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中华肺部疾病杂志(电子版) ›› 2024, Vol. 17 ›› Issue (04) : 548 -552. doi: 10.3877/cma.j.issn.1674-6902.2024.04.008

论著

EPHA5突变预测肺腺癌免疫检查点抑制剂治疗预后的临床意义
郑琪1, 马婕群1, 张彦兵1, 廖子君1, 张锐2,†()   
  1. 1. 710061　西安，陕西省肿瘤医院肿瘤内科
    2. 710061　西安，陕西省肿瘤医院重症医学科
  • 收稿日期:2024-04-14 出版日期:2024-08-25
  • 通信作者: 张锐
  • 基金资助:
    陕西省科技发展计划项目(23YXYJ0173)

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

Qi Zheng1, Jiequn Ma1, Yanbing Zhang1, Zijun Liao1, Rui Zhang2,†()   

  1. 1. Department of Medical Oncology, Affiliated Shaanxi Provincial Tumor Hospital, Xi′an Shanxi 710061, China
    2. Department of Critical Care Medicine, Affiliated Shaanxi Provincial Tumor Hospital, Xi′an Shanxi 710061, China
  • Received:2024-04-14 Published:2024-08-25
  • Corresponding author: Rui Zhang
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引用本文：

郑琪, 马婕群, 张彦兵, 廖子君, 张锐. EPHA5突变预测肺腺癌免疫检查点抑制剂治疗预后的临床意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 548-552.

Qi Zheng, Jiequn Ma, Yanbing Zhang, Zijun Liao, Rui Zhang. Clinical value of EPHA5 mutation in predicting the prognosis of lung adenocarcinoma treated with immune checkpoint inhibitors[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2024, 17(04): 548-552.

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。

关键词: 肺腺癌, EPHA5突变, 免疫检查点抑制剂, 预后
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.

Key words: Lung adenocarcinoma, EPHA5 mutation, Immune checkpoint inhibitors, Prognosis
图1 生物信息学分析结果。注：A：GDSC-LUAD、TCGA-LUAD数据集中EPHA5-MT亚组及EPHA5-WT亚组的TMB值；B：TCGA-LUAD数据集中EPHA5-MT亚组及EPHA5-WT亚组的PFS关系；C：TCGA-LUAD数据集中EPHA5-MT亚组及EPHA5-WT亚组的PFS关系DFS、OS
图2 不同EPHA5状态LUAD患者的TMB值比较
表1 单因素及多因素COX回归分析LUAD患者ICI治疗后PFS的影响因素
临床资料 单因素分析 多因素分析
OR(95%CI) P值 OR(95%CI) P值
年龄(<60岁vs.≥60岁) 0.839(0.471～1.495) 0.551 － －
性别(女vs.男) 0.794(0.418～1.508) 0.481 － －
吸烟史(否vs.是) 1.264(0.674～2.370) 0.465 － －
临床分期(Ⅲ期vs. Ⅳ期) 2.225(1.880～5.630) 0.031 2.231(0.882～5.645) 0.090
肿瘤最大直径(<4.95 cm vs.≥4.95 cm) 0.999(0.558～1.790) 0.998 － －
卡铂＋培美曲塞(否vs.是) 1.569(0.796～3.093) 0.193 － －
胸部放疗(否vs.是) 0.699(0.276～1.767) 0.449 － －
根治性手术(否vs.是) 0.834(0.414～1.680) 0.612 － －
CEA(<4.79 ng/ml vs.≥4.79 ng/ml) 1.144(0.641～2.043) 0.649 － －
EPHA5状态(WT vs. MT) 0.270(0.125～0.581) 0.001 0.269(0.125～0.580) 0.001
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