Background and objective: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become first-line treatment drugs for lung adenocarcinoma patients with EGFR gene mutations. Significant interindividual variations in response rate, progression-free survival (PFS), and overall survival (OS) have been observed. The 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. The 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 first-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: The Nrf2-positive rate was 77.4%, whereas Nrf2 nuclear high-expression rate was 38.7%. The nuclear expression level of Nrf2 was significantly correlated with response rate (RR) and PFS of EGFR-TKIs (P<0.05), but not with gender, age, smoking, differentiation, and OS (P>0.05). The Nrf2-positive level was significantly 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). The PFS and OS of patients with Nrf2-positive expression were significantly 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).
Conclusions: The expression level of Nrf2 is significantly correlated with response rate (RR) of EGFR-TKIs, PFS, and OS. Therefore, Nrf2 may be a useful biomarker in predicting response of EGFR-TKIs in patients with advanced-stage lung adenocarcinoma harboring EGFR gene mutations.
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。