表皮生长因子受体突变晚期肺腺癌中β-catenin表达与酪氨酸激酶抑制剂临床疗效及患者预后的关系

Correlations of β-catenin expression with clinical efficacy of tyrosine kinase inhibitors and prognosis of advanced lung adenocarcinoma patients with epidermal growth factor receptor mutations

目的探讨表皮生长因子受体(EGFR)突变晚期肺腺癌患者β-catenin蛋白的表达与EGFR酪氨酸激酶抑制剂(EGFR-TKI)疗效和预后的关系。方法收集解放军联勤保障部队第九○一医院2016年1月至2019年12月收治的Ⅲ_(B)~Ⅳ期接受EGFR-TKI一线治疗的125例肺腺癌患者的临床资料。采用免疫组织化学法检测β-catenin蛋白的表达,扩增阻滞突变系统检测EGFR突变类型,分析β-catenin表达与患者临床病理特征、EGFR-TKI疗效及预后的关系。同时选取EGFR-TKI治疗前和耐药后均有活组织检查的配对标本28对,观察β-catenin的表达变化。结果125例EGFR突变的晚期肺腺癌患者中,EGFR 19 del 60例,L858R突变55例,少见敏感突变10例;β-catenin细胞膜表达减少79例(63.2%),细胞质异位表达66例(52.8%),细胞核异位表达28例(22.4%);β-catenin不同异常表达模式组Napsin A蛋白阳性率均低于相应正常表达组(均P<0.001),国际肺癌研究协会(IASLC)Ⅲ级患者β-catenin细胞质和细胞核异位表达率均高于Ⅰ~Ⅱ级患者(细胞质异位表达:χ^(2)=3.99,P=0.046,细胞核异位表达:χ^(2)=11.07,P=0.001)。β-catenin细胞膜表达减少、细胞核异位表达患者客观缓解率(ORR)均低于细胞膜表达正常(χ^(2)=4.66,P=0.031)和细胞核异位表达阴性(χ^(2)=10.22,P=0.001)患者,细胞核异位表达阳性患者疾病控制率(DCR)低于相应正常表达组(χ^(2)=10.95,P=0.001)。β-catenin细胞核和细胞质异位表达阳性患者的无进展生存(PFS)及总生存(OS)均差于相应的细胞质和细胞核异位表达阴性组(均P<0.05),多因素Cox回归分析结果显示,β-catenin细胞核异位表达是患者PFS、OS独立的危险因素(PFS:HR=2.088,95%CI 1.331~3.274,P=0.001;OS:HR=3.656,95%CI 1.795~7.444,P<0.001)。28例二次活检的组织样本中,同治疗前比较,11例β-catenin细胞膜表达减少(P=0.049)。结论EGFR敏感突变的晚期肺腺癌中β-catenin的表达可作为预测EGFR-TKI疗效和患者预后的分子标志物。

Objective To investigate the correlations ofβ-catenin expression with the efficacy of tyrosine kinase inhibitor(TKI)and prognosis of patients with advanced lung adenocarcinoma harboring epidermal growth factor receptor(EGFR)mutations.Methods The clinical data of 125 patients with stageⅢ_(B)-Ⅳlung adenocarcinoma who were treated with first-line EGFR-TKI treatment in the 901st Hospital of Joint Logistic Support Force of Chinese PLA from January 2016 to December 2019 were collected.The expression ofβ-catenin protein was detected by immunohistochemistry,and subtypes of EGFR mutations were detected by amplification refractory mutation system(ARMS).Correlations ofβ-catenin expression with clinicopathological features,efficacy of EGFR-TKI and prognosis were analyzed.Twenty-eight pairs of specimens were selected before EGFR-TKI treatment and after resistance to EGFR-TKI to observe the changes ofβ-catenin expression.Results Among 125 advanced lung adenocarcinoma patients with EGFR mutations,there were 60 cases of EGFR 19 del,55 cases of L858R mutation and 10 cases of rare sensitive mutation;79 cases(63.2%)had reduced membranous expression ofβ-catenin,66 cases(52.8%)had ectopic expression in cytoplasm and 28 cases(22.4%)had ectopic expression in nucleus.The positive rates of Napsin A protein in the groups with different abnormal expression patterns ofβ-catenin were lower than those in the corresponding normal expression groups(all P<0.001).Patients with International Association for the Study of Lung Cancer(IASLC)gradeⅢshowed more frequent translocation in cytoplasma and nucleus ofβ-catenin than patients with IASLC gradeⅠ-Ⅱ(ectopic expression in cytoplasm:χ^(2)=3.99,P=0.046,ectopic expression in nucleus:χ^(2)=11.07,P=0.001).The objective remission rate(ORR)in patients with reduced membranous expression ofβ-catenin and ectopic expression in nucleus was lower than that in patients with normal membranous expression(χ^(2)=4.66,P=0.031)and negative ectopic expression in nucleus(χ^(2)=10.22,P=0.001),and the disease control rate(DCR)in patients with ectopic expression in nucleus was lower than that in the corresponding normal expression group(χ^(2)=10.95,P=0.001).Patients with ectopic expression ofβ-catenin in nucleus and cytoplasma had worse progression-free survival(PFS)and overall survival(OS)than the corresponding cytoplasmic and nuclear ectopic expression negative groups(both P<0.05).Multivariate Cox regression analysis showed that nuclearβ-catenin ectopic expression was an independent risk factor for both PFS and OS(PFS:HR=2.088,95%CI 1.331-3.274,P=0.001;OS:HR=3.656,95%CI 1.795-7.444,P<0.001).β-catenin membranous expression was reduced in 11 of 28 tissue samples that underwent secondary biopsy compared with pre-treatment(P=0.049).Conclusionsβ-catenin expression in advanced lung adenocarcinoma with EGFR-sensitive mutations can be used as a molecular marker to predict the efficacy of EGFR-TKI and prognosis of patients.