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

被引：277

作者：

Aguirre, Andrew J. ^{[1
,2
,3
,4
]}

Nowak, Jonathan A. ^{[1
,4
,5
]}

Camarda, Nicholas D. ^{[1
,2
,6
,7
]}

Moffitt, Richard A. ^{[8
]}

Ghazani, Arezou A. ^{[1
,2
,6
]}

Hazar-Rethinam, Mehlika ^{[9
]}

Raghavan, Srivatsan ^{[1
,2
,3
,4
]}

Kim, Jaegil ^{[2
]}

Brais, Lauren K. ^{[1
]}

Ragon, Dorisanne ^{[1
]}

Welch, Marisa W. ^{[1
]}

Reilly, Emma ^{[1
]}

McCabe, Devin ^{[1
,2
,6
,7
]}

Marini, Lori ^{[1
,5
,6
]}

Anderka, Kristin ^{[2
]}

Helvie, Karla ^{[1
,6
]}

Oliver, Nelly ^{[1
,6
]}

Babic, Ana ^{[1
,4
]}

Da Silva, Annacarolina ^{[1
,4
,5
]}

Nadres, Brandon ^{[9
]}

Van Seventer, Emily E. ^{[9
]}

Shahzade, Heather A. ^{[9
]}

St Pierre, Joseph P. ^{[1
]}

Burke, Kelly P. ^{[1
,3
,4
]}

Clancy, Thomas ^{[1
,4
,10
]}

Cleary, James M. ^{[1
,3
,4
]}

Doyle, Leona A. ^{[1
,4
,5
]}

Jajoo, Kunal ^{[1
,4
,11
]}

McCleary, Nadine J. ^{[1
,3
,4
]}

Meyerhardt, Jeffrey A. ^{[1
,3
,4
]}

Murphy, Janet E. ^{[9
]}

Ng, Kimmie ^{[1
,3
,4
]}

Patel, Anuj K. ^{[1
,3
,4
]}

Perez, Kimberly ^{[1
,3
,4
]}

Rosenthal, Michael H. ^{[1
,4
,12
]}

Rubinson, Douglas A. ^{[1
,3
,4
]}

Ryou, Marvin ^{[1
,4
,11
]}

Shapiro, Geoffrey I. ^{[1
,3
,4
]}

Sicinska, Ewa ^{[1
,4
]}

Silverman, Stuart G. ^{[1
,4
,12
]}

Nagy, Rebecca J. ^{[13
]}

Lanman, Richard B. ^{[13
]}

Knoerzer, Deborah ^{[14
]}

Welsch, Dean J. ^{[14
]}

Yurgelun, Matthew B. ^{[1
,3
,4
]}

Fuchs, Charles S. ^{[1
,4
,6
,7
]}

Garraway, Levi A. ^{[1
,2
,3
,4
,6
]}

Getz, Gad ^{[2
,4
,9
]}

Hornick, Jason L. ^{[1
,4
,5
]}

Johnson, Bruce E. ^{[1
,2
,3
,4
,6
]}

机构：

[1] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA

[2] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[3] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[4] Harvard Med Sch, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dana Farber Canc Inst, Joint Ctr Canc Precis Med, Boston, MA 02115 USA

[7] Harvard TH Chan Sch Publ Hlth, Boston, MA USA

[8] SUNY Stony Brook, Dept Pathol, Dept Biomed Informat, Stony Brook, NY 11794 USA

[9] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[10] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA

[11] Brigham & Womens Hosp, Dept Gastroenterol, 75 Francis St, Boston, MA 02115 USA

[12] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA

[13] GuardantHlth Inc, Dept Med Affairs, Redwood City, CA USA

[14] BioMed Valley Discoveries, Kansas City, MO USA

[15] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA

[16] Lustgarten Fdn, Pancreat Canc Res Lab, Cold Spring Harbor, NY USA

[17] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Surg, Chapel Hill, NC 27515 USA

[18] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27515 USA

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 09期

基金：

美国国家卫生研究院;

关键词：

SOMATIC ERCC2 MUTATIONS; DUCTAL ADENOCARCINOMA; INHIBITION; HETEROGENEITY; SIGNATURE; SUBTYPES; BRAF; MEK; FIBROBLASTS; RESISTANCE;

D O I：

10.1158/2159-8290.CD-18-0275

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2018 AACR.

引用

页码：1096 / 1111

页数：16

共 53 条

[41] Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer [J].

Russo, Mariangela ;

Siravegna, Giulia ;

Blaszkowsky, Lawrence S. ;

Corti, Giorgio ;

Crisafulli, Giovanni ;

Ahronian, Leanne G. ;

Mussolin, Benedetta ;

Kwak, Eunice L. ;

Buscarino, Michela ;

Lazzari, Luca ;

Valtorta, Emanuele ;

Truini, Mauro ;

Jessop, Nicholas A. ;

Robinson, Hayley E. ;

Hong, Theodore S. ;

Mino-Kenudson, Mari ;

Di Nicolantonio, Federica ;

Thabet, Ashraf ;

Sartore-Bianchi, Andrea ;

Siena, Salvatore ;

Iafrate, A. John ;

Bardelli, Alberto ;

Corcoran, Ryan B. .

CANCER DISCOVERY, 2016, 6 (02) :147-153

[42] Pancreatic Adenocarcinoma [J].

Ryan, David P. ;

Hong, Theodore S. ;

Bardeesy, Nabeel .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (11) :1039-1049

[43] Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy [J].

Sahin, Ibrahim H. ;

Iacobuzio-Donahue, Christine A. ;

O'Reilly, Eileen M. .

EXPERT OPINION ON THERAPEUTIC TARGETS, 2016, 20 (03) :341-359

[44] Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy [J].

Sherman, Mara H. ;

Yu, Ruth T. ;

Engle, Dannielle D. ;

Ding, Ning ;

Atkins, Annette R. ;

Tiriac, Herve ;

Collisson, Eric A. ;

Connor, Frances ;

Van Dyke, Terry ;

Kozlov, Serguei ;

Martin, Philip ;

Tseng, Tiffany W. ;

Dawson, David W. ;

Donahue, Timothy R. ;

Masamune, Atsushi ;

Shimosegawa, Tooru ;

Apte, Minoti V. ;

Wilson, Jeremy S. ;

Ng, Beverly ;

Lau, Sue Lynn ;

Gunton, Jenny E. ;

Wahl, Geoffrey M. ;

Hunter, Tony ;

Drebin, Jeffrey A. ;

O'Dwyer, Peter J. ;

Liddle, Christopher ;

Tuveson, David A. ;

Downes, Michael ;

Evans, Ronald M. .

CELL, 2014, 159 (01) :80-93

[45] Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma [J].

Shindo, Koji ;

Yu, Jun ;

Suenaga, Masaya ;

Fesharakizadeh, Shahriar ;

Cho, Christy ;

Macgregor-Das, Anne ;

Siddiqui, Abdulrehman ;

Witmer, P. Dane ;

Tamura, Koji ;

Song, Tae Jun ;

Almario, Jose Alejandro Navarro ;

Brant, Aaron ;

Borges, Michael ;

Ford, Madeline ;

Barkley, Thomas ;

He, Jin ;

Weiss, Matthew J. ;

Wolfgang, Christopher L. ;

Roberts, Nicholas J. ;

Hruban, Ralph H. ;

Klein, Alison P. ;

Goggins, Michael .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (30) :3382-+

[46] f Institutional implementation of clinical tumor profiling on an unselected cancer population [J].

Sholl, Lynette M. ;

Do, Khanh ;

Shivdasani, Priyanka ;

Cerami, Ethan ;

Dubuc, Adrian M. ;

Kuo, Frank C. ;

Garcia, Elizabeth P. ;

Jia, Yonghui ;

Davineni, Phani ;

Abo, Ryan P. ;

Pugh, Trevor J. ;

van Hummelen, Paul ;

Thorner, Aaron R. ;

Ducar, Matthew ;

Berger, Alice H. ;

Nishino, Mizuki ;

Janeway, Katherine A. ;

Church, Alanna ;

Harris, Marian ;

Ritterhouse, Lauren L. ;

Campbell, Joshua D. ;

Rojas-Rudilla, Vanesa ;

Ligon, Azra H. ;

Ramkissoon, Shakti ;

Cleary, James M. ;

Matulonis, Ursula ;

Oxnard, Geoffrey R. ;

Chao, Richard ;

Tassell, Vanessa ;

Christensen, James ;

Hahn, William C. ;

Kantoff, Philip W. ;

Kwiatkowski, David J. ;

Johnson, Bruce E. ;

Meyerson, Matthew ;

Garraway, Levi A. ;

Shapiro, Geoffrey I. ;

Rollins, Barrett J. ;

Lindeman, Neal I. ;

MacConaill, Laura E. .

JCI INSIGHT, 2016, 1 (19)

[47] Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma [J].

Torphy, Robert J. ;

Wang, Zhen ;

True-Yasaki, Aisha ;

Volmar, Keith E. ;

Rashid, Naim ;

Yeh, Benjamin ;

Johansen, Julia S. ;

Hollingsworth, Michael A. ;

Yeh, Jen Jen ;

Collisson, Eric A. .

JCO PRECISION ONCOLOGY, 2018, 2 :1-12

[48] Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma [J].

Van Allen, Eliezer M. ;

Mouw, Kent W. ;

Kim, Philip ;

Iyer, Gopa ;

Wagle, Nikhil ;

Al-Ahmadie, Hikmat ;

Zhu, Cong ;

Ostrovnaya, Irina ;

Kryukov, Gregory V. ;

O'Connor, Kevin W. ;

Sfakianoss, John ;

Garcia-Grossman, Ilana ;

Kim, Jaegil ;

Guancial, Elizabeth A. ;

Bambury, Richard ;

Bahl, Samira ;

Gupta, Namrata ;

Farlow, Deborah ;

Qu, Angela ;

Signoretti, Sabina ;

Barletta, Justine A. ;

Reuter, Victor ;

Boehm, Jesse ;

Lawrence, Michael ;

Getz, Gad ;

Kantoff, Philip ;

Bochner, Bernard H. ;

Choueiri, Toni K. ;

Bajorin, Dean F. ;

Solit, David B. ;

Gabriel, Stacey ;

D'Andrea, Alan ;

Garraway, Levi A. ;

Rosenberg, Jonathan E. .

CANCER DISCOVERY, 2014, 4 (10) :1140-1153

[49] Whole genomes redefine the mutational landscape of pancreatic cancer [J].

Waddell, Nicola ;

Pajic, Marina ;

Patch, Ann-Marie ;

Chang, David K. ;

Kassahn, Karin S. ;

Bailey, Peter ;

Johns, Amber L. ;

Miller, David ;

Nones, Katia ;

Quek, Kelly ;

Quinn, Michael C. J. ;

Robertson, Alan J. ;

Fadlullah, Muhammad Z. H. ;

Bruxner, Tim J. C. ;

Christ, Angelika N. ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Manning, Suzanne ;

Nourse, Craig ;

Nourbakhsh, Ehsan ;

Wani, Shivangi ;

Wilson, Peter J. ;

Markham, Emma ;

Cloonan, Nicole ;

Anderson, Matthew J. ;

Fink, J. Lynn ;

Holmes, Oliver ;

Kazakoff, Stephen H. ;

Leonard, Conrad ;

Newell, Felicity ;

Poudel, Barsha ;

Song, Sarah ;

Taylor, Darrin ;

Waddell, Nick ;

Wood, Scott ;

Xu, Qinying ;

Wu, Jianmin ;

Pinese, Mark ;

Cowley, Mark J. ;

Lee, Hong C. ;

Jones, Marc D. ;

Nagrial, Adnan M. ;

Humphris, Jeremy ;

Chantrill, Lorraine A. ;

Chin, Venessa ;

Steinmann, Angela M. ;

Mawson, Amanda ;

Humphrey, Emily S. ;

Colvin, Emily K. ;

Chou, Angela .

NATURE, 2015, 518 (7540) :495-501

[50] Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets [J].

Witkiewicz, Agnieszka K. ;

McMillan, Elizabeth A. ;

Balaji, Uthra ;

Baek, GuemHee ;

Lin, Wan-Chi ;

Mansour, John ;

Mollaee, Mehri ;

Wagner, Kay-Uwe ;

Koduru, Prasad ;

Yopp, Adam ;

Choti, Michael A. ;

Yeo, Charles J. ;

McCue, Peter ;

White, Michael A. ;

Knudsen, Erik S. .

NATURE COMMUNICATIONS, 2015, 6

← 1 2 3 4 5 6 →