, resulting in sex-dependent metastatic differences in experimental models. Methods: We retrospectively identified patients with early-onset metastatic PDAC between January 2015 and December 2025 using ICD-10 codes and pathologically confirmed PDAC. Clinical, demographic, molecular, and treatment data were abstracted from the EHR. The primary endpoint was presence of liver metastasis at diagnosis. Secondary endpoints included metastatic distribution and overall survival. Results: Of the 95 patients in this cohort, at diagnosis, liver metastases were present in 54.4% of males and 44.7% of females, corresponding to an absolute risk difference of 9.7% with higher prevalence among men. The unadjusted odds of liver metastasis were higher in men compared with women (OR 1.47, 95% CI 0.60–3.62). Bone metastases were about three-fold more frequent in women than in men (10.5% vs 3.5%). Among patients who developed recurrent disease following surgical resection, women had a lower proportion of liver-first recurrence compared with men (45% vs 67%), with an odds ratio of 0.42. This difference was not statistically significant (Fisher’s exact p = 0.41) and should be considered hypothesis-generating. Reproductive and hormonal factors appeared to modulate outcomes. Recent pregnancy was associated with improved overall survival (HR 1.76, 95% CI 0.60–5.17), whereas peri- or post-menopausal status was associated with worse survival compared with pre-menopausal status (HR 0.30, 95% CI 0.07–1.29). Conclusions: Sex was associated with differences in metastatic organ distribution rather than overall metastatic incidence. Men demonstrated higher prevalence of hepatic involvement at diagnosis and a greater proportion of liver-first recurrence following resection, whereas women exhibited greater extra-hepatic dissemination, including increased bone involvement. These patterns suggest sex-conditioned differences in hepatic metastatic niche permissiveness. Reproductive and hormonal state may further influence metastatic progression and survival. Although underpowered and hypothesis-generating, these trends are biologically plausible and concordant with preclinical models, warranting validation in larger, multi-institutional cohorts. Metastatic distribution at diagnosis for early-onset PDAC. Female Male Liver 44.74% 54.39% Lung 7.89% 7.02% Peritoneum/omentum 13.16% 14.04% Distant lymph node 15.79% 10.53% Bone 10.53% 3.51% Brain 0.00% 1.75% Other 10.53% 1.75%