外周血表皮生长因子受体蛋白浓度与吉非替尼治疗晚期非小细胞肺癌疗效的相关性

Association of serum EGFR protein concentration with the efficacy of Gefitinib in the treatment of advanced non-small cell lung cancer

目的探讨外周血中表皮生长因子受体（EGFR）蛋白表达和EGFR基因突变的相关性，及其与吉非替尼治疗晚期非小细胞肺癌（NSCLC）疗效和生存的关系。方法收集100例接受吉非替尼单药治疗的晚期NSCLC患者的临床资料、病理组织标本和配对外周血标本。采用直接测序法检测肿瘤组织EGFR基因第19号和21号外显子的基因突变情况。采用酶联免疫吸附（ELISA）法检测外周血EGFR蛋白的表达情况。将EGFR基因突变和蛋白表达与患者的疗效和生存之间的关系进行统计学分析。结果获得随访的患者共99例。吉非替尼治疗晚期NSCLC的有效率为51．5％，临床获益率为79．8％。99例患者标本中，有35例存在EGFR基因突变，突变率为35．4％。EGFR基因突变患者的有效率和临床获益率分别为65．7％和94．3％，均明显高于无基因突变的患者（43．8％和71．9％，均P〈0．05）。EGFR基因突变患者的中位无进展生存时间（PFS）为23个月（95％CI为12．9～33．0个月），明显长于无突变的患者（10个月，95％CI为7．3—12．6个月；P=0．014）。EGFR蛋白高表达（≥55．42μg/L）患者的吉非替尼治疗临床获益率为90．O％，明显高于低表达（〈55．42μg/L）的患者（64．1％，P=0．004）。EGFR蛋白高表达患者的中位PFS为21个月（95％CI为14．3～27．6个月），明显长于低表达的患者（8个月，95％CI为5．5—10．4个月；P=0．016）。EGFR蛋白表达是EGFR基因突变的独立影响因素，两者呈显著的正相关（P=0．000）。结论EGFR基因突变和外周血EGFR蛋白高表达的NSCLC患者，应用吉非替尼治疗有效。外周血EGFR蛋白表达有可能作为预测和评价吉非替尼治疗晚期NSCLC疗效和患者预后的分子生物学指标。

Objective To analyze the association between the EGFR protein level and the EGFR gene mutation status in advanced non-small cell lung cancer （ NSCLC ）, and to explore whether the EGFR protein level is related to the efficacy and survival of the EGFR-TKI drug Gifitinib-treated patients with advanced NSCLC. Methods Ninety-nine cases were enrolled in this study. Pathological tissue specimens and paired peripheral blood samples were collected. Exons 19 and 21 of the EGFR gene mutation were detected by direct sequencing. The concentration of plasma EGFR protein was detected by ELISA. Univariate and multivariate statistical analyses of the efficacy and survival were performed using SPSS 13. 0 software. Results The response rate （RR） and clinical benefit rate （CBR） of Gefitinib-treated patients were 51.5% and 79.8% , respectively. There were 35 （35.4%） with positive EGFR gene mutation of the 99 samples. The concentration limit of EGFR protein was 55.42 μg/L. The RR and CBR of patients with EGFR gene mutation was significantly higher than those without mutation （65.7% vs. 43.8%, P =0.037 ; 94.3% vs. 71.9% ,P = 0.008）. The median PFS was prolonged （23 months vs. 10 months,P = 0. 014）. The CBR of patients with high EGFR protein expression （concentration ≥ 55.42 μg/L） was significantly higher than those with low expression （90.0% vs 64.1% , P =0,004）, and the median PFS was prolonged （21 months vs. 8 months,P =0. 016）. EGFR protein level was an independent factor affecting the EGFR gene mutation status. The Correlation between EGFR gene mutation status and EGFR protein level was positive. Conclusions Gefitinib is effective in the treatment of advanced NSCLC patients with EGFR gene mutation and high EGFR protein expression. EGFR protein level in peripheral blood may be a molecular biomarker in prediction of efficacy and survival of the Gefitinib treatment in patients with advanced NSCLC.