Tumor mutational load predicts survival after immunotherapy across multiple cancer types

被引：3198

作者：

Samstein, Robert M. ^{[1
,2
]}

Lee, Chung-Han ^{[3
,4
]}

Shoushtari, Alexander N. ^{[3
,4
]}

Hellmann, Matthew D. ^{[3
,4
]}

Shen, Ronglai ^{[5
]}

Janjigian, Yelena Y. ^{[3
,4
]}

Barron, David A. ^{[1
,2
]}

Zehir, Ahmet ^{[6
]}

Jordan, Emmet J. ^{[2
]}

Omuro, Antonio ^{[7
]}

Kaley, Thomas J. ^{[7
]}

Kendall, Sviatoslav M. ^{[8
]}

Motzer, Robert J. ^{[3
,4
]}

Hakimi, A. Ari ^{[9
]}

Voss, Martin H. ^{[3
,4
]}

Russo, Paul ^{[9
]}

Rosenberg, Jonathan ^{[3
,4
]}

Iyer, Gopa ^{[3
,4
]}

Bochner, Bernard H. ^{[9
]}

Bajorin, Dean F. ^{[3
,4
]}

Al-Ahmadie, Hikmat A. ^{[6
]}

Chaft, Jamie E. ^{[3
,4
]}

Rudin, Charles M. ^{[3
,4
]}

Riely, Gregory J. ^{[3
,4
]}

Baxi, Shrujal ^{[3
,4
]}

Ho, Alan L. ^{[3
,4
]}

Wong, Richard J. ^{[9
]}

Pfister, David G. ^{[3
,4
]}

Wolchok, Jedd D. ^{[3
,4
]}

Barker, Christopher A. ^{[1
]}

Gutin, Philip H. ^{[9
]}

Brennan, Cameron W. ^{[9
]}

Tabar, Viviane ^{[9
]}

Mellinghoff, Ingo K. ^{[8
]}

DeAngelis, Lisa M. ^{[8
]}

Ariyan, Charlotte E. ^{[9
]}

Lee, Nancy ^{[1
]}

Tap, William D. ^{[3
,4
]}

Gounder, Mrinal M. ^{[3
,4
]}

D'Angelo, Sandra P. ^{[3
,4
]}

Saltz, Leonard ^{[3
,4
]}

Stadler, Zsofia K. ^{[3
,4
]}

Scher, Howard I. ^{[3
,4
]}

Baselga, Jose ^{[3
,4
]}

Razavi, Pedram ^{[3
,4
]}

Klebanoff, Christopher A. ^{[3
,4
]}

Yaeger, Rona ^{[3
,4
]}

Segal, Neil H. ^{[3
,4
]}

Ku, Geoffrey Y. ^{[3
,4
]}

DeMatteo, Ronald P. ^{[9
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[4] Weill Cornell Med Ctr, Dept Med, New York, NY USA

[5] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA

[8] Mem Sloan Kettering Canc Ctr, Immunogenom & Precis Oncol Platform, 1275 York Ave, New York, NY 10021 USA

[9] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA

[10] Columbia Univ, Dept Med, Med Ctr, New York, NY USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 02期

关键词：

CTLA-4; BLOCKADE; PD-1; LANDSCAPE; NEOANTIGENS; SENSITIVITY; THERAPY;

D O I：

10.1038/s41588-018-0312-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

引用

页码：202 / +

页数：6

共 31 条

[1]

Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[2]

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer [J].

Balachandran, Vinod P. ;

Luksza, Marta ;

Zhao, Julia N. ;

Makarov, Vladimir ;

Moral, John Alec ;

Remark, Romain ;

Herbst, Brian ;

Askan, Gokce ;

Bhanot, Umesh ;

Senbabaoglu, Yasin ;

Wells, Daniel K. ;

Cary, Charles Ian Ormsby ;

Grbovic-Huezo, Olivera ;

Attiyeh, Marc ;

Medina, Benjamin ;

Zhang, Jennifer ;

Loo, Jennifer ;

Saglimbeni, Joseph ;

Abu-Akeel, Mohsen ;

Zappasodi, Roberta ;

Riaz, Nadeem ;

Smoragiewicz, Martin ;

Kelley, Z. Larkin ;

Basturk, Olca ;

Goenen, Mithat ;

Levine, Arnold J. ;

Allen, Peter J. ;

Fearon, Douglas T. ;

Merad, Miriam ;

Gnjatic, Sacha ;

Iacobuzio-Donahue, Christine A. ;

Wolchok, Jedd D. ;

DeMatteo, Ronald P. ;

Chan, Timothy A. ;

Greenbaum, Benjamin D. ;

Merghoub, Taha ;

Leach, Steven D. .

NATURE, 2017, 551 (7681) :512-+

[3]

Bendell J., 2018, ANN ONCOL, V29

[4]

Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency [J].

Bouffet, Eric ;

Larouche, Valerie ;

Campbell, Brittany B. ;

Merico, Daniele ;

de Borja, Richard ;

Aronson, Melyssa ;

Durno, Carol ;

Krueger, Joerg ;

Cabric, Vanja ;

Ramaswamy, Vijay ;

Zhukova, Nataliya ;

Mason, Gary ;

Farah, Roula ;

Afzal, Samina ;

Yalon, Michal ;

Rechavi, Gideon ;

Magimairajan, Vanan ;

Walsh, Michael F. ;

Constantini, Shlomi ;

Dvir, Rina ;

Elhasid, Ronit ;

Reddy, Alyssa ;

Osborn, Michael ;

Sullivan, Michael ;

Hansford, Jordan ;

Dodgshun, Andrew ;

Klauber-Demore, Nancy ;

Peterson, Lindsay ;

Patel, Sunil ;

Lindhorst, Scott ;

Atkinson, Jeffrey ;

Cohen, Zane ;

Laframboise, Rachel ;

Dirks, Peter ;

Taylor, Michael ;

Malkin, David ;

Albrecht, Steffen ;

Dudley, Roy W. R. ;

Jabado, Nada ;

Hawkins, Cynthia E. ;

Shlien, Adam ;

Tabori, Uri .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (19) :2206-+

[5]

Targeting T Cell Co-receptors for Cancer Therapy [J].

Callahan, Margaret K. ;

Postow, Michael A. ;

Wolchok, Jedd D. .

IMMUNITY, 2016, 44 (05) :1069-1078

[6]

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer [J].

Carbone, D. P. ;

Reck, M. ;

Paz-Ares, L. ;

Creelan, B. ;

Horn, L. ;

Steins, M. ;

Felip, E. ;

van den Heuvel, M. M. ;

Ciuleanu, T. -E. ;

Badin, F. ;

Ready, N. ;

Hiltermann, T. J. N. ;

Nair, S. ;

Juergens, R. ;

Peters, S. ;

Minenza, E. ;

Wrangle, J. M. ;

Rodriguez-Abreu, D. ;

Borghaei, H. ;

Blumenschein, G. R. ;

Villaruz, L. C. ;

Havel, L. ;

Krejci, J. ;

Corral Jaime, J. ;

Chang, H. ;

Geese, W. J. ;

Bhagavatheeswaran, P. ;

Chen, A. C. ;

Socinski, M. A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (25) :2415-2426

[7]

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden [J].

Chalmers, Zachary R. ;

Connelly, Caitlin F. ;

Fabrizio, David ;

Gay, Laurie ;

Ali, Siraj M. ;

Ennis, Riley ;

Schrock, Alexa ;

Campbell, Brittany ;

Shlien, Adam ;

Chmielecki, Juliann ;

Huang, Franklin ;

He, Yuting ;

Sun, James ;

Tabori, Uri ;

Kennedy, Mark ;

Lieber, Daniel S. ;

Roels, Steven ;

White, Jared ;

Otto, Geoffrey A. ;

Ross, Jeffrey S. ;

Garraway, Levi ;

Miller, Vincent A. ;

Stephens, Phillip J. ;

Frampton, Garrett M. .

GENOME MEDICINE, 2017, 9

[8]

Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology [J].

Cheng, Donavan T. ;

Mitchell, Talia N. ;

Zehir, Ahmet ;

Shah, Ronak H. ;

Benayed, Ryma ;

Syed, Aijazuddin ;

Chandramohan, Raghu ;

Liu, Zhen Yu ;

Won, Helen H. ;

Scott, Sasinya N. ;

Brannon, A. Rose ;

O'Reilly, Catherine ;

Sadowska, Justyna ;

Casanova, Jacklyn ;

Yannes, Angela ;

Hechtman, Jaclyn F. ;

Yao, Jinjuan ;

Song, Wei ;

Ross, Dara S. ;

Oultache, Alifya ;

Dogan, Snjezana ;

Borsu, Laetitia ;

Hameed, Meera ;

Nafa, Khedoudja ;

Arcila, Maria E. ;

Ladanyi, Marc ;

Berger, Michael F. .

JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (03) :251-264

[9]

Chowell D., 2017, SCIENCE, V62

[10]

Cohen E. E., 2017, ANN ONCOL, V28

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