Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer

被引：148

作者：

Anagnostou, Valsamo ^{[1
,2
]}

Niknafs, Noushin ^{[1
]}

Marrone, Kristen ^{[1
,2
]}

Bruhm, Daniel C. ^{[1
]}

White, James R. ^{[1
]}

Naidoo, Jarushka ^{[1
,2
]}

Hummelink, Karlijn ^{[3
]}

Monkhorst, Kim ^{[3
]}

Lalezari, Ferry ^{[3
]}

Lanis, Mara ^{[1
]}

Rosner, Samuel ^{[1
]}

Reuss, Joshua E. ^{[1
]}

Smith, Kellie N. ^{[1
,2
]}

Adleff, Vilmos ^{[1
]}

Rodgers, Kristen ^{[4
]}

Belcaid, Zineb ^{[1
]}

Rhymee, Lamia ^{[1
]}

Levy, Benjamin ^{[1
,2
]}

Feliciano, Josephine ^{[1
,2
]}

Hann, Christine L. ^{[1
,2
]}

Ettinger, David S. ^{[1
,2
]}

Georgiades, Christos ^{[5
]}

Verde, Franco ^{[6
]}

Illei, Peter ^{[1
,7
]}

Li, Qing Kay ^{[7
]}

Baras, Alexander S. ^{[7
]}

Gabrielson, Edward ^{[7
]}

Brock, Malcolm V. ^{[4
]}

Karchin, Rachel ^{[1
,8
]}

Pardoll, Drew M. ^{[1
,2
]}

Baylin, Stephen B. ^{[1
]}

Brahmer, Julie R. ^{[1
,2
]}

Scharpf, Robert B. ^{[1
]}

Forde, Patrick M. ^{[1
,2
]}

Velculescu, Victor E. ^{[1
,2
,7
,8
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Sch Med, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD USA

[3] Antoni van Leeuwenhoek Nederlands Kanker Inst, Amsterdam, Netherlands

[4] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Radiol & Surg, Baltimore, MD USA

[6] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Inst Computat Med, Baltimore, MD USA

来源：

NATURE CANCER | 2020年 / 1卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PD-1; BLOCKADE; ACQUIRED-RESISTANCE; REPAIR DEFICIENCY; TUMOR; LANDSCAPE; IMMUNOTHERAPY; MUTATIONS; MECHANISM; RESPONSES; TRIAL;

D O I：

10.1038/s43018-019-0008-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of whole-exome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated. Anagnostou et al. present an improved predictor of response to immune checkpoint blockade that integrates estimates of tumor mutational burden corrected for tumor purity, RTK genomic alterations, a smoking-related mutational signature and HLA status.

引用

页码：99 / +

页数：32

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