Zhao Mingchuan, Zhang Yishi, Cai Weijing, Li Jiayu, Zhou Fei, Cheng Ningning, Ren Ruixin, Zhao Chao, Li Xuefei, Ren Shengxiang, Zhou Caicun, Hirsch Fred R
Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Cancer. 2014 Aug 1;120(15):2299-307. doi: 10.1002/cncr.28725. Epub 2014 Apr 15.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have EGFR mutations. Recent studies have indicated that some patients with positive mutations were refractory to EGFR TKIs if they harbored a B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (Bim) deletion polymorphism. The objective of the current work was to retrospectively study the Bim deletion polymorphism in Chinese patients with NSCLC and its correlation with the efficacy of EGFR TKIs.
Distribution of the Bim polymorphism was detected using polymerase chain reaction analysis and direct sequencing of DNA from peripheral neutrophils in samples from 352 patients with NSCLC. Of the 352 patients, 166 who received TKI therapy and had an activating mutation identified were involved in further analysis. Progression-free survival (PFS) was the primary endpoint of the subsequent analyses, and the incidence of the Bim polymorphism and its relation to clinical benefit from EGFR TKIs also were investigated.
In total, 45 of 352 patient samples (12.8%) had the Bim deletion polymorphism, which was distributed randomly with regard to various clinical characteristics. In patients with EGFR mutations who received treatment with TKIs, the median PFS and the median objective response rate were 4.7 months and 25%, respectively, for those with the Bim deletion polymorphism versus 11 months (P = .003) and 66% (P = .001), respectively, for those with wild-type Bim. Cox regression analysis identified Bim status (P = .016) and sex (P = .002) as independent factors predicting clinical benefit from EGFR TKIs in patients with EGFR-mutated NSCLC.
The incidence of the Bim deletion polymorphism was approximately 13% in this study, and it was associated with a poor clinical response to EGFR TKIs in patients who had NSCLC with EGFR mutations.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）被广泛用于治疗具有EGFR突变的晚期非小细胞肺癌（NSCLC）患者。最近的研究表明，一些具有阳性突变的患者如果携带B细胞慢性淋巴细胞白血病/淋巴瘤（Bcl-2）样11（Bim）缺失多态性，则对EGFR TKIs耐药。当前研究的目的是回顾性研究中国NSCLC患者中的Bim缺失多态性及其与EGFR TKIs疗效的相关性。
采用聚合酶链反应分析和对352例NSCLC患者样本中外周血中性粒细胞DNA进行直接测序，检测Bim多态性的分布。在这352例患者中，166例接受了TKI治疗且具有激活突变的患者参与了进一步分析。无进展生存期（PFS）是后续分析的主要终点，同时还研究了Bim多态性的发生率及其与EGFR TKIs临床获益的关系。
在352例患者样本中，共有45例（12.8%）具有Bim缺失多态性，其在各种临床特征中随机分布。在接受TKIs治疗的EGFR突变患者中，具有Bim缺失多态性的患者的中位PFS和中位客观缓解率分别为4.7个月和25%，而野生型Bim患者分别为11个月（P = 0.003）和66%（P = 0.001）。Cox回归分析确定Bim状态（P = 0.016）和性别（P = 0.002）是预测EGFR突变的NSCLC患者从EGFR TKIs中获得临床获益的独立因素。
本研究中Bim缺失多态性的发生率约为13%，并且它与具有EGFR突变的NSCLC患者对EGFR TKIs的临床反应较差相关。
