Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Department of Oncology, Oslo University Hospital, Oslo, Norway.
Mol Cancer Ther. 2018 Nov;17(11):2473-2480. doi: 10.1158/1535-7163.MCT-18-0174. Epub 2018 Aug 10.
Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing tumor-specific aberrations through noninvasive sampling. In gastrointestinal stromal tumor (GIST), analysis of and mutations is important for therapeutic decisions, but the invasiveness of traditional biopsies limits the possibilities for repeated sampling. Using targeted next-generation sequencing, we have analyzed circulating cell-free DNA from 50 GIST patients. Tumor-specific mutations were detected in 16 of 44 plasma samples (36%) from treatment-naïve patients and in three of six (50%) patients treated with tyrosine kinase inhibitors. A significant association between detection of ctDNA and the modified National Institutes of Health risk classification was found. All patients with metastatic disease had detectable ctDNA, and tumor burden was the most important detection determinant. Median tumor size was 13.4 cm for patients with detectable mutation in plasma compared with 4.4 cm in patients without detectable mutation ( = 0.006). ctDNA analysis of a patient with disease progression on imatinib revealed that multiple resistance mutations were synchronously present, and detailed analysis of tumor tissue showed that these were spatially distributed in the primary tumor. Plasma samples taken throughout the course of treatment demonstrated that clonal evolution can be monitored over time. In conclusion, we have shown that detection of GIST-specific mutations in plasma is particularly feasible for patients with high tumor burden. In such cases, we have demonstrated that mutational analysis by use of liquid biopsies can capture the molecular heterogeneity of the whole tumor, and may guide treatment decisions during progression. .
循环肿瘤 DNA（ctDNA）的分子分析通过非侵入性采样捕获肿瘤特异性异常，具有很大的临床应用潜力。在胃肠道间质瘤（GIST）中， 和 突变分析对于治疗决策很重要，但传统活检的侵入性限制了重复采样的可能性。我们使用靶向下一代测序分析了 50 名 GIST 患者的循环无细胞 DNA。在 44 份治疗前患者的血浆样本（36%）和 6 份接受酪氨酸激酶抑制剂治疗的患者的 3 份（50%）中检测到肿瘤特异性突变。检测到 ctDNA 与改良的美国国立卫生研究院风险分类之间存在显著相关性。所有转移性疾病患者均检测到 ctDNA，肿瘤负荷是最重要的检测决定因素。与血浆中未检测到突变的患者相比，检测到突变的患者的中位肿瘤大小为 13.4cm（ = 0.006）。对接受伊马替尼治疗疾病进展的患者进行 ctDNA 分析显示，多个耐药突变同时存在，对肿瘤组织的详细分析表明，这些突变在原发性肿瘤中呈空间分布。在整个治疗过程中采集的血浆样本表明，克隆进化可以随时间监测。总之，我们已经证明，在高肿瘤负荷的患者中，检测血浆中的 GIST 特异性突变特别可行。在这种情况下，我们已经证明，使用液体活检进行突变分析可以捕获整个肿瘤的分子异质性，并可能在进展期间指导治疗决策。
