Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Ann Oncol. 2014 Nov;25(11):2272-2277. doi: 10.1093/annonc/mdu386. Epub 2014 Aug 22.
An exploratory translational analysis was conducted as part of a phase II study of dovitinib to assess the relevance of soluble serum proteins and circulating tumor (ct) DNA (ctDNA) as biomarkers in patients with tyrosine kinase inhibitor (TKI)-refractory gastrointestinal stromal tumors (GISTs).
Predose serum samples were collected from 30 patients on day 1 of cycle 1 and cycle 2. Serum levels of angiogenesis-related proteins were assessed by enzyme-linked immunosorbent assay, and Beads, emulsions, amplification, and magnetics (BEAMing) assays were carried out to detect mutations in serum ctDNA.
Dovitinib increased vascular endothelial growth factor (VEGF)165 (1.26-fold, P = 0.006), VEGF-A (1.27-fold, P = 0.004), placental growth factor (6.0-fold, P = 0.002), fibroblast growth factor 23 (1.45-fold, P = 0.02), and interleukin 8 (1.75-fold, P = 0.04) levels, and decreased soluble vascular endothelial growth factor receptor (sVEGFR)-2 levels (0.8-fold, P = 0.001). The changes in sVEGFR-2 were significantly associated with metabolic response determined by positron emission tomography (P = 0.02) and progression-free survival (PFS; P = 0.02). Secondary kinase mutations were identified in the ctDNA of 11 patients (41%), and these patients all had mutations involving KIT exon 17. Patients with secondary KIT mutations had significantly worse overall survival {median, 5.5 months [95% confidence interval (CI) 3.8-7.2 months]} than those with no detectable secondary mutations [9.8 months (95% CI 9.6-10.0 months); hazard ratio = 2.7 (95% CI 1.0-7.3); P = 0.047].
Changes in sVEGFR-2 levels were associated with dovitinib-mediated antitumor activity. Genotyping of serum ctDNA with BEAMing is useful for the identification of resistant mutations potentially associated with poor prognosis in patients with GISTs.
作为多韦替尼（一种酪氨酸激酶抑制剂）治疗耐药胃肠道间质瘤的 II 期研究的一部分，进行了探索性转化分析，以评估可溶性血清蛋白和循环肿瘤（ct）DNA（ctDNA）作为生物标志物的相关性。
在第 1 周期和第 2 周期的第 1 天采集了 30 名患者的预剂量血清样本。通过酶联免疫吸附试验评估血管生成相关蛋白的水平，并通过 Beads、emulsions、amplification、and magnetics（BEAMing）检测血清 ctDNA 中的突变。
多韦替尼增加了血管内皮生长因子（VEGF）165（1.26 倍，P=0.006）、VEGF-A（1.27 倍，P=0.004）、胎盘生长因子（6.0 倍，P=0.002）、成纤维细胞生长因子 23（1.45 倍，P=0.02）和白细胞介素 8（1.75 倍，P=0.04）的水平，并降低了可溶性血管内皮生长因子受体（sVEGFR）-2 水平（0.8 倍，P=0.001）。sVEGFR-2 的变化与正电子发射断层扫描（PET）确定的代谢反应（P=0.02）和无进展生存期（PFS；P=0.02）显著相关。在 11 名患者（41%）的 ctDNA 中发现了继发性激酶突变，这些患者均有 KIT 外显子 17 的突变。继发性 KIT 突变的患者总生存期明显较差[中位数，5.5 个月（95%置信区间（CI）3.8-7.2 个月）]，而无检测到继发性突变的患者总生存期较长[9.8 个月（95%CI 9.6-10.0 个月）；危险比=2.7（95%CI 1.0-7.3）；P=0.047]。
sVEGFR-2 水平的变化与多韦替尼介导的抗肿瘤活性相关。利用 BEAMing 对血清 ctDNA 进行基因分型有助于鉴定与胃肠道间质瘤患者预后不良相关的耐药突变。
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