JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

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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, School of Medicine, Zhejiang University, Hangzhou 310058, China; more
Corresponding email(s): georgewu@zju.edu.cn, dxia@zju.edu.cn
Key Words: Immune checkpoint inhibitor (ICI); Lung cancer; Usher syndrome type-2A (USH2A) missense mutation; Kirsten rat sarcoma viral oncogene homolog G12C (KRAS^G12C) mutation combined with tumor protein P53 (TP53) mutation; Epidermal growth factor receptor (EGFR) mutation

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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,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200292

@article{title="USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer",
author="Dexin YANG, Yuqin FENG, Haohua LU, Kelie CHEN, Jinming XU, Peiwei LI, Tianru WANG, Dajing XIA, Yihua WU",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2200292"
}

%0 Journal Article
%T USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer
%A Dexin YANG
%A Yuqin FENG
%A Haohua LU
%A Kelie CHEN
%A Jinming XU
%A Peiwei LI
%A Tianru WANG
%A Dajing XIA
%A Yihua WU
%J Journal of Zhejiang University SCIENCE B
%P 143-156
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2200292"

TY - JOUR
T1 - USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer
A1 - Dexin YANG
A1 - Yuqin FENG
A1 - Haohua LU
A1 - Kelie CHEN
A1 - Jinming XU
A1 - Peiwei LI
A1 - Tianru WANG
A1 - Dajing XIA
A1 - Yihua WU
J0 - Journal of Zhejiang University Science B
SP - 143
EP - 156
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B2200292"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

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 Kirsten rat sarcoma viral oncogene homolog G12C (KRAS^G12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFR^L858R and EGFR^Δ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (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 EGFR^T790M showed no difference compared to classical activating mutations without EGFR^T790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A (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 odds ratio (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 and the KRAS^G12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFR^T790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

USH2A突变和其他关键驱动基因突变亚型与免疫检查点抑制剂在肺癌患者中临床联系的关联研究

杨德馨^1,4，冯愉沁¹，鲁昊骅¹，陈柯列¹，徐金明²，李培伟⁵，王天如⁶，夏大静¹，吴一华^1,3
¹浙江大学医学院公共卫生学院毒理学系，附属妇产医院妇科肿瘤科，中国杭州市， 310058
²浙江大学附属第一医院胸外科，中国杭州市， 310003
³中国医学科学院肿瘤病理智能分型和精准治疗创新单元(2019RU042)，中国杭州市， 310058
⁴德克萨斯大学安德森癌症中心，德克萨斯大学健康科学中心麦戈文医学院生物化学与分子生物学系，美国休斯顿， TX 77030
⁵浙江大学附属第二医院消化内科，中国杭州市， 310009
⁶多伦多大学达拉拉娜公共卫生学院流行病学系，加拿大多伦多， M5S 2E8
概要：本研究以探索与免疫检查点抑制剂（ICIs）效果有关联的基因突变亚型为目标，进行了系统文献检索（电子数据库截至2021年5月31日）。与肿瘤基因特征相关联的主要结局事件包括：总生存期、无进展生存期、客观反应率、持久临床获益。我们从14项研究中总计提取了1546个有基因突变数据的肺癌患者，发现ICIs治疗在KRAS^G12C联合TP53双突变的患者中有更好的疗效，而在携带EGFR经典激活突变（包括EGFR^L585R和EGFR^Δ19）的患者中的效果则截然相反：总生存期（调整后HR, 1.40; 95% CI, 1.01-1.95; P=0.0411），无进展生存期（调整后HR, 1.98; 95% CI, 1.49-2.63; P<0.0001）。另外，ICIs治疗在EGFR经典突变联合EGFR^T790M双突变患者与仅有EGFR经典突变的患者在总生存期（调整后HR, 0.96; 95% CI, 0.48-1.94; P=0.9157）与无进展生存期（调整后HR, 0.72; 95% CI, 0.39-1.35; P=0.3050）中均无明显差异。更重要的是，我们发现ICIs在携带USH2A错义突变的患者中可能有更好的疗效：总生存期（调整后HR, 0.52; 95% CI, 0.32-0.82; P=0.0077），无进展生存期（调整后HR, 0.51; 95% CI, 0.38-0.69; P<0.0001），持久临床获益（调整后OR, 4.74; 95% CI, 2.75-8.17; P<0.0001）与客观反应率（调整后OR, 3.45; 95% CI, 1.88-6.33; P<0.0001）。综上，我们的研究发现在使用ICIs疗法的肺癌患者中，USH2A错义突变、KRAS^G12C联合TP53双突变与更好的疗效和生存结局有关，而EGFR经典突变无论是否合并EGFR^T790M突变都预示着不良结局，我们的结果可能会对在肿瘤ICIs的精准治疗方案提供新的依据和靶标。

关键词组：免疫检查点抑制剂（ICIs）；肺癌； USH2A错义突变； KRAS^G12C与TP53双突变； EGFR突变

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USH2A突变和其他关键驱动基因突变亚型与免疫检查点抑制剂在肺癌患者中临床联系的关联研究

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