Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine
Creators: name: McCabe, Devin
name: McCleary, Nadine J
name: Jajoo, Kunal
name: Rosenthal, Michael H
name: Wagle, Nikhil
name: Cleary, James M
name: Murphy, Janet E
name: Kim, Jaegil
name: Ryou, Marvin
name: Yeh, Jen Jen
name: Babic, Ana
name: Lanman, Richard B
name: Nadres, Brandon
name: Silverman, Stuart G
name: Perez, Kimberly
name: Hazar-Rethinam, Mehlika
name: Shyn, Paul B
name: Moffitt, Richard A
name: Raghavan, Srivatsan
name: Tuveson, David A
name: Clancy, Thomas
name: St Pierre, Joseph P
name: Garraway, Levi A
name: Sicinska, Ewa
name: Fuchs, Charles S
name: Yurgelun, Matthew B
name: Wolpin, Brian M
name: Ragon, Dorisanne
name: Corcoran, Ryan B
name: Johnson, Bruce E
name: Patel, Anuj K
name: Welsch, Dean J
name: Ng, Kimmie
name: Marini, Lori
name: Rubinson, Douglas A
name: Welch, Marisa W
name: Reilly, Emma
name: Brais, Lauren K
name: Shahzade, Heather A
name: Hornick, Jason L
name: Hahn, William C
name: Knoerzer, Deborah
name: Oliver, Nelly
name: Van Seventer, Emily E
name: Miller, Jeffrey W
name: Ghazani, Arezou A
name: Doyle, Leona A
name: Anderka, Kristin
name: Helvie, Karla
name: Aguirre, Andrew J
name: Meyerhardt, Jeffrey A
name: Burke, Kelly P
name: Getz, Gad
name: Carter, Scott L
name: Shapiro, Geoffrey I
name: Kulke, Matthew H
name: Da Silva, Annacarolina
name: Nowak, Jonathan A
name: Mayer, Robert J
name: Camarda, Nicholas D
name: Nagy, Rebecca J
Publisher: name: American Association for Cancer Research (AACR)
Year: 2018

description: Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.