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. 2019 May 1;5(5):696-702.
doi: 10.1001/jamaoncol.2018.7098.

Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel

Zhijie Wang  1 , Jianchun Duan  1 , Shangli Cai  2 , Miao Han  3 , Hua Dong  3 , Jun Zhao  4 , Bo Zhu  5 , Shuhang Wang  6 , Minglei Zhuo  4 , Jianguo Sun  5 , Qiming Wang  7 , Hua Bai  1 , Jiefei Han  1 , Yanhua Tian  1 , Jing Lu  3 , Tongfu Xu  2 , Xiaochen Zhao  2 , Guoqiang Wang  2 , Xinkai Cao  3 , Fugen Li  3 , Dalei Wang  8 , Yuejun Chen  8 , Yuezong Bai  2 , Jing Zhao  2 , Zhengyi Zhao  2 , Yuzi Zhang  2 , Lei Xiong  2 , Jie He  1 , Shugeng Gao  1 , Jie Wang  1
Affiliations

Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel

"VSports最新版本" Zhijie Wang et al. JAMA Oncol. .

"VSports注册入口" Abstract

Importance: Tumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored VSports手机版. .

Objectives: To explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy. V体育安卓版.

Design, setting, and participants: In this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database V体育ios版. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018. .

Main outcomes and measures: Assessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES VSports最新版本. Evaluation of the association of bTMB level with progression-free survival and response to anti-PD-1 and anti-PD-L1 therapy. .

Results: This study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31. 2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30. 0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r2 = 0. 91; interquartile range, 0. 89-0. 92), especially when synonymous mutations were included (median r2 = 0. 92; interquartile range, 0. 91-0. 93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0 V体育平台登录. 62). In the anti-PD-1 and anti-PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0. 39; 95% CI, 0. 18-0. 84; log-rank P = . 01) and objective response rates (bTMB ≥6: 39. 3%; 95% CI, 23. 9%-56. 5%; bTMB <6: 9. 1%; 95% CI, 1. 6%-25. 9%; P = . 02). .

Conclusions and relevance: The findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti-PD-1 and anti-PD-L1 agents. VSports注册入口.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs M. Han, Dong, Lu, Cao, Li, D V体育官网入口. Wang, Chen, Xu, X. Zhao, G. Wang, Y. Bai, J. Zhao, Z. Zhao, Zhang, Xiong, and Cai are employees of 3D Medicines Inc. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Panel Design and Virtual Validation of the Association Between Blood and Tissue Tumor Mutational Burden (TMB)
A, Distribution of Pearson correlations between whole-exome sequencing (WES) and different numbers of genes randomly chosen (50 times) from gene panels. Syn + and Syn − indicate that synonymous mutations were included or excluded, respectively. B, Comparison of the performance of the NCC-GP150 panel and 150 randomly extracted genes (RAN150) among different tumor types. C, Pearson correlation of TMB between different public cancer gene panels and WES. D, Progression-free survival (PFS) by TMB status based on NCC-GP150 genes in the cohort studied by Rizvi et al. F1CDx indicates FoundationOne CDx; MSK-IMPACT, Memorial Sloan Kettering Cancer Center’s Integrated Mutation Profiling of Actionable Cancer Targets.
Figure 2.
Figure 2.. Clinical Validation of the Association Between NCC-GP150–Derived Blood Tumor Mutational Burden (bTMB) and Clinical Benefit in Patients With Non–Small Cell Lung Cancer
A, Progression-free survival (PFS) by bTMB status. B, Waterfall plot of observed best response from anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1) checkpoint inhibitors. C, Comparison of objective response rates (ORRs) between the high and low bTMB groups (P = .02). D, Comparison of bTMB level between nonresponse and response groups (P = .02). HR indicates hazard ratio.
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