1. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
- Author
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Emily E. Van Seventer, Ana Babic, Jeffrey W. Miller, Deborah Knoerzer, Marvin Ryou, Heather A. Shahzade, Nadine Jackson McCleary, Jaegil Kim, Douglas A. Rubinson, Mehlika Hazar-Rethinam, Rebecca J. Nagy, Kristin Anderka, David A. Tuveson, Robert J. Mayer, Scott L. Carter, Leona A. Doyle, Nelly Oliver, Nicholas D. Camarda, Kimmie Ng, Matthew B. Yurgelun, Lauren K. Brais, Levi A. Garraway, Jeffrey A. Meyerhardt, Arezou A. Ghazani, Richard A. Moffitt, Stuart G. Silverman, Thomas E. Clancy, Srivatsan Raghavan, Annacarolina da Silva, Brandon Nadres, James M. Cleary, Andrew J. Aguirre, Kunal Jajoo, Kelly P. Burke, Michael H. Rosenthal, Emma Reilly, Kimberly Perez, Jonathan A. Nowak, Charles S. Fuchs, Dean Welsch, Jen Jen Yeh, Matthew H. Kulke, Marisa W. Welch, William C. Hahn, Anuj K. Patel, Ryan B. Corcoran, Karla Helvie, Paul B. Shyn, Gad Getz, Nikhil Wagle, Dorisanne Y. Ragon, Lori Marini, Geoffrey I. Shapiro, Janet E. Murphy, Brian M. Wolpin, Richard B. Lanman, Devin McCabe, Jason L. Hornick, Bruce E. Johnson, Ewa Sicinska, and Joseph P. St. Pierre
- Subjects
Adult ,Male ,0301 basic medicine ,DNA Repair ,MAP Kinase Signaling System ,DNA repair ,Germline ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Pancreatic cancer ,Exome Sequencing ,Carcinoma ,medicine ,Humans ,Gene Regulatory Networks ,Clinical significance ,Precision Medicine ,Homologous Recombination ,Germ-Line Mutation ,Exome sequencing ,Aged ,Aged, 80 and over ,Sequence Analysis, RNA ,business.industry ,Gene Expression Profiling ,Genetic Variation ,Genomics ,Middle Aged ,medicine.disease ,Precision medicine ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Carcinoma, Pancreatic Ductal - Abstract
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. 1062. This article is highlighted in the In This Issue feature, p. 1047
- Published
- 2018