CECs and IL-8 have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: Biomarker correlates from the randomized phase-2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive ovarian cancer

Jung Min Lee*, Jane B. Trepel, Peter Choyke, Liang Cao, Tristan Sissung, Nicole Houston, Minshu Yu, William D. Figg, Ismail Baris Turkbey, Seth M. Steinberg, Min Jung Lee, S. Percy Ivy, Joyce F. Liu, Ursula A. Matulonis, Elise C. Kohn

*Corresponding author for this work

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24 Scopus citations

Abstract

Objective: Olaparib (O), a polyADPribose polymerase (PARP) inhibitor, and cediranib (C), a VEGF receptor (VEGFR)1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. Methods: A self-selected group of patients participated in a prospectively planned exploratory biomarker substudy of the randomized phase II study of O versus O + C. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and polyADPribose (PAR) incorporation were performed. Single nucleotide polymorphism analysis of XRCC1 280H, R194W, and Q399R was done. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. Kaplan-Meier and log-rank tests were used to examine survival outcome. Results: Thirteen patients elected to participate in the translational substudy, seven patients on O and six patients on O + C. Patients on O + C had a greater decrease in IL-8 concentration and larger CEC fold increase compared with those on O alone (p = 0.026, p = 0.032). The fold increase in CEC on day 3 was associated with duration of progression-free survival (PFS) (R2 = 0.77, 95% CI 0.55-0.97, p < 0.001). IL-8 post-pretreatment changes correlate with PFS (p = 0.028). XRCC1 DNA polymorphisms were not related to PFS. All patients had reduction in PAR incorporation, and all except one had reduction in vascular flow on DCE-MRI. Conclusion: Our exploratory correlative studies indicate that CEC and IL-8 changes may be predictive for response to O + C and prognostic in recurrent platinum-sensitive OvCa, requiring prospective validation.

Original languageEnglish
Article number123
JournalFrontiers in Oncology
Volume5
Issue numberJUN
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Biomarkers
  • CEC
  • Cediranib
  • IL-8
  • Olaparib
  • Ovarian cancer

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