CAJ | 학술논문

背景与目的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）是含有EGFR基因敏感突变肺腺癌患者一线治疗首选药物，但其疗效存在个体差异。已有研究表明核因子E2相关因子2（nuclear factor erythroid-2-related factor 2, Nrf2）在肺癌患者中存在个体表达差异，且其与化疗药物疗效相关。Nrf2激活可抑制EGFR-TKIs在EGFR基因突变细胞株中的敏感性。本研究旨在探讨Nrf2在含有EGFR基因突变肺腺癌患者中的表达及其与一线EGFR-TKIs疗效的相关性。方法应用免疫组化检测31例进展期含有EGFR基因突变的肺腺癌患者组织标本中Nrf2的表达。结果含有EGFR基因突变的进展期肺腺癌患者中Nrf2表达存在个体差异，Nrf2阳性率为77.4%，Nrf2核高表达率为38.7%；Nrf2在核内的表达水平与EGFR-TKIs缓解程度、无进展生存期（progression free survival, PFS）相关（P<0.05），而与性别、年龄、吸烟、分化程度、EGFR基因突变状态和总生存期（Overall survival, OS）无关（P>0.05）。Nrf2阳性程度与PFS和OS显著相关（P<0.05），Nrf2阳性组中位PFS、OS低于阴性组（P<0.05）。多因素分析表明Nrf2在肿瘤细胞核内的表达水平是EGFR-TKIs PFS的独立预测因素，Nrf2在肿瘤细胞内的整体阳性程度是OS的独立预测因素（P<0.05）。结论 Nrf2在含有EGFR基因突变的肺腺癌患者中的表达水平与EGFR-TKIs疗效相关，Nrf2可能成为预测EGFR-TKIs疗效的一个理想指标。
배경여목적표피생장인자수체락안산격매억제제（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）시함유EGFR기인민감돌변폐선암환자일선치료수선약물，단기료효존재개체차이。이유연구표명핵인자E2상관인자2（nuclear factor erythroid-2-related factor 2, Nrf2）재폐암환자중존재개체표체차이，차기여화료약물료효상관。Nrf2격활가억제EGFR-TKIs재EGFR기인돌변세포주중적민감성。본연구지재탐토Nrf2재함유EGFR기인돌변폐선암환자중적표체급기여일선EGFR-TKIs료효적상관성。방법응용면역조화검측31례진전기함유EGFR기인돌변적폐선암환자조직표본중Nrf2적표체。결과함유EGFR기인돌변적진전기폐선암환자중Nrf2표체존재개체차이，Nrf2양성솔위77.4%，Nrf2핵고표체솔위38.7%；Nrf2재핵내적표체수평여EGFR-TKIs완해정도、무진전생존기（progression free survival, PFS）상관（P<0.05），이여성별、년령、흡연、분화정도、EGFR기인돌변상태화총생존기（Overall survival, OS）무관（P>0.05）。Nrf2양성정도여PFS화OS현저상관（P<0.05），Nrf2양성조중위PFS、OS저우음성조（P<0.05）。다인소분석표명Nrf2재종류세포핵내적표체수평시EGFR-TKIs PFS적독립예측인소，Nrf2재종류세포내적정체양성정도시OS적독립예측인소（P<0.05）。결론 Nrf2재함유EGFR기인돌변적폐선암환자중적표체수평여EGFR-TKIs료효상관，Nrf2가능성위예측EGFR-TKIs료효적일개이상지표。
Background and objective Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have be-come ifrst-line treatment drugs for lung adenocarcinoma patients with EGFR gene mutations. Signiifcant interindividual varia-tions in response rate, progression-free survival (PFS), and overall survival (OS) have been observed. hTe expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) is related to chemoresistance against platinum drugs. Nrf2 overexpression can inhibit the sensitivity of EGFR-TKIs in cells with EGFR-sensitive mutations. hTe aim of this study is to investigate the protein expression level of Nrf2 in lung adenocarcinoma patients with EGFR gene mutations and to elucidate the correlation between Nrf2 expression and response rate of ifrst-line EGFR-TKIs, as well as PFS and OS. Methods Immunohistochemical analysis of Nrf2 in tumor specimens was performed on 31 patients with stage III or IV adenocarcinoma harboring EGFR gene mutations. Results hTe Nrf2-positive rate was 77.4%, whereas Nrf2 nuclear high-expression rate was 38.7%. hTe nuclear expression level of Nrf2 was signiifcantly correlated with response rate (RR) and PFS of EGFR-TKIs (P<0.05), but not with gender, age, smok-ing, differentiation, and OS (P>0.05). hTe Nrf2-positive level was signiifcantly correlated with PFS and OS of EGFR-TKIs (P<0.05), but not with gender, age, smoking, differentiation, EGFR gene mutation status, and RR (P>0.05). hTe PFS and OS of patients with Nrf2-positive expression were signiifcantly shorter than those in patients with negative expression (P<0.05). Furthermore, the nuclear expression level of Nrf2 was the independent predictive factor for EGFR-TKI-induced PFS, and the Nrf2-positive level was the independent predictive factor for EGFR-TKI-induced OS (P<0.05). Conclusion hTe expression level of Nrf2 is signiifcantly correlated with response rate (RR) of EGFR-TKIs, PFS, and OS. hTerefore, Nrf2 may be a useful biomarker in predicting response of EGFR-TKIs in patients with advanced-stage lung adenocarcinoma harboring EGFR gene mutations.