TitleAllele Frequency-Adjusted Blood-Based Tumor Mutational Burden as a Predictor of Overall Survival for Patients With NSCLC Treated With PD-(L)1 Inhibitors
AuthorsWang, Zhijie
Duan, Jianchun
Wang, Guoqiang
Zhao, Jing
Xu, Jiachen
Han, Jiefei
Zhao, Zhengyi
Zhao, Jun
Zhu, Bo
Zhuo, Minglei
Sun, Jianguo
Bai, Hua
Wan, Rui
Wang, Xin
Fei, Kailun
Wang, Shuhang
Zhao, Xiaochen
Zhang, Yuzi
Huang, Mengli
Huang, Depei
Qi, Chuang
Gao, Chan
Bai, Yuezong
Dong, Hua
Xiong, Lei
Tian, Yanhua
Wang, Di
Xu, Chunwei
Wang, Wenxian
Li, Junling
Hu, Xingsheng
Cai, Shangli
Wang, Jie
AffiliationChinese Acad Med Sci & Peking Union Med Coll, State Key Lab Mol Oncol, Dept Med Oncol, Natl Canc Ctr,Nat Clin Res Ctr Canc,Canc Hosp, 17 Pan Jia Yuan South Lane, Beijing 100021, Peoples R China
3D Med Inc, Dept Med, Shanghai, Peoples R China
Peking Univ, Dept Thorac Med Oncol, Sch Oncol, Beijing Canc Hosp & Inst, Beijing, Peoples R China
Army Med Univ, Canc Inst, Xinqiao Hosp, Chongqing, Peoples R China
Chinese Acad Med Sci & Peking Union Med Coll, GCP Ctr, Natl Canc Ctr, Canc Hosp, Beijing, Peoples R China
3D Med Inc, Bioinformat Dept, Shanghai, Peoples R China
Fujian Med Univ, Dept Pathol, Fujian Canc Hosp, Fuzhou, Fujian, Peoples R China
Zhejiang Canc Hosp, Dept Chemotherapy, Hangzhou, Zhejiang, Peoples R China
Issue DateApr-2020
AbstractIntroduction: Blood-based tumor mutational burden (bTMB) has been studied to identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. Methods: Three independent cohorts of patients with NSCLC treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N = 211, and OAK, N = 462) and further validated in the third National Cancer Center (NCC) cohort (N = 64). Results: bTMB-H (bTMB >= cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r = 0.65), whereas a low AF bTMB (LAF-bTMB, mutation counts with an AF <= 5%) was not (Pearson r = 0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.52-0.95, p = 0.02), progression-free survival (PFS; HR = 0.62, 95% CI: 0.47-0.80, p < 0.001), and objective response rate (ORR) (p < 0.001) after immunotherapy but not chemotherapy, with a cutoff point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR = 0.20, 95% CI: 0.05-0.84, p = 0.02), PFS (HR = 0.30, 95% CI: 0.13-0.70, p = 0.003), and ORR (p = 0.001). Conclusions: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and ORR after anti-PD-(L)1 therapies in patients with NSCLC, which needs to be prospectively validated. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Appears in Collections:北京肿瘤医院

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