Real-world clinical outcomes and molecular features of lung-specific and liver-specific metastases in pancreatic ductal adenocarcinoma (PDAC)

532 Background: PDAC remains one of the most lethal malignancies following metastatic presentation, typically to the liver or lung. Previous studies have observed that advanced PDAC patients have variable outcomes depending on site of involvement. Here, we aim to understand survival outcomes and molecular features for PDAC based on involvement of lung vs liver. Methods: We retrospectively analyzed longitudinal clinical outcomes across 787 patients with PDAC with next generation sequencing (NGS) from Perthera’s Real-World Evidence database whose tumors first metastasized to either the lung or the liver. Median overall survival (mOS) was measured from either the date of initial diagnosis (resectable cases only, stage I-III) or advanced diagnosis (stage IV) until death. Differences in survival and frequencies of mutations were evaluated between patients with lung-specific and liver-specific metastases using Cox regression and Fisher's exact test, respectively. Results: Among resectable PDAC, mOS from initial diagnosis was significantly shorter in patients that developed liver only metastasis (Table, left) compared to those patients that developed lung only metastasis (p=2.4e-08, HR=3.04 [2.06-4.49]). In the advanced PDAC cohort, mOS from diagnosis of advanced disease was also significantly shorter (Table, right) in liver only versus lung only metastasis (p=0.0013, HR=1.62 [1.21-2.18]). Differences in treatment-specific outcomes were not significant supporting a potential prognostic role for lung only metastases. PDAC tumors presenting to the liver first were modestly enriched (unadjusted p<0.05) for TP53 mutations (81.4% in liver vs 69.2% in lung), MYC amplifications (8.6% vs 3.0%), and inactivating CDK2NA alterations (51.5% vs 39.1%) whereas lung-specific mutation frequencies were higher for STK11 mutations (2.4% in liver vs 7.5% in lung), CCND1 amplifications (0.5% vs 3.0%), GNAS alterations (2.0% vs 8.5%). No differences in KRAS mutations nor specific isoforms were noted between lung vs liver only metastasis. Conclusions: Lung only metastasis in both resectable and advanced PDAC confers a significant survival advantage compared to liver only metastasis. Deeper investigation into the molecular drivers of site-specific metastases is warranted.[Table: see text]