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

Ann Oncol. 2014 Nov;25(11):2272-2277. doi: 10.1093/annonc/mdu386. Epub 2014 Aug 22.

Abstract

Background: 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).

Patients and methods: 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.

Results: 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].

Conclusions: 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.

Keywords: BEAMing; biomarker; circulating tumor DNA; dovitinib; gastrointestinal stromal tumor.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Benzimidazoles / administration & dosage*
  • Biomarkers, Tumor / blood*
  • DNA, Neoplasm / blood
  • DNA, Neoplasm / genetics
  • Disease-Free Survival
  • Female
  • Gastrointestinal Stromal Tumors / blood*
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Gastrointestinal Stromal Tumors / pathology
  • Humans
  • Male
  • Middle Aged
  • Neoplastic Cells, Circulating / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins B-raf / blood
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-kit / blood
  • Proto-Oncogene Proteins c-kit / genetics
  • Quinolones / administration & dosage*
  • Receptor, Platelet-Derived Growth Factor beta / blood
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Vascular Endothelial Growth Factor A / blood
  • Vascular Endothelial Growth Factor Receptor-2 / blood

Substances

  • 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
  • Benzimidazoles
  • Biomarkers, Tumor
  • DNA, Neoplasm
  • Protein Kinase Inhibitors
  • Quinolones
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor beta
  • Vascular Endothelial Growth Factor Receptor-2
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf