Clinical outcomes and molecular characteristics of patients with metastatic pancreatic ductal adenocarcinoma according to involved metastatic sites.

4179 Background: It is well documented that Pancreatic ductal adenocarcinoma (PDAC) metastasize to the liver had worse outcome than to the lung, but the molecular basis was less clear. We employ a large Real-World Evidence dataset to evaluate clinical and molecular features of PDAC according to involved metastatic sites. Methods: The Foundry software platform was used to query electronic medical records of patients with metastatic PDAC who underwent Next-Generation Sequencing (NGS) at MD Anderson. Involved metastatic sites were extracted using natural language process from imaging reports then manually verified. Overall survival (OS) was calculated from date of diagnosis. Results: We identified 1,095 patients with metastatic PDAC diagnosed between May 2003 and Oct 2024. Median follow up was 41.8 months and median OS was 22.8 (95%CI: 20.2-25.2) months. Most patients (52.9%) had multiple metastatic sites including liver, 28.5% had liver only metastases, while 8.7% had lung only metastases. 10% had metastases not including liver. Patients with lung only metastasis had the best outcomes (median = 57.6 months, HR = 0.37 relative to liver only, 95%CI = 0.27-0.52, p = 9.3e-9), followed by patients with metastases not involving liver (median = 41.3 months, HR = 0.65, 95%CI = 0.49-0.87, p = 0.003). Patients with liver only metastasis (median OS = 19.5 months) had similar survival to those with multiple sites including liver (median = 19.3 months, HR = 1.1, 95%CI = 0.96-1.4, p = 0.13). TP53 was more frequently mutated in patients with liver only metastasis (84%) and multiple metastases including liver (85%) compared to patients with lung only (73%) and multiple sites not including liver (67%, p = 9.3e-5). GNAS showed lower frequency (5%) in patients with liver only and patients with multiple metastasis including liver (2%) compared to patients with lung only (8%) or non-liver metastases (10%, p = 0.003). In patients with liquid biopsy (n = 240), lung only metastasis showed significantly lower positivity rate for mutation detection (50% vs 65% for liver only, 62% for other or multiple not including liver and 79% for multiple including liver, p = 0.009), and lower TP53 detection rate (23% for lung only vs 46% for liver only, p = 0.02). The frequency of KRAS mutation and mutant allele distribution were not significantly different in tissue NGS. However, patients with lung only metastasis showed significantly less frequent KRAS mutation detection by liquid biopsy (10% vs 52% in liver only metastasis, p = 9.6e-4). Conclusions: PDAC patients without liver metastasis have markedly improved OS relative to patients with liver metastasis, and lower rates of TP53 mutation. Similar frequencies of KRAS mutation were found in different patients by tissue testing. However, patients with lung only metastasis had lower positivity rate of ctDNA, and lower detection rate of KRAS mutation by liquid biopsy.