低频率预处理 T790M 突变对接受 EGFR 酪氨酸激酶抑制剂治疗的 EGFR 突变型非小细胞肺癌患者的预测影响。
Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.
机构信息
Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Internal Medicine III, Wakayama Medical University, Wakayama, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.
出版信息
Lung Cancer. 2020 Jan;139:80-88. doi: 10.1016/j.lungcan.2019.10.029. Epub 2019 Nov 2.
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.
目的
低频表皮生长因子受体（EGFR）T790M 突变可通过超敏方法在 EGFR 酪氨酸激酶抑制剂（TKI）初治非小细胞肺癌（NSCLC）中检测到。然而，预处理 T790M（preT790M）对 EGFR-TKIs 疗效和耐药性的影响仍不清楚。
材料和方法
本研究纳入了接受一线 EGFR-TKIs 治疗的晚期 EGFR 突变型 NSCLC 患者的两个独立队列，一个是 2013 年 8 月至 2016 年 7 月间开始治疗的验证队列（队列 A，n=44），另一个是 2016 年 8 月至 2017 年 12 月间开始治疗的验证队列（队列 B，n=22）。其中，28 例患者在疾病进展时进行了再次活检。通过 Cobas EGFR Mutation Test v2（Cobas）检测预处理肿瘤活检样本和再次活检样本中的 T790M，通过数字液滴聚合酶链反应（ddPCR）定量检测 T790M。
结果
在队列 A 中，ddPCR 检测到 preT790M 的检出率为 40.9%（18/44），队列 B 为 45.5%（10/22），而 Cobas 均未检测到。通过队列 A 的受试者工作特征曲线分析，确定将高-与低-preT790M 等位基因频率进行区分的截断值为 0.3%。在高 preT790M 组（n=12）中，无进展生存期（PFS）明显短于低 preT790M 组（n=6）和阴性（n=26）组（低 preT790M 联合组）（中位：6.9 vs. 13.8 个月，P=0.00073）。这些结果在队列 B 中得到了验证[中位：6.2 个月（n=5）vs. 15.3 个月（n=17），P=0.0029]。在 28 对活检中，Cobas 在 60%（3/5）高 preT790M、57%（4/7）低 preT790M 和 56%（9/16）阴性 preT790M 组中检测到了 post-progression T790M。
结论
EGFR-TKIs 治疗的 EGFR 突变型 NSCLC 中，高 preT790M 患者的 PFS 明显缩短。然而，preT790M 的丰度不一定会导致 post-TKI T790M 耐药。
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