AUTHOR=Lee Jung-Min , Trepel Jane B. , Choyke Peter , Cao Liang , Sissung Tristan , Houston Nicole , Yu Minshu , Figg William D. , Turkbey Ismail Baris , Steinberg Seth M. , Lee Min-Jung , Ivy S. Percy , Liu Joyce F. , Matulonis Ursula A. , Kohn Elise C. 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 JOURNAL=Frontiers in Oncology VOLUME=Volume 5 - 2015 YEAR=2015 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2015.00123 DOI=10.3389/fonc.2015.00123 ISSN=2234-943X 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.