背景:TP53突变如何影响晚期表皮生长因子受体(EGFR)突变型肺腺癌的靶向治疗仍存在争议,特别是TP53突变的深度分类。
方法:回顾性分析苏州大学附属第一医院EGFR-酪氨酸激酶抑制剂治疗晚期EGFR突变肺腺癌患者的临床资料。使用Log-rank检验比较生存率。使用多变量Cox风险回归模型确定潜在的预后因素。
结果:共156例用EGFR-TKIs治疗的晚期肺腺癌患者纳入本研究。多因素分析显示男性[危险率(HR):1.537,95%置信区间(CI):1.055-2.240,P=0.025],脑转移(HR:1.707,95CI:1.086-2.682,P=0.020)和并发TP53突变(HR:1.569,95CI:1.051-2.341,P=0.028)是无进展生存期(PFS)的独立阴性预测因子.EGFRL858R突变(HR:2.475,95CI:1.443-4.248,p=0.001),吸烟史(HR:2.530,95CI:1.352-4.733,P=0.004)和并发TP53突变(HR:2.326,95CI:1.283-4.218,P=0.005)与较差的生存率相关.进一步分析显示,TP53外显子4、5和8的突变(P<0.05),错义突变(P=0.006)和非破坏性突变(P<0.001)与较短的PFS相关,而TP53外显子5和7的突变(P<0.05),错义突变和非错义突变(P=0.006;P=0.007),破坏性突变和非破坏性突变(P=0.013;P=0.013)均与较差的生存时间相关.此外,第7外显子非破坏性突变的PFS和总生存期(OS)比其他外显子差(P=0.041;P<0.001).
结论:TP53突变导致晚期EGFR突变型肺腺癌EGFR-TKIs疗效和预后更差,不同TP53突变类型的影响是异质性的。
How concurrent TP53 mutations affect targeted therapy of advanced Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinoma remains controversial, particularly the deep classification of TP53 mutations.
This study retrospectively analyzed the clinical data of advanced EGFR mutant lung adenocarcinoma patients treated with EGFR-tyrosine kinase inhibitors (TKIs) in the First Affiliated Hospital of Soochow University. The survival rates were compared using Log-rank tests. Potential prognostic factors were identified using multivariate Cox hazard regression models.
Total 156 advanced lung adenocarcinoma patients treated with EGFR-TKIs were included in this study. Multivariate analysis showed that male [hazard rate (HR): 1.537, 95% confidence interval (CI): 1.055-2.240, P = 0.025], brain metastasis (HR: 1.707, 95%CI: 1.086-2.682, P = 0.020) and concurrent TP53 mutations (HR: 1.569, 95%CI: 1.051-2.341, P = 0.028) were independent negative predictors of progression-free survival (PFS). EGFR L858R mutations (HR: 2.475, 95%CI: 1.443-4.248, p = 0.001), smoking history (HR: 2.530, 95%CI: 1.352-4.733, P = 0.004) and concurrent TP53 mutations (HR: 2.326, 95%CI: 1.283-4.218, P = 0.005) were associated with worse survival. Further analysis revealed that mutations in TP53 exons 4, 5 and 8 (P<0.05), missense mutations (P = 0.006) and nondisruptive mutations (P<0.001) were associated with shorter PFS, whereas mutations in TP53 exons 5 and 7 (P<0.05), missense mutations and non-missense mutations (P = 0.006; P = 0.007), disruptive mutations and nondisruptive mutations (P = 0.013; P = 0.013) were all associated with poorer survival times. In addition, the PFS and overall survival (OS) of nondisruptive mutations in exon 7 were worse than those in other exons (P = 0.041; P<0.001).
Concurrent TP53 mutations conferred worse EGFR-TKIs efficacy and prognosis in advanced EGFR mutant lung adenocarcinoma and the effects of different TP53 mutation types were heterogeneous.