鉴定与 EGFR 敏感突变的晚期非小细胞肺癌患者对 EGFR-TKIs 原发性耐药相关的基因改变。
Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations.
机构信息
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P.R. China.
Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P.R. China.
出版信息
Cancer Commun (Lond). 2019 Mar 2;39(1):7. doi: 10.1186/s40880-019-0354-z.
BACKGROUND
Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations.
METHODS
We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS.
RESULTS
Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor.
CONCLUSIONS
We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.
背景
表皮生长因子受体（EGFR）突变的识别和 EGFR-酪氨酸激酶抑制剂（EGFR-TKIs）的应用极大地改变了非小细胞肺癌（NSCLC）的治疗策略。然而，由于耐药性的发展，EGFR-TKI 治疗的长期疗效有限。本研究旨在探讨晚期 NSCLC 患者中 EGFR 突变激活与 EGFR-TKI 原发性耐药相关的 8 个驱动基因异常改变之间的相关性。
方法
我们回顾性分析了 2004 年 4 月至 2011 年 3 月中山大学肿瘤防治中心收治的 416 例接受初始 EGFR-TKI 治疗的 III/IV 期或复发性 NSCLC 患者的临床资料。通过常规临床技术检测与 EGFR-TKI 疗效相关的几种遗传改变，包括 BIM、ALK、KRAS、PIK3CA、PTEN、MET、IGF1R 和 ROS1 的改变。采用 Kaplan-Meier 生存分析和对数秩检验比较不同组之间的无进展生存期（PFS）和总生存期（OS）。采用 Cox 回归模型估计与 PFS 和 OS 相关的多变量调整危险比（HR）及其 95%置信区间（95%CI）。
结果
在所研究的患者中，169 例 NSCLC 患者存在 EGFR 敏感突变。与 PTEN 完整的患者相比，存在 PTEN 缺失的 EGFR 突变患者的 PFS 和 OS 更短（PFS 为 0.003，OS 为 0.034）。在 EGFR 信号通路和耐药基因的联合分子分析中，我们发现 EGFR 突变患者同时存在 EGFR 信号通路的异常改变，以及存在耐药基因的患者的 PFS 明显差于无此类改变的患者（P<0.001）。Cox 比例风险回归模型确定，PTEN 缺失（HR=4.29，95%CI=1.72-10.70）和低 PTEN 表达（HR=1.96，95%CI=1.22-3.13）、MET FISH+（HR=2.83，95%CI=1.37-5.86）是调整多种因素后 EGFR-TKI 治疗患者 PFS 的独立预测因素。
结论
我们确定，癌症基因中的遗传改变的共存可能解释 EGFR-TKI 的原发性耐药。
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