Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Pulmonary Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China.
Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
J Thorac Oncol. 2017 Sep;12(9):1388-1397. doi: 10.1016/j.jtho.2017.06.006. Epub 2017 Jun 15.
A qualitative detection method for EGFR mutations is not sufficient to guide precise targeted therapy in clinical practice. The aim of this study was to explore the relationship between the abundance of EGFR mutations and efficacy of EGFR tyrosine kinase inhibitors (TKIs).
We used the amplification refractory mutation system (ARMS) method optimized with competitive blockers and specific mutation quantitation (ARMS+) to quantitatively evaluate the abundance of EGFR mutations in 201 patients with advanced NSCLC. A cutoff value of the abundance of EGFR mutations was determined by receiver operating characteristic analysis in a training group and validated in a validation group.
The abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of 19DEL was significantly higher than that of L858R, with cutoff values for 19DEL and L858R of 4.9% and 9.5%, respectively. The median progression-free survival in the high group was significantly longer than that in the low group (19DEL, 15.0 versus 2.0 months [p < 0.001] and L858R, 12.3 versus 2.0 months [p < 0.001]) in the training set. Similar results were also observed in the validation set. Nine of 13 patients harboring T790M mutation achieved a partial response to EGFR TKIs. Most (seven of nine) were identified to have a low abundance of T790M mutation. The abundance of EGFR mutations appeared to be more significantly associated with the copy number of EGFR mutations from circulating tumor DNA in 19DEL group.
The abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of EGFR mutation may have an adverse impact on progression-free survival rather than on objective response rate in patients with advanced EGFR-mutant NSCLC treated with EGFR TKIs.
一种 EGFR 突变的定性检测方法不足以指导临床实践中的精确靶向治疗。本研究旨在探讨 EGFR 突变丰度与 EGFR 酪氨酸激酶抑制剂（TKI）疗效之间的关系。
我们使用竞争性阻断剂优化的扩增不可阻挡突变系统（ARMS）方法和特定突变定量（ARMS+），定量评估 201 例晚期 NSCLC 患者 EGFR 突变的丰度。通过训练组中的接收者操作特征分析确定 EGFR 突变丰度的截止值，并在验证组中进行验证。
ARMS+检测到的 EGFR 激活突变丰度与 EGFR TKI 的客观反应显著相关。19DEL 的丰度明显高于 L858R，19DEL 和 L858R 的截断值分别为 4.9%和 9.5%。高组的中位无进展生存期明显长于低组（19DEL，15.0 与 2.0 个月[P<0.001]和 L858R，12.3 与 2.0 个月[P<0.001]）在训练集中。验证集中也观察到了类似的结果。13 例 T790M 突变患者中有 9 例对 EGFR TKI 产生部分反应。大多数（9 例中的 7 例）被鉴定为 T790M 突变丰度低。在 19DEL 组中，EGFR 突变的丰度似乎与循环肿瘤 DNA 中 EGFR 突变的拷贝数更显著相关。
ARMS+检测到的 EGFR 激活突变丰度与 EGFR TKI 的客观反应显著相关。在接受 EGFR TKI 治疗的晚期 EGFR 突变 NSCLC 患者中，EGFR 突变的丰度可能对无进展生存期有不利影响，而不是对客观反应率有不利影响。
