Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR-Mutant Lung Adenocarcinoma.
Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR-Mutant Lung Adenocarcinoma.
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DOI：
10.1016/j.jtho.2022.02.011
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发表时间：
2022-06
影响因子：
20.4
通讯作者：
Janne, Pasi A.
中科院分区：
文献类型：
--
作者：
Vokes, Natalie, I;Chambers, Emily;Nguyen, Tom;Coolidge, Alexis;Lydon, Christine A.;Le, Xiuning;Sholl, Lynette;Heymach, John, V;Nishino, Mizuki;Van Allen, Eliezer M.;Janne, Pasi A.
EGFR突变型非小细胞肺癌（NSCLC）患者接受EGFR酪氨酸激酶抑制剂（TKI）治疗的获益持续时间各不相同。并发基因组改变对结果的影响尚未完全描述。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有针对性的下一代测序数据。收集临床数据并与体细胞突变数据相关联。分析TP 53突变状态、基因组特征和突变过程之间的关联。确定了269例患者纳入队列。在185例具有治疗前标本的缓解可评价患者中，TP 53改变是与一线无进展生存期（PFS）降低相关的最常见事件，并与总生存期降低相关，沿着DNMT 3A、KEAP 1和ASXL 1改变。33例患者接受奥希替尼一线治疗后PFS降低与MET、APC和ERBB 4改变相关。对TP 53改变的影响的进一步研究表明，即使在具有良好初始放射学反应的患者中，TP 53改变也与更差的结局相关，并且T790 M和其他抵抗机制的采集更快。TP 53突变的肿瘤具有较高的突变负荷，并且暴露于治疗和烟草的诱变增加。细胞周期的改变不是独立的预测，但预示着更糟糕的OS与TP 53的改变。TP 53改变与EGFR突变型NSCLC中的耐药演变速度加快相关，与机制无关，并可能与其他基因组事件协同作用，介导EGFR TKI耐药突变的获得。
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. 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. 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. 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.
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影响因子：
30.8
作者：
Blakely CM;Watkins TBK;Wu W;Gini B;Chabon JJ;McCoach CE;McGranahan N;Wilson GA;Birkbak NJ;Olivas VR;Rotow J;Maynard A;Wang V;Gubens MA;Banks KC;Lanman RB;Caulin AF;St John J;Cordero AR;Giannikopoulos P;Simmons AD;Mack PC;Gandara DR;Husain H;Doebele RC;Riess JW;Diehn M;Swanton C;Bivona TG
通讯作者：
Bivona TG
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.2214/ajr.12.9668
发表时间：
2013-07
期刊：
AJR. American journal of roentgenology
影响因子：
--
作者：
Nishino M;Cardarella S;Jackman DM;Ramaiya NH;Rabin MS;Hatabu H;Jänne PA;Johnson BE
通讯作者：
Johnson BE
DOI：
10.1158/1078-0432.ccr-18-1102
发表时间：
2019-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Offin M;Rizvi H;Tenet M;Ni A;Sanchez-Vega F;Li BT;Drilon A;Kris MG;Rudin CM;Schultz N;Arcila ME;Ladanyi M;Riely GJ;Yu H;Hellmann MD
通讯作者：
Hellmann MD
影响因子：
45.3
作者：
Lee, June-Koo;Lee, Junehawk;Ju, Young Seok
通讯作者：
Ju, Young Seok