Circulating Tumor DNA in Advanced EGFRex20+ NSCLC: Concordance with Tissue Biopsy, Monitoring of Response, and Resistance to High-Dose Osimertinib.

IF 4.4 3区医学 Q2 ONCOLOGY

Targeted Oncology Pub Date : 2025-06-05 DOI:10.1007/s11523-025-01153-5

Fenneke Zwierenga, M Benthe Muntinghe-Wagenaar, Pim Rozendal, Adrianus J de Langen, Lizza E L Hendriks, Michel van den Heuvel, Cor van der Leest, Sayed M S Hashemi, Paul van der Leest, T Jeroen N Hiltermann, Ed Schuuring, Anthonie J van der Wekken

{"title":"Circulating Tumor DNA in Advanced EGFRex20+ NSCLC: Concordance with Tissue Biopsy, Monitoring of Response, and Resistance to High-Dose Osimertinib.","authors":"Fenneke Zwierenga, M Benthe Muntinghe-Wagenaar, Pim Rozendal, Adrianus J de Langen, Lizza E L Hendriks, Michel van den Heuvel, Cor van der Leest, Sayed M S Hashemi, Paul van der Leest, T Jeroen N Hiltermann, Ed Schuuring, Anthonie J van der Wekken","doi":"10.1007/s11523-025-01153-5","DOIUrl":null,"url":null,"abstract":"Background: High-dose osimertinib shows modest anti-tumor activity and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor exon 20 mutation (EGFRex20+). Plasma-derived circulating tumor DNA (ctDNA) is promising in monitoring responses and detecting resistance mechanisms to therapy.Objective: We aimed to assess the concordance between variants detected in ctDNA to those found in corresponding tissue samples at baseline and progression, to analyze alterations in mutant ctDNA levels of EGFRex20+ variants as predictors of therapy response, and to identify resistance mechanisms to high-dose osimertinib as well as examine changes in mutant ctDNA levels of EGFRex20+ variants.Patients and methods: Twenty-five patients with EGFRex20+ NSCLC received double dose (160 mg) osimertinib daily. Blood plasma was collected at baseline, 6 weeks after therapy start (T6), and at progression. ctDNA analysis was performed using the NGS Guardant360 CDx panel. The molecular profile at progression was compared with baseline/T6, and changes in ctDNA levels of the EGFRex20+ variants were linked to response or resistance.Results: Collected ctDNA samples were analyzed retrospectively. Baseline ctDNA showed somatic alterations in 19/20 patients (95%) and the corresponding tumor biopsy NGS EGFRex20+ variant in 65%. Among 14 patients with profiling at all timepoints, there was no significant correlation between changes in mutant ctDNA levels and osimertinib response. At T6, nine patients showed decreased EGFRex20+ levels, with eight also showing tumor shrinkage. At disease progression, 9/14 (64%) patients had increased EGFRex20+ levels, correlating with tumor growth. Variants potentially associated with resistance were found in 11/18 patients (61%): single nucleotide variants (SNV, n = 14), insertions (n = 2), and gene fusions (n = 1). Mutations previously related to osimertinib resistance were found, including EGFR p.C797S (n = 1).Conclusions: ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with EGFRex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Targeted Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11523-025-01153-5","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: High-dose osimertinib shows modest anti-tumor activity and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor exon 20 mutation (EGFRex20+). Plasma-derived circulating tumor DNA (ctDNA) is promising in monitoring responses and detecting resistance mechanisms to therapy.

Objective: We aimed to assess the concordance between variants detected in ctDNA to those found in corresponding tissue samples at baseline and progression, to analyze alterations in mutant ctDNA levels of EGFRex20+ variants as predictors of therapy response, and to identify resistance mechanisms to high-dose osimertinib as well as examine changes in mutant ctDNA levels of EGFRex20+ variants.

Patients and methods: Twenty-five patients with EGFRex20+ NSCLC received double dose (160 mg) osimertinib daily. Blood plasma was collected at baseline, 6 weeks after therapy start (T6), and at progression. ctDNA analysis was performed using the NGS Guardant360 CDx panel. The molecular profile at progression was compared with baseline/T6, and changes in ctDNA levels of the EGFRex20+ variants were linked to response or resistance.

Results: Collected ctDNA samples were analyzed retrospectively. Baseline ctDNA showed somatic alterations in 19/20 patients (95%) and the corresponding tumor biopsy NGS EGFRex20+ variant in 65%. Among 14 patients with profiling at all timepoints, there was no significant correlation between changes in mutant ctDNA levels and osimertinib response. At T6, nine patients showed decreased EGFRex20+ levels, with eight also showing tumor shrinkage. At disease progression, 9/14 (64%) patients had increased EGFRex20+ levels, correlating with tumor growth. Variants potentially associated with resistance were found in 11/18 patients (61%): single nucleotide variants (SNV, n = 14), insertions (n = 2), and gene fusions (n = 1). Mutations previously related to osimertinib resistance were found, including EGFR p.C797S (n = 1).

Conclusions: ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with EGFRex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.

查看原文本刊更多论文

晚期EGFRex20+ NSCLC的循环肿瘤DNA：与组织活检、监测反应和对大剂量奥西替尼的耐药性的一致性

背景：大剂量奥西替尼在表皮生长因子受体外显子20突变（EGFRex20+）的晚期非小细胞肺癌（NSCLC）患者中显示出适度的抗肿瘤活性和可接受的毒性。血浆来源的循环肿瘤DNA （ctDNA）在监测反应和检测对治疗的耐药机制方面很有前景。目的：我们旨在评估ctDNA中检测到的变体与基线和进展时相应组织样本中发现的变体之间的一致性，分析EGFRex20+变体中突变ctDNA水平的变化作为治疗反应的预测因素，并确定对大剂量奥西替尼的耐药机制，以及检查EGFRex20+变体中突变ctDNA水平的变化。患者和方法：25例EGFRex20+ NSCLC患者每天接受双倍剂量（160 mg）奥西替尼治疗。在基线、治疗开始后6周（T6）和进展时采集血浆。ctDNA分析采用NGS guarant360 CDx面板。将进展过程中的分子谱与基线/T6进行比较，发现EGFRex20+变异的ctDNA水平变化与反应或耐药性有关。结果：回顾性分析收集的ctDNA样本。基线ctDNA显示19/20患者（95%）的体细胞改变，65%的患者相应的肿瘤活检NGS EGFRex20+变异。在所有时间点进行分析的14例患者中，突变ctDNA水平的变化与奥西替尼反应之间没有显著相关性。T6时，9例患者EGFRex20+水平下降，8例患者肿瘤缩小。在疾病进展时，9/14（64%）患者EGFRex20+水平升高，与肿瘤生长相关。在11/18例（61%）患者中发现了可能与耐药性相关的变异：单核苷酸变异（SNV, n = 14）、插入（n = 2）和基因融合（n = 1）。发现了先前与奥西替尼耐药相关的突变，包括EGFR p.C797S （n = 1）。结论：ctDNA分析可追踪变异动力学，并可识别高剂量奥西替尼治疗EGFRex20+ NSCLC患者的耐药机制，提供有价值的新见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.