title: 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.
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) (R (2) = 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Cao
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Tristan
authors.initials: T
authors.lastname: Sissung
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Houston
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Minshu
authors.initials: M
authors.lastname: Yu
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Ismail Baris
authors.initials: IB
authors.lastname: Turkbey
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute , Bethesda, MD , USA.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: Dana-Farber Cancer Institute , Boston, MA , USA.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Dana-Farber Cancer Institute , Boston, MA , USA.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Center for Cancer Research , Bethesda, MD , USA.
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
keywords: CEC; IL-8; biomarkers; cediranib; olaparib; ovarian cancer