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《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2024年04期

页码:

548-552

栏目:

出版日期:

2024-08-25

文章信息/Info

Title:

Clinical value of EPHA5 mutation in predicting the prognosis of lung adenocarcinoma treated with immune checkpoint inhibitors

作者:

郑 琪¹; 马婕群¹; 张彦兵¹; 廖子君¹; 张 锐²

710061 西安,陕西省肿瘤医院肿瘤内科¹、重症医学科²

Author(s):

Zheng Qi¹;  Ma Jiequn¹;  Zhang Yanbing¹;  Liao Zijun¹;  Zhang Rui².

¹Department of Medical Oncology, Affiliated Shaanxi Provincial Tumor Hospital, Xi’an Shanxi 710061, China; ²Department of Critical Care Medicine, Affiliated Shaanxi Provincial Tumor Hospital, Xi’an Shanxi 710061, China

关键词:

肺腺癌;  EPHA5突变;  免疫检查点抑制剂;  预后

Keywords:

Lung adenocarcinoma;  EPHA5 mutation;  Immune checkpoint inhibitors;  Prognosis

分类号:

R734.2

DOI:

10.3877/cma.j.issn.1674-6902.2024.04.008

摘要:

目的 分析Eph受体A(Eph receptor A, EPHA)5突变预测肺腺癌(lung adenocarcinoma, LUAD)免疫检查点抑制剂(immune checkpoint inhibitors, ICI)治疗预后的临床意义。方法 通过生物信息学分析癌症药物敏感性基因组学(genomics of drug sensitivity in cancer, GDSC)-LUAD数据集、癌症基因组图谱(the cancer genome atlas, TCGA)-LUAD数据集中可能与LUAD患者ICI应答相关的突变基因。选择2020年1月至2021年1月我院接受帕博利珠单抗治疗的96例LUAD患者,收集患者的石蜡包埋组织肿瘤标本和匹配的血液样本,采用二代基因测序。根据检测结果分为EPHA5-WT亚组66例和EPHA5-MT亚组30例。记录患者的客观缓解率(objective response rate, ORR)、疾病控制率(disease control rate, DCR)及无进展生存期(progression-free survival, PFS)。结果 生物信息学分析显示,EPHA5-MT的LUAD患者可从ICI治疗中获益。临床队列分析结果显示,EPHA5-MT亚组LUAD的肿瘤突变负荷值27.34(19.98,53.24)mut/Mb高于EPHA5-WT亚组13.70(10.77,17.75)mut/Mb(P<0.001)。EPHA5-WT亚组ORR 22.73% 低于EPHA5-MT亚组33.33%(P>0.05),EPHA5-MT亚组的DCR 86.67% 高于EPHA5-WT亚组62.12%(P<0.05)。EPHA5-WT亚组疾病进展36例(54.55%),其中死亡11例。高于EPHA5-MT亚组8例(26.67%),其中死亡4例。单因素及多因素COX回归分析显示,EPHA5-WT相较于EPHA5-MT是LUAD患者ICI治疗后发生疾病进展的危险因素。绘制Kaplan-Meier生存曲线显示,EPHA5-MT组LUAD患者PFS 14.53[5.71～26.23]个月长于EPHA5-WT组 7.89(0.59～30.67)个月(P<0.005)。结论 EPHA5-MT是影响LUAD ICI治疗预后的生物标志物。

Abstract:

Objective To analyze the clinical value of Eph receptor A(EPHA)5 mutation in predicting the prognosis of lung adenocarcinoma(LUAD)treated with immune checkpoint inhibitors(ICI). Methods The mutation genes that may be associated with ICI response in LUAD patients were analyzed by bioinformatics in the genomics of drug sensitivity in cancer(GDSC)-LUAD dataset and the cancer genome atlas(TCGA)-LUAD dataset. A clinical cohort of 96 LUAD patients treated with pembrolizumab in our hospital from January 2020 to January 2021 was retrospectively enrolled. The patients’paraffin-embedded tissue tumor specimens and matched blood samples were collected for next-generation sequencing. According to the results, the patients were divided into EPHA5-WT subgroup 66 cases and EPHA5-MT 30 cases subgroup. The objective response rate(ORR), disease control rate(DCR)and progression-free survival(PFS)were recorded. Results Bioinformatics analysis showed that LUAD patients with EPHA5-MT could benefit from ICI treatment. The results of clinical cohort analysis showed that the tumor mutation burden value of LUAD patients in the EPHA5-MT subgroup was significantly higher than that in the EPHA5-WT subgroup [27.34(19.98, 53.24)mut/Mb vs. 13.70(10.77, 17.75)mut/Mb, P<0.001]. There was no significant difference in ORR between EPHA5-WT subgroup and EPHA5-MT subgroup(22.73% vs. 33.33%, P=0.272), but the DCR of EPHA5-MT subgroup was higher than that of EPHA5-WT subgroup(86.67% vs. 62.12%, P=0.029). Thirty-six patients(54.55%)in the EPHA5-WT subgroup and 8 patients(26.67%)in the EPHA5-MT subgroup experienced disease progression. Univariate and multivariate COX regression analysis showed that EPHA5-WT was an independent risk factor for LUAD disease progression compared with EPHA5-MT. Kaplan-Meier survival curve showed that the PFS of EPHA5-MT group was longer than that of EPHA5-WT group[14.53(5.71～26.23) months vs. 7.89(0.59～30.67)months, P<0.001]. Conclusion EPHA5-MT is a potential biomarker for the prognosis of LUAD patients treated with ICI.

参考文献/References:

1 马小雯, 范明伟, 杜 江. 锌指蛋白502在肺腺癌中的表达及作用机制[J]. 中国医科大学学报, 2023, 52(9): 798-804.
2 Liu L, Wang C, Li S, et al. ERO1L is a novel and potential biomarker in lung adenocarcinoma and shapes the immune-suppressive tumor microenvironment[J]. Front Immunol, 2021, 12: 677169.
3 Sun H, Liu SY, Zhou JY, et al. Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma[J]. E Bio Medicine, 2020, 60: 102990.
4 李慧婷, 莫冉冉, 宋 鹏, 等. 非小细胞肺癌免疫检查点抑制剂治疗进展[J/CD]. 中华肺部疾病杂志(电子版), 2019, 12(3): 382-386.
5 Mori K, Pradere B, Moschini M, et al. First-line immune-checkpoint inhibitor combination therapy for chemotherapy-eligible patients with metastatic urothelial carcinoma: A systematic review and meta-analysis[J]. Eur J Cancer, 2021, 151: 35-48.
6 Palmer AC, Izar B, Hwangbo H, et al. Predictable clinical benefits without evidence of synergy in trials of combination therapies with immune-checkpoint inhibitors[J]. Clin Cancer Res, 2022, 28(2): 368-377.
7 Honrubia-Peris B, Garde-Noguera J, García-Sánchez J, et al. Soluble biomarkers with prognostic and predictive value in advanced non-small cell lung cancer treated with immunotherapy[J]. Cancers, 2021, 13(17): 4280-4295.
8 Lin ZF, Qin LX, Chen JH. Biomarkers for response to immunotherapy in hepatobiliary malignancies[J]. Hepatobiliary Pancreat Dis Int, 2022, 21(5): 413-419.
9 Yoon SJ, Lee CB, Chae SU, et al. The comprehensive “Omics” approach from metabolomics to advanced omics for development of immune checkpoint inhibitors: Potential strategies for next generation of cancer immunotherapy[J]. Int J Mol Sci, 2021, 22(13): 6932-6956.
10 Bai H, Duan J, Li C, et al. EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma[J]. J Immunother Cancer, 2020, 8(2): e001315.
11 张海涛, 王 春, 张映铭, 等. 非小细胞肺癌患者EGFR突变率及与临床病理关系和TKI靶向治疗效果[J/CD]. 中华肺部疾病杂志(电子版), 2019, 12(2): 175-180.
12 Anderton M, van der Meulen E, Blumenthal MJ, et al. The role of the Eph receptor family in tumorigenesis[J]. Cancers(Basel), 2021, 13(2): 206.
13 Zhang J, Zhang Z, Song W, et al. EPHA5 mutation impairs natural killer cell-mediated cytotoxicity against non-small lung cancer cells and promotes cancer cell migration and invasion[J]. Mol Cell Probes, 2020, 52: 101566.
14 Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100, 000 human cancer genomes reveals the landscape of tumor mutational burden[J]. Genome Med, 2017, 9(1): 34.
15 Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data[J]. Bioinformatics, 2016, 32(18): 2847-2849.
16 Hu F, Peng J, Niu Y, et al. Clinical predictors of treatment efficacy and a prognostic nomogram in patients with lung adenocarcinoma receiving immune checkpoint inhibitors: a retrospective study[J]. J Thorac Dis, 2022, 14(10): 4096-4112.
17 Jiang T, Li X, Wang J, et al. Mutational landscape of cfDNA identifies distinct molecular features associated with therapeutic response to first-line platinum-based doublet chemotherapy in patients with advanced NSCLC[J]. Theranostics, 2017, 7(19): 4753-4762.
18 Nishino M, Wang X, Ricciuti B, et al. Advanced non-small-cell lung cancer treated with first-line pembrolizumab plus chemotherapy: tumor response dynamics as a marker for survival[J]. Eur Radiol, 2023, 33(10): 7284-7293.
19 Song Q, Zhou R, Shu F, et al. Cuproptosis scoring system to predict the clinical outcome and immune response in bladder cancer[J]. Front Immunol, 2022, 13: 958368-958383.
20 Sha S, Si L, Wu X, et al. Prognostic analysis of cuproptosis-related gene in triple-negative breast cancer[J]. Front Immunol, 2022, 13: 922780-922800.
21 Jiao X, Wei X, Li S, et al. A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer[J]. NPJ Precis Oncol, 2021, 5(1): 36.
22 Pan YH, Zhang JX, Chen X, et al. Predictive value of the TP53/PIK3CA/ATM mutation classifier for patients with bladder cancer responding to immune checkpoint inhibitor therapy[J]. Front Immunol, 2021, 12: 643282.
23 Sahoo AR, Buck M. Structural and functional insights into the transmembrane domain association of Eph receptors[J]. Int J Mol Sci, 2021, 22(16): 8593-8605.
24 Kaczmarek R, Gajdzis P, Gajdzis M. Eph receptors and Ephrins in retinal diseases[J]. Int J Mol Sci, 2021, 22(12): 6207-6224.
25 Anderton M, van der Meulen E, Blumenthal MJ, et al. The role of the Eph receptor family in tumorigenesis[J]. Cancers, 2021, 13(2): 206-220.

备注/Memo

备注/Memo:

基金项目: 陕西省科技发展计划项目(23YXYJ0173)
通信作者: 张 锐, Email: Zhangrui_7885@163.com

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更新日期/Last Update: 2024-08-25