Abstract 3036: Real-time genomic characterization of metastatic pancreatic cancer to enable precision medicine

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.3036-3036
• Main Authors: Aguirre, Andrew J., Carter, Scott, Camarda, Nicholas, Ghazani, Arezou, Nowak, Jonathan, Silva, Annacarolina Da, Brais, Lauren, Ragon, Dorisanne, McCabe, Devin, Marini, Lori, Anderka, Kristin, Helvie, Karla, Oliver, Nelly, Babic, Ana, Shyn, Paul, Rubinson, Douglas, Patel, Anuj, Cleary, James, McCleary, Nadine, Kulke, Matthew, Clancy, Thomas, Doyle, Leona, Hornick, Jason, Ardito-Abraham, Christine, Yu, Ruth, Downes, Michael, Evans, Ronald, Moffitt, Richard A., Yeh, Jen Jen, Hahn, William C., Fuchs, Charles, Mayer, Robert, Wagle, Nikhil, Tuveson, David, Garraway, Levi A., Wolpin, Brian M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-3036

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth-leading cause of cancer-related death in the United States and is projected to become the second leading cause by 2030. Most patients present with advanced disease and die within 12 months of diagnosis. Recent genomic studies of primary pancreatic cancer resection specimens have identified several molecular alterations and genomic subtypes of the disease that may guide precision medicine approaches to clinical management. However, the molecular landscape of metastatic PDAC has been less well characterized. Moreover, biopsy-driven studies in metastatic PDAC have been historically very challenging due to the aggressive course of this disease as well as the low-volume and heterogeneous nature of biopsies that makes deep molecular characterization difficult. Insufficient genomic analysis of a patient’s tumor early in their disease course is a major barrier to enrollment on clinical trials of targeted therapies. To address these limitations, we have implemented a multi-disciplinary clinical and research biopsy protocol to enable real time comprehensive molecular characterization of metastatic PDAC biopsy specimens. We have performed core needle biopsies of metastatic lesions in the liver or peritoneal cavity in 42 patients at the time of initial presentation. A low rate of complications was observed, with only a single patient having a self-limited hemorrhagic complication after liver biopsy. On average, 4-6 separate biopsy specimens were collected from each patient for histopathology and genomic analysis. Whole exome sequencing (WES) was performed in a CLIA-certified laboratory and a comprehensive molecular report of somatic alterations and selected pathogenic germline variants was returned to the referring clinician with a typical turn-around time of 3-5 weeks. We observed a striking incidence of recurrent germline and somatic alterations in DNA-damage repair genes, such as BRCA2, ATM and CHEK2. We also observed alterations in genes with known therapeutic implications, such as BRAF, RNF43, STK11 and ROS, and in select cases, these results guided choice of second or third line therapy. In parallel to WES, we performed RNA sequencing on bulk tumor tissue and readily identified expression signatures defining multiple subtypes of tumor and stroma that may have prognostic or therapeutic implications for tumor- or stroma-directed therapies. Collectively, these results demonstrate the feasibility and va