TP53同时突变促进EGFR突变型肺腺癌的耐药性进化

2022-04-06 18:08

TP53改变与EGFR突变与NSCLC中独立于机制的更快的耐药性进化相关，并且可能与其他基因组事件合作，以介导对EGFR TKIs的耐药性突变的获得。

SCI

5 April 2022

Concurrent TP53 mutations facilitate resistance evolution in EGFR mutant lung Adenocarcinoma

(IF: JTO, 15.609)

Vokes NI, Chambers E, Nguyen T, Coolidge A, Lydon CA, Le X, Sholl L, Heymach JV, Nishino M, Van Allen EM, Jänne PA, Concurrent TP53 mutations facilitate resistance evolution in EGFR mutant lung adenocarcinoma, Journal of Thoracic Oncology (2022)
Address correspondence to:Pasi A. Jänne, MD, PhD、Lowe Center for Thoracic Oncology、Dana Farber Cancer Institute、450 Brookline Avenue; LC4114、Boston, MA 02215、Email: pasi_janne@dfci.harvard.edu、Phone: 617-632-6076

PURPOSE 目的

Patients with EGFR-mutant non-small cell lung cancer (NSCLC) experience variable duration of benefit on EGFR tyrosine kinase inhibitors (TKI). The effect of concurrent genomic alterations on outcome has been incompletely described.

EGFR突变型非小细胞肺癌（NSCLC）患者服用EGFR酪氨酸激酶抑制剂（TKI）的获益持续时间不用。尚未完全描述同时发生的基因组改变对结果的影响。

MATERIAL AND METHODS 材料与方法

In this retrospective study, targeted next-generation sequencing data was collected from patients with EGFR-mutant lung cancer treated at the Dana-Farber Cancer Institute. Clinical data were collected and correlated with somatic mutation data. Associations between TP53 mutation status, genomic features, and mutational processes were analyzed.

在这项回顾性研究中，从Dana-Farber癌症研究所治疗的EGFR突变型肺癌患者中收集了二代靶向测序数据。收集临床数据并与体细胞突变数据相关联。分析了TP53突变状态、基因组特征和突变过程之间的关联。

RESULTS 结果

269 patients were identified for inclusion in the cohort. Among 185 response evaluable patients with pre-treatment specimens, TP53 alterations were the most common event associated with decreased first-line progression-free survival (PFS), and associated with decreased overall survival along with DNMT3A, KEAP1 and ASXL1 alterations. Reduced PFS on later-line osimertinib in 33 patients was associated with MET, APC and ERBB4 alterations. Further investigation of the effect of TP53 alterations demonstrated an association with worse outcomes even in patients with good initial radiographic response, and faster acquisition of T790M and other resistance mechanisms. TP53 mutated tumors had higher mutational burdens and increased mutagenesis with exposure to therapy and tobacco. Cell cycle alterations were not independently predictive, but portended worse OS in conjunction with TP53 alterations.

269名患者被确定纳入队列。在185名具有治疗前标本的可评价疗效的患者中，TP53改变是与一线无进展生存率（PFS）降低相关的最常见事件，且与DNMT3A、KEAP1和ASXL1改变一起与总生存率降低相关。33名患者的后线奥希替尼PFS降低与MET、APC和ERBB4改变有关。对TP53改变影响的进一步研究表明，即使在初始放射反应良好、T790M和其他耐药机制获得更快的患者中，TP53改变也与更差的预后相关。TP53突变的肿瘤具有更高的突变负荷，并随着暴露于治疗和烟草而增加了诱变。细胞周期的改变不是独立预测的，但与TP53的改变一起预示着更糟糕的OS。

CONCLUSIONS 结论

TP53 alterations associate with faster resistance evolution independent of mechanism in EGFR mutant NSCLC, and may cooperate with other genomic events to mediate acquisition of resistance mutations to EGFR TKIs.

TP53改变与EGFR突变与NSCLC中独立于机制的更快的耐药性进化相关，并且可能与其他基因组事件合作，以介导对EGFR TKIs的耐药性突变的获得。