BP22. Landscape of molecular subtypes in metastatic pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with most patients diagnosed at advanced stages and facing limited treatment options. Although PDAC frequently metastasizes to multiple organs, patients with lung-only metastases consistently demonstrate better overall survival (OS) than those with liver-only metastases. The molecular underpinnings of these survival differences remain unclear.


Methods:

Retrospective analysis of PDAC patients treated with neoadjuvant therapy and surgical resection at a single institution was performed. RNA sequencing was performed on primary tumors as well as matched metastatic biopsies when available. Additional data from three public datasets were integrated into paired analysis. Molecular subtyping was performed using PurIST, a single-sample classifier for PDAC subtyping.


Results:

Among 144 patients, 54 (38%) did not develop documented progression. Metastatic progression included liver-only (23; 16%), lung-only (20; 14%), peritoneum-only (15; 10%), other sites (8; 5%), and multifocal (24; 17%). Patients with lung-only metastases had significantly longer median OS (51 months; 95% CI, 38-66) than those with liver-only (20 months; 95% CI, 17-24), peritoneum-only (28 months; 95% CI, 25-33), or multifocal (20 months; 95% CI, 17-25) metastases (log-rank P < 0.0001). Notably, lung metastases were transcriptionally more classical than their matched primaries (paired Wilcoxon P = 0.0313), while liver metastases exhibited no consistent shift. Gene set enrichment analysis further revealed that lung metastases were positively enriched for epithelial differentiation programs and negatively enriched for mesenchymal and neuronal pathways.


Conclusions:

These findings suggest that the lung microenvironment may favor more classical and differentiated transcriptional programs in metastatic PDAC, potentially contributing to the observed survival advantage.