Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance — A study of the OVCAD consortium

ObjectiveThe study aims at identifying novel markers for circulating tumor cells (CTCs) in patients with epithelial ovarian cancer (EOC), and at evaluating their impact on outcome.MethodsMicroarray analysis comparing matched EOC tissues and peripheral blood leucocytes (N = 35) was performed to identify novel CTC markers. Gene expression of these novel markers and of EpCAM was analyzed using RT-qPCR in blood samples taken from healthy females (N = 39) and from EOC patients (N = 216) before primary treatment and six months after adjuvant chemotherapy. All samples were enriched by density gradient centrifugation. CTC positivity was defined by over-expression of at least one gene as compared to the healthy control group.ResultsCTC were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two thirds were identified by overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. The presence of CTCs at baseline correlated with the presence of ascites, sub-optimal debulking, and elevated CA-125 and HE-4 levels, whereas CTC during follow-up occurred more often in older and platinum resistant patients. PPIC positive CTCs during follow-up were significantly more often detected in the platinum resistant than in the platinum sensitive patient group, and indicated poor outcome independent from classical prognostic parameters.ConclusionsMolecular characterization of CTC is superior to a mere CTC enumeration or even be the rationale for CTC diagnostics at all. Ultimately CTC diagnostics may lead to more personalized treatment of EOC, especially in the recurrent situation.

► We identified 11 gene markers for circulating tumor cells (CTCs) in ovarian cancer.
► The gene panel comprising PPIC outperforms EpCAM as marker for the detection of CTCs.
► PPIC expression in the post-therapeutic CTC containing cell fraction is associated with platinum resistance.
► PPIC expression in the post-therapeutic CTC containing cell fraction independently predicts worse outcome.