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Journal of Zhejiang University SCIENCE B 1998 Vol.-1 No.-1 P.

http://doi.org/10.1631/jzus.B2200292


USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer


Author(s):  Dexin YANG, Yuqin FENG, Haohua LU, Kelie CHEN, Jinming XU, Peiwei LI, Tianru WANG, Dajing XIA, Yihua WU

Affiliation(s):  Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; more

Corresponding email(s):   georgewu@zju.edu.cn, dxia@zju.edu.cn

Key Words:  Immune Checkpoint Inhibitors, Lung cancer, USH2A missense mutations, KRASG12C mutation combined with TP53 mutation, EGFR mutations


Dexin YANG, Yuqin FENG, Haohua LU, Kelie CHEN, Jinming XU, Peiwei LI, Tianru WANG, Dajing XIA, Yihua WU. USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer[J]. Journal of Zhejiang University Science B, 1998, -1(-1): .

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Abstract: 
This study aimed to identify subtypes of genomic variants associated with the efficacy of immune Checkpoint Inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The KRASG12C mutation combined with TP53 mutation revealed the promising efficacy of ICIs therapy in these patients. Furthermore, patients with EGFR classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted HR, 1.40 [95%CI, 1.01-1.95]; P=0.0411) and PFS (adjusted HR, 1.98 [95%CI, 1.49-2.63]; P<0.0001) , while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96 [95%CI, 0.48-1.94]; P=0.9157) and PFS (adjusted HR, 0.72 [95%CI, 0.39-1.35]; P=0.3050). Of note, for patients harboring the USH2A missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52 [95%CI, 0.32-0.82]; P=0.0077), PFS (adjusted HR, 0.51 [95%CI, 0.38-0.69]; P<0.0001), DCB (adjusted OR, 4.74 [95%CI, 2.75-8.17]; P<0.0001), and ORR (adjusted OR, 3.45[95%CI, 1.88-6.33]; P<0.0001). Our findings indicated that, USH2A missense mutations, the KRASG12C mutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICIs therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

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