循环肿瘤 DNA 是晚期甲状腺癌疾病进展和对靶向治疗反应的潜在生物标志物。
Circulating tumour DNA is a potential biomarker for disease progression and response to targeted therapy in advanced thyroid cancer.
机构信息
Radiotherapy and Imaging Division, The Institute of Cancer Research, London, UK.
Centre for Molecular Pathology, The Royal Marsden Hospital, London, UK.
出版信息
Eur J Cancer. 2018 Nov;103:165-175. doi: 10.1016/j.ejca.2018.08.013. Epub 2018 Sep 22.
BACKGROUND
Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer.
METHODS
Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria.
RESULTS
Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies.
CONCLUSION
The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer.
背景
甲状腺癌的传统生物标志物不具有疾病特异性，并且在晚期疾病中波动，使得解释变得困难。循环肿瘤 DNA（ctDNA）已被证明在其他实体瘤中是一种有用的生物标志物。这是一项针对多个时间点 ctDNA 的多突变研究，旨在检验 ctDNA 是晚期甲状腺癌患者潜在生物标志物的假设。
方法
使用靶向基因 panel 的 NGS 对存档肿瘤组织进行突变分析。使用数字液滴聚合酶链反应为 ctDNA 检测设计了定制的 TaqMan 检测。检测到的 ctDNA 浓度与常规生物标志物浓度和实体瘤反应评估标准定义的轴向成像状态相关。
结果
获得了 51 例患者的肿瘤组织，其组织学类型如下：32 例分化型（分化型甲状腺癌 [DTC]）、15 例髓样（髓样甲状腺癌 [MTC]）、3 例低分化和 1 例间变性。NGS 分析在 42 例（82%）病例中检测到变异。对这些患者的 190 个样本进行了血浆检测，在 67%的患者中检测到了 ctDNA。在 3 例 MTC 患者中更早地发现了疾病进展。在 2 例（PTC 和 ATC）中，由于无法检测到常规生物标志物，在疾病进展前检测到了 ctDNA。在接受靶向治疗的多名 DTC 患者中，ctDNA 浓度的变化比常规标志物更早地发生，以响应疾病进展。
结论
大多数晚期甲状腺癌患者有可检测到的 ctDNA。ctDNA 测量可能在几种情况下优于常规标志物：MTC 中更早地发现进展；在常规标志物不可用时作为替代生物标志物；更快速地评估对靶向治疗的疾病状态，从而可能更及时地停止无效治疗。这些早期结果支持 ctDNA 可能是甲状腺癌临床有用的生物标志物的假设。
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