Cheng Ying, Ma Lixia, Liu Ying, Zhu Jing, Xin Ying, Liu Xianhong, Wang Ying, Zhang Tingting, Yang Changliang, Wang Sheng, Cui Hongxia, Zhang Liang, Dai Jixin, Shao Lin, Lin Jing, Ye Junyi, Liu Hao
Jilin Cancer Hospital, Changchun, China.
Jilin Cancer Hospital, Changchun, China.
Lung Cancer. 2020 Jul;145:63-70. doi: 10.1016/j.lungcan.2020.04.004. Epub 2020 Apr 17.
Although the majority of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients respond to EGFR tyrosine kinase inhibitors (TKIs), significant heterogeneity in clinical response is observed which might be attributed to the distinct sub-molecular characteristics. The present study aims to identify genetic alterations correlated with clinical outcomes and treatment response to different EGFR-TKI inhibitors.
We integrated the genomic data and clinical outcomes including progression-free survival (PFS) and overall survival (OS) in 179 patients with advanced EGFR-mutant NSCLC who were treated with EGFR-TKI as 1st line of treatment.
We found that EGFR-mutant patients harboring concomitant TP53 mutation (OS: 21 vs. 40 months, P = 0.05), ERBB2 amplification (PFS: 6.1 vs. 12.5 months, P = 0.01) or FGF19 amplification (OS: 11.2 vs. 27.1 months, P = 0.01) were significantly associated with a poorer clinical prognosis after treated with 1st generation EGFR-TKI. In contrast, the presence of TP53 mutation did not affect the PFS nor OS of patients treated with 2nd generation EGFR-TKI. Furthermore, EGFR-mutant and TP53-wild type (WT) patients benefited more from a combinatorial treatment consisting of EGFR-TKI and bevacizumab comparing to EGFR-TKI as a single agent (PFS: 21.7 vs. 9.3 months, P < 0.01). Copy number variation (CNV) (PFS: 4.6 vs.9.4 months, p = 0.018) was identified as an unfavorable predictive factor to 3rd-generation TKI. We also revealed distinct resistance mechanisms associated with different EGFR-TKIs.
Our study highlights the heterogeneity both in the primary molecular landscape and acquired alterations in EGFR-mutated NSCLCs, which might play a role in determining the clinical efficacy of EGFR-TKIs. We also revealed the differential prognostic role of TP53 mutation in patients treated with the 1st or 2nd generation of EGFR-TKI. Our study also suggests that EGFR-mutant and TP53-WT patients may benefit more from combinatorial treatment consisting of EGFR-TKI and bevacizumab, highlighting the importance of further stratifying EGFR-mutant patients.
虽然大多数表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者对EGFR酪氨酸激酶抑制剂（TKIs）有反应，但观察到临床反应存在显著异质性，这可能归因于不同的亚分子特征。本研究旨在确定与临床结果以及对不同EGFR-TKI抑制剂治疗反应相关的基因改变。
我们整合了179例接受EGFR-TKI一线治疗的晚期EGFR突变NSCLC患者的基因组数据和临床结果，包括无进展生存期（PFS）和总生存期（OS）。
我们发现，携带TP53伴随突变（OS：21个月对40个月，P = 0.05）、ERBB2扩增（PFS：6.1个月对12.5个月，P = 0.01）或FGF19扩增（OS：11.2个月对27.1个月，P = 0.01）的EGFR突变患者在接受第一代EGFR-TKI治疗后临床预后明显较差。相比之下，TP53突变的存在并不影响接受第二代EGFR-TKI治疗患者的PFS和OS。此外，与单一使用EGFR-TKI相比，EGFR突变且TP53野生型（WT）的患者从EGFR-TKI与贝伐单抗的联合治疗中获益更多（PFS：21.7个月对9.3个月，P < 0.01）。拷贝数变异（CNV）（PFS：4.6个月对9.4个月，p = 0.018）被确定为第三代TKI的不良预测因素。我们还揭示了与不同EGFR-TKIs相关的不同耐药机制。
我们的研究突出了EGFR突变的NSCLCs在原发性分子格局和获得性改变方面的异质性，这可能在决定EGFR-TKIs的临床疗效中起作用。我们还揭示了TP�3突变在接受第一代或第二代EGFR-TKI治疗患者中的不同预后作用。我们的研究还表明，EGFR突变且TP53-WT的患者可能从EGFR-TKI与贝伐单抗的联合治疗中获益更多，突出了进一步对EGFR突变患者进行分层的重要性。
