Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
Mol Cancer Ther. 2021 Dec;20(12):2568-2576. doi: 10.1158/1535-7163.MCT-21-0403. Epub 2021 Sep 22.
The majority of patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) are successfully treated with a combination of surgery and tyrosine kinase inhibitors (TKIs). However, it remains challenging to monitor treatment efficacy and identify relapse early. Here, we utilized a sequencing strategy based on molecular barcodes and developed a GIST-specific panel to monitor tumor-specific and TKI resistance mutations in cell-free DNA and applied the approach to patients undergoing surgical treatment. Thirty-two patients with GISTs were included, and 161 blood plasma samples were collected and analyzed at routine visits before and after surgery and at the beginning, during, and after surgery. Patients were included regardless of their risk category. Our GIST-specific sequencing approach allowed detection of tumor-specific mutations and TKI resistance mutations with mutant allele frequency < 0.1%. Circulating tumor DNA (ctDNA) was detected in at least one timepoint in nine of 32 patients, ranging from 0.04% to 93% in mutant allele frequency. High-risk patients were more often ctDNA positive than other risk groups ( < 0.05). Patients with detectable ctDNA also displayed higher tumor cell proliferation rates ( < 0.01) and larger tumor sizes ( < 0.01). All patients who were ctDNA positive during surgery became negative after surgery. Finally, in two patients who progressed on TKI treatment, we detected multiple resistance mutations. Our data show that ctDNA may become a clinically useful biomarker in monitoring treatment efficacy in patients with high-risk GISTs and can assist in treatment decision making.
大多数诊断为晚期胃肠道间质瘤（GIST）的患者通过手术和酪氨酸激酶抑制剂（TKI）的联合治疗可以成功治愈。然而，监测治疗效果并尽早发现复发仍然具有挑战性。在这里，我们利用基于分子条码的测序策略，开发了一种 GIST 特异性 panel，用于监测游离 DNA 中的肿瘤特异性和 TKI 耐药突变，并将该方法应用于接受手术治疗的患者。共纳入 32 名 GIST 患者，在手术前后及手术开始、期间和结束时采集了 161 份血浆样本进行分析。无论患者的风险类别如何，均纳入本研究。我们的 GIST 特异性测序方法可以检测到突变等位基因频率 < 0.1%的肿瘤特异性突变和 TKI 耐药突变。在 32 名患者中有 9 名至少在一个时间点检测到循环肿瘤 DNA（ctDNA），其突变等位基因频率范围为 0.04%至 93%。高危患者的 ctDNA 阳性率高于其他风险组（< 0.05）。可检测到 ctDNA 的患者的肿瘤细胞增殖率也更高（< 0.01），肿瘤体积更大（< 0.01）。所有在手术期间 ctDNA 阳性的患者在手术后均转为阴性。最后，在两名接受 TKI 治疗进展的患者中，我们检测到了多个耐药突变。我们的数据表明，ctDNA 可能成为监测高危 GIST 患者治疗效果的一种有临床应用价值的生物标志物，并有助于治疗决策。
