Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, C/ Natzaret 115-117, 08035, Barcelona, Spain.
Department of Medical Oncology, Vall d'Hebron University Hospital, P/Vall d'Hebron 119, 08035, Barcelona, Spain.
Curr Treat Options Oncol. 2021 Feb 27;22(4):32. doi: 10.1007/s11864-021-00832-5.
Gastrointestinal stromal tumor (GIST) constitutes a paradigm for clinically effective targeted inhibition of oncogenic driver mutations. Therefore, GIST has emerged as a compelling clinical and biological model to study oncogene addiction and to validate preclinical concepts for drug response and drug resistance. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the essential drivers of GIST progression throughout all stages of the disease. Interestingly, KIT/PDGFRA genotype predicts the response to first-line imatinib and to all tyrosine kinase inhibitors (TKIs) approved or in investigation after imatinib failure. Considering that TKIs are effective only against a subset of KIT or PDGFRA resistance mutations, close monitoring of tumor dynamics with non-invasive methods such as liquid biopsy emerges as a necessary step forward in the field. Liquid biopsy, in contrast to solid tumor biopsy, aims to characterize tumors irrespective of heterogeneity. Although there are several components in the peripheral blood, most recent studies have been focused on circulating tumor (ct)DNA, due to the technological feasibility, the stability of DNA itself and DNA alterations, and the therapeutic development in precision oncology largely based on the identification of genetic driver mutations. In the present review, we systematically dissect the current wealth of data of ctDNA in GIST. To do so, a critical understanding of the promises and limitations of the current technologies will be followed by an exposition of the knowledge gathered with such studies in GIST. Collectively, our goal is to establish clear premises that can be used as the foundations to build future studies towards the clinical implementation of ctDNA evaluation in GIST patients.
胃肠道间质瘤（GIST）为临床有效抑制致癌驱动突变提供了范例。因此，GIST 已成为研究致癌基因成瘾和验证药物反应和耐药性的临床前概念的引人注目的临床和生物学模型。KIT 或 PDGFRA 受体酪氨酸激酶的致癌激活是 GIST 进展的必要驱动因素，贯穿疾病的所有阶段。有趣的是，KIT/PDGFRA 基因型预测了对一线伊马替尼和所有批准用于伊马替尼失败后的酪氨酸激酶抑制剂（TKI）的反应。考虑到 TKI 仅对 KIT 或 PDGFRA 耐药突变的亚组有效，因此，使用液体活检等非侵入性方法密切监测肿瘤动态成为该领域的必要步骤。液体活检与实体肿瘤活检不同，旨在描述肿瘤的特征，而不考虑异质性。尽管外周血中有几个成分，但由于技术可行性、DNA 本身的稳定性和 DNA 改变以及基于鉴定遗传驱动突变的精准肿瘤学的治疗开发，最近的研究主要集中在循环肿瘤（ct）DNA 上。在本综述中，我们系统地剖析了 GIST 中 ctDNA 的现有丰富数据。为此，我们将首先批判性地了解当前技术的优缺点，然后阐述利用这些研究在 GIST 中获得的知识。总的来说，我们的目标是建立明确的前提，作为未来研究的基础，旨在将 ctDNA 评估应用于 GIST 患者的临床实施。
