OBJECTIVES Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve 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.

中文翻译：

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低频预处理T790M突变对用EGFR酪氨酸激酶抑制剂治疗的EGFR突变的非小细胞肺癌患者的预测影响。

目的通过超敏感方法可在未使用EGFR酪氨酸激酶抑制剂（TKI）的非小细胞肺癌（NSCLC）中检测低频表皮生长因子受体（EGFR）T790M突变。但是，尚不清楚预处理T790M（preT790M）对EGFR-TKIs疗效和耐药性的影响。材料与方法两个独立的队列，由一线EGFR-TKIs治疗的晚期EGFR突变晚期NSCLC患者组成，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）和一个验证队列于2016年8月之间。和这项研究（2017年12月，B组，n = 22）。在这些患者中，有28位患者在疾病进展时进行了再次活检。通过Cobas EGFR突变测试v2（Cobas）对来自预处理的肿瘤活检样品和再活检样品的DNA进行评估，以检测T790M，并通过液滴数字聚合酶链反应（ddPCR）对T790M进行定量。结果ddPCR检测的前T790M组的检出率为40.9％（18/44），队列B的检出率为45.5％（10/22），而Cobas检测的检出率均未检测到。通过队列A的受试者工作特征曲线分析确定了分为高-低preT790M等位基因频率的临界值0.3％。高-preT790M组的无进展生存期（PFS）明显缩短（n = 12 ）低于低preT790M（n = 6）和阴性（n = 26）组（合并低preT790M）（中位数：6.9 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对配对的活组织检查中，Cobas在高preT790M的60％（3/5），低preT790M的57％（4/7）和56％（9/16）的血浆中检测到了进展后的T790M。阴性-preT790M组。结论高preT790M的EGFR突变NSCLC在EGFR-TKIs上的PFS明显缩短。但是，T790M之前的丰度未必会赋予TKI后的T790M抵抗力。