Adaptive Biotechnologies TCRbeta sequencing of 174 primary and 42 metastatic pancreatic ductal adenocarcinoma tumor samples from FFPE curls and 215 matched blood plus 73 additional blood samples

Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer if disease spreads to the lung but not the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a pORG gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU Cancer Registry and disease-relevant computed tomography (CT) scans to allow for cohort classification. Patients whose primary tumor was located at the Ampulla of Vater but classified as pancreatobiliary subtype were included (N=9). The Adaptive Biotechnologies human TCRB sequencing service was used to sequence both primary and metastatic tumors (25mm thick FFPE curls) and matched blood (frozen leukocytes). Blood specimens were categorized as associated with primary disease or metastatic disease based on the following criteria: The blood specimen was considered primary-associated if it was collected before or on the day of primary tumor resection, metastasis-associated if it was collected after a recurrence, or uncharacterized if it was collected after resection and before recurrence. For patients not treated by resection, the blood was considered primary-associated if it was collected 180 days before the latest date the patient was confirmed metastasis free on imaging. The blood was considered metastasis-associated if it was collected after the patient had metastasis confirmed on imaging or was collected within 30 days before metastasis was detected on imaging. *************************************************************** *** Adaptive Biotechnologies does not release raw data *** ***************************************************************