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Cancer Discov. 2018 Sep;8(9):1096-1111. doi: 10.1158/2159-8290.CD-18-0275. Epub 2018 Jun 14.

Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.

Aguirre AJ#1,2,3,4, Nowak JA#5,4,6, Camarda ND#5,2,7,8, Moffitt RA#9, Ghazani AA5,2,7, Hazar-Rethinam M10, Raghavan S5,2,3,4, Kim J2, Brais LK5, Ragon D5, Welch MW5, Reilly E5, McCabe D5,2,7,8, Marini L5,6,7, Anderka K2, Helvie K5,7, Oliver N5,7, Babic A5,4, Da Silva A5,4,6, Nadres B10, Van Seventer EE10, Shahzade HA10, St Pierre JP5, Burke KP5,3,4, Clancy T5,4,11, Cleary JM5,3,4, Doyle LA5,4,6, Jajoo K5,4,12, McCleary NJ5,3,4, Meyerhardt JA5,3,4, Murphy JE10, Ng K5,3,4, Patel AK5,3,4, Perez K5,3,4, Rosenthal MH5,4,13, Rubinson DA5,3,4, Ryou M5,4,12, Shapiro GI5,3,4, Sicinska E5,4, Silverman SG5,4,13, Nagy RJ14, Lanman RB14, Knoerzer D15, Welsch DJ15, Yurgelun MB5,3,4, Fuchs CS5,4,7,8, Garraway LA5,2,3,4,7, Getz G2,4,10, Hornick JL5,4,6, Johnson BE5,2,3,4,7, Kulke MH5,3,4, Mayer RJ5,3,4, Miller JW8, Shyn PB5,4,13, Tuveson DA16, Wagle N5,2,3,4,7, Yeh JJ17, Hahn WC5,2,3,4, Corcoran RB4,10, Carter SL1,2,7,8, Wolpin BM1,3,4.

Author information

1
Dana-Farber Cancer Institute, Boston, Massachusetts. andrew_aguirre@dfci.harvard.edu carter.scott@jimmy.harvard.edu brian_wolpin@dfci.harvard.edu.
2
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
3
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
4
Harvard Medical School, Boston, Massachusetts.
5
Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
7
Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
8
Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
9
Department of Biomedical Informatics, Department of Pathology, Stony Brook University, Stony Brook, New York.
10
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
11
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
12
Department of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts.
13
Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.
14
Department of Medical Affairs, Guardant Health, Inc., Redwood City, California.
15
BioMed Valley Discoveries, Kansas City, Missouri.
16
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
17
Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
#
Contributed equally

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. 1062This article is highlighted in the In This Issue feature, p. 1047.

PMID:
29903880
PMCID:
PMC6192263
[Available on 2019-09-01]
DOI:
10.1158/2159-8290.CD-18-0275

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