Analysis of serum protein biomarkers, circulating tumor DNA, and dovitinib activity in patients with tyrosine kinase inhibitor-refractory gastrointestinal stromal tumors

作者：Yoo C; Ryu M H; Na Y S; Ryoo B Y; Park S R; Kang Y K^*

来源：Annals of Oncology, 2014, 25(11): 2272-2277.

DOI：10.1093/annonc/mdu386

• gastrointestinal stromal tumor
• dovitinib
• biomarker
• BEAMing
• circulating tumor DNA

To identify biomarkers of dovitinib, a novel antiangiogenic tyrosine kinase inhibitor, soluble serum protein markers involved in the VEGF and FGF pathways and mutations in circulating tumor (ct) DNA were examined in patients with gastrointestinal stromal tumors. Changes in sVEGFR-2 levels were associated with dovitinib activity and secondary mutations in ctDNA were related with poor prognosis .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). %26lt;br%26gt;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. %26lt;br%26gt;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]. %26lt;br%26gt;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.

• 出版日期2014-11