Ruglioni Martina, Petrini Iacopo, Crucitta Stefania, Sbrana Andrea, Luculli Giovanna Irene, Sadeghi Gol Leila, Forte Carola, Chella Antonio, Rolfo Christian, Danesi Romano, Del Re Marzia
Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
Unit of Pneumology, Department of Translational Research and New Technologies in Medicine, University Hospital of Pisa, Pisa, Italy.
Transl Oncol. 2025 Feb;52:102228. doi: 10.1016/j.tranon.2024.102228. Epub 2024 Dec 21.
Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.
Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.
A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA ("shedders"). Higher ECOG PS (p = 0.04), bilateral localization of primary tumor (p = 0.04), and the presence of intrathoracic/extrathoracic disease (p = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (p = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (p = 0.05).
Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.
循环肿瘤DNA（ctDNA）通过实现可操作突变的非侵入性、灵敏鉴定，彻底改变了肺癌的分子诊断。然而，由于肿瘤脱落的变异性，ctDNA分析可能具有挑战性，会导致假阴性结果。本研究旨在基于肺癌患者的临床特征了解ctDNA脱落的决定因素，以便在临床实践中进行ctDNA分析时能更好地解读假阴性结果。
在治疗前从IV期表皮生长因子受体突变（mEGFR）非小细胞肺癌（NSCLC）患者中采集血样，并监测至疾病进展。通过标准程序评估组织中的表皮生长因子受体（EGFR），而在基线和首次重新评估时使用数字PCR检测ctDNA上的EGFR状态。在疾病进展时使用二代测序（NGS）评估患者的突变状态。
共收集了40份mEGFR组织样本。在开始一线治疗前分析血浆样本中的mEGFR，65%的患者在ctDNA中检测到可检测的mEGFR（“脱落者”)。较高的东部肿瘤协作组（ECOG）体力状态评分（p = 0.04）、原发肿瘤的双侧定位（p = 0.04）以及存在胸内/胸外疾病（p = 0.05）与mEGFR脱落相关。与非脱落者相比，脱落者的无进展生存期（PFS）更短（p = 0.03）。与ctDNA清除的患者相比，在首次影像学评估时ctDNA中可检测到mEGFR的患者表现出更差的PFS（p = 0.05）。
我们的初步数据表明，特定的临床特征可预测NSCLC的ctDNA中mEGFR的脱落，这表明在理解潜在的假阴性结果以及在临床实践中进行适当报告方面具有潜在的临床适用性。
