T790M突变与TKI获得性耐药的晚期肺腺癌患者预后的相关性

目的 前瞻性分析T790M突变与一代TKI获得性耐药的晚期肺腺癌患者预后的相关性。方法 选择符合条件入组的肺腺癌患者93例,经二代测序(NGS)测出表皮生长因子受体(EGFR)敏感突变及T790M的突变状态,分二线或三线使用奥希替尼作为EGFR-TKI治疗方案,对照选择化疗和或放疗治疗方案。评估二三线治疗的客观缓解率(ORR), 疾病控制率(DCR)和无疾病进展生存期(PFS)。结果 T790M阳性和阴性患者组中的ORR差异无统计学意义( P=0.084),而DCR差异有统计学意义(P=0.01)。将治疗线数分开,二线使用奥希替尼在T790M的两种不同状态下,ORR和DCR差异均有统计学意义(ORR :P =0.022;DCR:P =0.016)。三线使用奥希替尼在T790M的两种不同状态下,同样发现差异也具有统计学意义(ORR: P=0.016;DCR: P=0.011)。通过Mann-WhitneyU检验提示,T790M的突变状态与PFS显著相关,其中所有人群中(P<0.01)、二线治疗人群中(P=0.022)和三线治疗人群中( P=0.016)。对所有的患者进行KM生存分析,观测到总体的PFS与T790M的突变状况有关(P<0.01)。在T790M阳性组中,患者基因检测中出现EGFR19外显子和21外显子的PFS差异有统计学意义(P=0.05)。多因素Cox比例风险回归分析,21外显子 vs 19外显子(HR=0.551, 95%CI =0.357~0.853, P=0.007);T790M阳性 vs T790M阴性( H R=2.972, 95% C I=1.643~5.379, P<0.01)。肿瘤直径≥5 cm vs 肿瘤直径<5 cm (HR=0.575, 95%CI =0.373~0.085, P=0.012)。结论 T790M突变阳性患者预后优于T790M突变阴性患者。对于T790M阳性的患者二线或三线使用奥希替尼未观测到PFS差异。晚期肺腺癌T790M阳性患者可在一代EGFR-TKI药物耐药后应用三代EGFR-TKI治疗。

The correlation between the prognosis of lung adenocarcinoma with acquired resistance to the first-generation EGFR TKI and the T790M mutation

Objective To prospectively analyze the correlation between the prognosis of lung adenocarcinoma with acquired resistance to the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and the T790M mutation. Methods A total of 93 eligible patients with lung adenocarcinoma were selected. The EGFR-sensitive mutation and T790M mutation status were detected by the next-generation sequencing (NGS). Osimertinib was used as the EGFR-TKI treatment in the second or third-line treatment, and patients in the control group were given chemotherapy and/or radiotherapy. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) of the second and third-line treatment were evaluated.Results The ORR was comparable between lung adenocarcinoma patients with positive or negative T790M mutation ( P=0.084); while a significant difference was detected in the DCR ( P=0.01). There were significant differences in the ORR ( P=0.022) and DCR ( P=0.016) in lung adenocarcinoma patients with positive or negative T790M mutation who were treated with the second-line treatment of osimertinib; similar results were obtained in the third-line treatment of osimertinib as well (ORR [ P=0.016] and DCR [ P=0.011]). The Mann-Whitney U test showed that the mutation status of T790M was significantly correlated with PFS in all lung adenocarcinoma patients ( P<0.01), and those treated with the second-line treatment ( P=0.022) and the third-line treatment ( P=0.016). Kaplan-Meier survival analysis showed that the T790M mutation significantly influenced the overall PFS in lung adenocarcinoma patients ( P<0.01). In the T790M-positive group, there was a significant difference in the PFS between those with EGFR exon 19 mutation and exon 21 mutation ( P=0.05). Multivariate Cox proportional hazards regression analysis showed significant differences in EGFR exon 21 vs exon 19 ( H R=0.551, 95% C I=0.357-0.853, P=0.007), T790M-positive mutation vs T790M-negative mutation ( H R=2.972, 95% C I=1.643-5.379, P<0.01), and tumor diameter ≥5 cm vs tumor diameter <5 cm ( H R=0.575, 95% C I=0.373-0.085, P=0.012). Conclusion The prognosis of T790M mutation-positive lung adenocarcinoma patients is better than that of T790M mutation-negative patients. PFS is comparable in T790M-positive lung adenocarcinoma patients treated with the second or third-line treatment of osimertinib. Advanced lung adenocarcinoma patients with the T790M mutation can be treated with the third-generation EGFR-TKI after the development of first-generation EGFR-TKI resistance.