Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors
Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors
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DOI：
10.1016/j.lungcan.2019.10.029
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发表时间：
2020-01-01
期刊：
影响因子：
5.3
通讯作者：
Kawaguchi, Tomoya
中科院分区：
文献类型：
--
作者：
Matsumoto, Yoshiya;Sawa, Kenji;Kawaguchi, Tomoya
目的：应用超敏方法检测EGFR酪氨酸激酶抑制剂（TKI）初始非小细胞肺癌（NSCLC）中低频表皮生长因子受体（EGFR） T790M突变。然而，预处理T790M （pre790m）对EGFR-TKIs疗效和耐药的影响尚不清楚。材料和方法：本研究检查了两个独立的队列，包括接受一线EGFR-TKIs治疗的晚期egfr突变NSCLC患者，一个衍生队列于2013年8月至2016年7月开始治疗（队列a， n = 44），一个验证队列于2016年8月至2017年12月（队列B， n = 22）。其中，28例患者在疾病进展时进行了再次活检。采用Cobas EGFR突变试验v2 （Cobas）检测T790M，采用液滴数字聚合酶链反应（ddPCR）定量T790M。结果：在A队列和B队列中，ddPCR检测pre790m的检出率分别为40.9%（18/44）和45.5% (10/22)，Cobas未检测到pre790m。在队列A中，通过受试者工作特征曲线分析确定了高pre790m等位基因频率与低pre790m等位基因频率划分的截断值为0.3%。高pre790m组（n = 12）的无进展生存期（PFS）显著短于低pre790m组（n = 6）和阴性（n = 26）组（低pre790m组合）（中位数：6.9个月vs 13.8个月，P = 0.00073）。这些观察结果在队列B中得到验证[中位数：6.2 （n = 5）对15.3个月（n = 17）， P = 0.0029]。在28个配对活检中，Cobas在60%（3/5）的高pre790m组、57%（4/7）的低pre790m组和56%（9/16）的pre790m阴性组中检测到进展后T790M。结论：高pre790m的egfr突变NSCLC在EGFR-TKIs上的PFS显著缩短。然而，pre790m的丰度不一定会导致tki后的T790M耐药性。
Objectives: Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naive non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear.Materials and methods: Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR).Results: Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups.Conclusion: EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.