Beagan Jamie J, Bach Sander, van Boerdonk Robert A, van Dijk Erik, Thunnissen Erik, van den Broek Daan, Weiss Janneke, Kazemier Geert, Pegtel D Michiel, Bahce Idris, Ylstra Bauke, Heideman Daniëlle A M
Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands.
Amsterdam UMC, Vrije Universiteit Amsterdam, Surgery, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands.
Lung Cancer. 2020 Jul;145:173-180. doi: 10.1016/j.lungcan.2020.04.039. Epub 2020 May 11.
Circulating tumor (ct)DNA analysis is rapidly gaining acceptance as a diagnostic tool to guide clinical management of advanced non-small cell lung cancer (NSCLC). Clinically-actionable EGFR mutations can be detected in ctDNA before or after first-line EGFR-Tyrosine Kinase Inhibitor (TKI) treatment, but data are limited for patients with a complex treatment history. This study aimed to explore the feasibility of ctDNA testing in a clinical setting of NSCLC patients receiving osimertinib as a second or third line EGFR-TKI.
Twenty EGFR T790M-positive NSCLC patients, who had received osimertinib as a second or third line EGFR-TKI and had donated blood samples while attending routine follow-up consultations between April and November 2016, were retrospectively selected to test plasma cfDNA for tumor-guided EGFR mutations. We used EGFR mutations previously identified in tumor-tissue to retrospectively test plasma ctDNA from 20 patients who had received osimertinib as a second or third line EGFR-TKI. Both EGFR-TKI sensitising and T790 M resistance mutations were analysed by droplet digital PCR (ddPCR) in plasma taken alongside routine consultations and ctDNA detection was correlated with response under osimertinib. Follow-up solid-tissue biopsies were obtained after disease progression.
CtDNA was detected under osimertinib treatment in four out of the eight patients (50 %) who showed no response, two out of the seven (29 %) who showed an initial response and none of the five patients (0 %) who showed an ongoing response. The fraction of EGFR-mutant ctDNA in plasma tended to be higher in non-responders (0.1-68 %), compared to the initial responders (0.2-1.1 %). Blood samples were donated up to 34, 27 and 49 weeks after the start of osimertinib for the non-, initial and ongoing responders, respectively.
These findings support a potential role for ctDNA analysis in response monitoring of NSCLC patients with a complex EGFR-TKI treatment history. The weak trend between ctDNA detection and disease progression warrants larger studies to further investigate potential clinical utility.
循环肿瘤（ct）DNA分析作为一种指导晚期非小细胞肺癌（NSCLC）临床管理的诊断工具正迅速得到认可。在一线表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）治疗之前或之后，可在ctDNA中检测到具有临床可操作性的EGFR突变，但对于治疗史复杂的患者，相关数据有限。本研究旨在探讨在接受奥希替尼作为二线或三线EGFR-TKI治疗的NSCLC患者的临床环境中进行ctDNA检测的可行性。
回顾性选择20例EGFR T790M阳性的NSCLC患者，这些患者接受奥希替尼作为二线或三线EGFR-TKI治疗，并于2016年4月至11月在进行常规随访咨询时捐献了血样，以检测血浆游离DNA（cfDNA）中的肿瘤导向性EGFR突变。我们使用先前在肿瘤组织中鉴定出的EGFR突变，回顾性检测20例接受奥希替尼作为二线或三线EGFR-TKI治疗患者的血浆ctDNA。在常规咨询时采集的血浆中，通过液滴数字PCR（ddPCR）分析EGFR-TKI敏感性和T790M耐药性突变，并将ctDNA检测结果与奥希替尼治疗反应相关联。疾病进展后获取随访实体组织活检样本。
在接受奥希替尼治疗的8例无反应患者中，有4例（50%）检测到ctDNA；7例初始有反应的患者中有2例（29%）检测到ctDNA；5例持续有反应的患者中无一例（0%）检测到ctDNA。与初始有反应者（0.2-1.1%）相比，无反应者血浆中EGFR突变ctDNA的比例往往更高（0.1-68%）。无反应者、初始有反应者和持续有反应者分别在奥希替尼开始治疗后34周、27周和49周捐献血样。
这些发现支持ctDNA分析在具有复杂EGFR-TKI治疗史的NSCLC患者反应监测中的潜在作用。ctDNA检测与疾病进展之间的微弱趋势需要更大规模的研究来进一步调查其潜在临床应用价值。
