Abstract
YKL-40 is a glycoprotein with pro-angiogenic functions. We hypothesized that patients with newly diagnosed glioblastoma and low baseline plasma YKL-40 levels derive greater benefit from first-line bevacizumab. Plasma samples were collected from 563 patients in the randomized, phase 3 AVAglio trial who received bevacizumab or placebo plus radiotherapy/temozolomide. Raw plasma YKL-40 concentrations were converted to age-corrected percentiles of normal healthy YKL-40 levels and divided into quartiles (Q). The impact of baseline plasma YKL-40 level on survival was investigated using Cox regression analyses. Patients with low baseline plasma YKL-40 (≤Q1) had an improved progression-free survival hazard ratio (HR) for bevacizumab versus placebo (0.37, 95% confidence interval [CI]: 0.25–0.55) compared with high plasma YKL-40 (> Q1) (0.71, 95% CI: 0.57–0.87). Overall survival HRs were comparable between the subgroups (≤ Q1: 0.69, 95% CI: 0.44–1.09; (> Q1: 0.88, 95% CI: 0.68–1.13). A trend for improved progression-free survival HR with low versus high YKL-40 was observed in proneural glioblastoma (0.41, 95% CI: 0.13–1.28 vs 0.80, 95% CI: 0.45–1.40, respectively), but not for proliferative/mesenchymal subtypes. Elevated plasma YKL-40 (> 90th percentile of normal) was an independent negative prognostic factor. In conclusion, the predictive value of baseline plasma YKL-40 level as a biomarker for bevacizumab efficacy in glioblastoma may be limited to patients with proneural tumors. Independent validation studies are required to confirm these results.
Highlights
CHI3L1 (Chitinase-3-like protein 1) is one of the most overexpressed genes in glioblastomas, relative to normal brain and low-grade gliomas [1]
Based on evidence suggesting a pro-angiogenic role of YKL-40 and interaction with vascular endothelial growth factor (VEGF) [18], we hypothesized that low levels of plasma YKL-40 could be predictive of greater clinical benefit from anti-VEGF treatment
Proliferative aPercentile of YKL-40 according to the established normal YKL-40 level in healthy individuals [39]. bp value from Mann-Whitney U test for two groups or Kruskal-Wallis test for > 2 groups comparing biomarker levels across the groups. cPartial resection meant that some extent of tumor debulking was undertaken but macroscopically visible tumor was left behind
Summary
CHI3L1 (Chitinase-3-like protein 1) is one of the most overexpressed genes in glioblastomas, relative to normal brain and low-grade gliomas [1]. CHI3L1 is a marker for the mesenchymal subtype of glioblastoma and is related to extracellular-signal-regulated kinases and protein kinase B phosphorylation [2]. YKL-40, which is encoded by the CHI3L1 gene, is produced by tumor cells, inflammatory cells, and stem cells [3,4,5]. YKL-40 induces vascular endothelial growth factor (VEGF) expression and both YKL-40 and VEGF are pro-angiogenic factors associated with tumor angiogenesis [11,12,13,14,15,16,17]. YKL-40 up-regulates VEGF in the U87 human glioblastoma cell line, and long-term inhibition of VEGF induces expression of www.impactjournals.com/oncotarget
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