Wang Jingyi, Chen Bolin, Pu Xingxiang, Li Jia, Xu Yan, Xu Li, Xu Fang, Li Kang, Kong Yi, Liu Liyu, Wang Qianzhi, Wu Lin
The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China.
Departments of Geriatrics and Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Ther Adv Med Oncol. 2025 Apr 30;17:17588359251336632. doi: 10.1177/17588359251336632. eCollection 2025.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the prognosis of EGFR-sensitive mutant non-small-cell lung cancer (NSCLC). However, the mechanisms underlying primary resistance to EGFR-TKIs remain unclear.
This study aimed to explore the biomarkers associated with primary resistance to first- and second-generation EGFR-TKIs. Primary resistance to EGFR-TKIs was defined as disease progression within 90 days (3 months) of treatment in patients with EGFR-sensitive mutant adenocarcinoma without any evidence of objective response.
Retrospective, single-center study.
This study retrospectively screened patients with NSCLC who received EGFR-TKIs at Hunan Cancer Hospital from January 2018 to December 2022. According to pre-determined clinical outcomes, we divided the patients into primary resistance and sensitivity groups. Only patients with sufficient samples that passed quality control were included in this study. Tumor tissue and paired peripheral blood samples collected from patients before treatment were subjected to next-generation sequencing using an 825-gene panel. In addition, tumor tissue samples were analyzed for programmed cell death ligand 1 (PD-L1) expression.
A total of 70 patients were enrolled in this study, with 35 in each of the primary resistant and sensitive groups. Patients with exon 4 mutations in the gene had significantly shorter progression-free survival (PFS) and overall survival (OS) compared to those without the mutation. and mutation frequencies were substantially higher in the primary resistant group and were associated with shorter PFS and OS. Furthermore, patients in the primary resistant group exhibited substantially higher levels of PD-L1 expression.
The potential mechanisms of primary resistance to EGFR-TKIs are highly heterogeneous. Combining some somatic variants affecting tumor function and high PD-L1 expression may contribute to this resistance.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）显著改善了EGFR敏感突变型非小细胞肺癌（NSCLC）的预后。然而，对EGFR-TKIs原发性耐药的潜在机制仍不清楚。
本研究旨在探索与第一代和第二代EGFR-TKIs原发性耐药相关的生物标志物。EGFR-TKIs原发性耐药定义为EGFR敏感突变腺癌患者在治疗90天（3个月）内疾病进展，且无任何客观缓解证据。
回顾性单中心研究。
本研究回顾性筛选了2018年1月至2022年12月在湖南省肿瘤医院接受EGFR-TKIs治疗的NSCLC患者。根据预先确定的临床结局，将患者分为原发性耐药组和敏感组。本研究仅纳入了有足够样本且通过质量控制的患者。对治疗前从患者采集的肿瘤组织和配对外周血样本使用825基因panel进行二代测序。此外，对肿瘤组织样本进行程序性细胞死亡配体1（PD-L1）表达分析。
本研究共纳入70例患者，原发性耐药组和敏感组各35例。与无该基因突变的患者相比，基因第4外显子突变的患者无进展生存期（PFS）和总生存期（OS）显著缩短。原发性耐药组中 和 突变频率显著更高，且与较短的PFS和OS相关。此外，原发性耐药组患者的PD-L1表达水平显著更高。
EGFR-TKIs原发性耐药的潜在机制高度异质性。结合一些影响肿瘤功能的体细胞变异和高PD-L1表达可能导致这种耐药。
