文章：

ALK融合基因阳性肺癌患者治疗前样本中存在靶向耐药突变

Presence of On-Target Resistant Mutation in Pre-Treatment Samples of ALK Fusion Gene Positive Lung Cancer Patients

原文发布日期：25 March 2025

DOI: 10.3390/cancers17071090

类型: Article

开放获取: 是

英文摘要：

A subset of ALK+ non-small cell lung cancer (NSCLC) patients relapse on ALK inhibitor (ALKi) treatment due to on-target resistance mutations affecting the tyrosine kinase domain. Objective: In this study, we investigated the presence of minor resistant clones in pre-treatment tissue samples and assessed their predictive value for subsequent resistance mechanisms. Methods: Using the highly sensitive digital droplet (dd)PCR technique, we analyzed 40 tissue samples obtained from 17 patients who had developed on-target resistance mutations after receiving ALKi between 2013 and 2022. We focused on 10 on-target ALKi resistant mutations identified in our patient cohort. Results: Fifteen ALKi resistance mutations were detected in 13 samples from 11/17 patients. Among these, four mutations were observed as resistance mutations in follow-up biopsies taken after first or subsequent lines of ALKi. Comparison of the test results from two subsequent biopsies, before and directly after therapy, revealed presence of the resistance mutation identified upon relapse in the pre-treatment sample of three cases that were all taken from the same tumor location. In six cases taken from different tumor locations, the resistant mutations were not found in the pre-treatment sample. Conclusions: By using the highly sensitive ddPCR approach, we detected minor clones with on-target resistant mutations in both treatment-naive and relapse biopsies from ALK-positive NSCLC patients. The predictive value of these mutations as the potential resistance-causing mechanism was limited to relapses occurring at the same tumor location as the pre-treatment sample.

摘要翻译： 

一部分ALK阳性非小细胞肺癌（NSCLC）患者在接受ALK抑制剂（ALKi）治疗期间因酪氨酸激酶结构域发生靶向耐药突变而复发。研究目的：本研究旨在检测治疗前组织样本中微量耐药克隆的存在情况，并评估其对后续耐药机制的预测价值。研究方法：采用高灵敏度微滴式数字PCR（ddPCR）技术，我们对2013年至2022年间接受ALKi治疗后出现靶向耐药突变的17例患者的40份组织样本进行分析，重点检测了该队列中发现的10种靶向ALKi耐药突变。研究结果：在17例患者中的11例（共13份样本）中检测到15种ALKi耐药突变。其中4种突变在首次或后续ALKi治疗后的随访活检中被确认为耐药突变。通过对比三例同部位肿瘤治疗前与治疗后即刻两次连续活检的检测结果，发现复发时检出的耐药突变均存在于治疗前样本中。而在六例不同部位肿瘤的样本中，治疗前样本未检测到相应耐药突变。研究结论：通过高灵敏度ddPCR技术，我们在ALK阳性NSCLC患者的初治与复发活检样本中均检测到携带靶向耐药突变的微量克隆。这些突变作为潜在耐药机制的预测价值，仅限于在与治疗前样本相同肿瘤部位发生的复发情况。

原文链接：

Presence of On-Target Resistant Mutation in Pre-Treatment Samples of ALK Fusion Gene Positive Lung Cancer Patients