The Plasticity of Circulating Tumor Cells in Ovarian Cancer During Platinum-containing Chemotherapy.

BACKGROUND

Circulating Tumor Cells (CTCs) are a potential source of metastases and relapses. The data on molecular characteristics of Ovarian Cancer (OC) CTCs are limited.

OBJECTIVE

This study aims to assess the TGFβ, CXCL2, VEGFA and ERCC1 expressions in two OC CTC subpopulations before and during chemotherapy (CT), and their relation to clinical characteristics.

METHODS

Two CTCs subpopulations (EpCAM+CK18+E-cadherin+; EpCAM+CK18+Vimentin+) were enriched using immunomagnetic separation before treatment and after 3 cycles of platinumcontaining CT. The expression of mRNA was assessed using RT-qPCR.

RESULTS

The study included 31 I-IV stage OC patients. During CT, TGFβ levels increased in both fractions (p=0.054) compared with the initial levels. ERCC1 expression in E-cadherin+ CTCs was higher during neoadjuvant than adjuvant CT (p=0.004). CXCL2 level in E-cadherin+ CTCs increased (p=0.038) during neoadjuvant CT compared with the initial. TGF-β expression in vimentin+ CTCs during CT was negatively correlated to disease stage (p=0.003). Principal component analysis before CT revealed a component combining VEGFA, TGFβ, CXCL2, and a component with ERCC1 and VEGFA; during CT, component 1 contained ERCC1 and VEGFA, and component 2 - TGFβ and CXCL2 in both fractions. Increased ERCC1 expression in E-cadherin+ CTCs during CT was associated with decreased Progression-Free Survival (PFS) (HR 1.11 (95% CI 1.03-1.21, p=0.009) in multivariate analysis.

CONCLUSION

EpCAM+ OC CTCs are phenotypically heterogeneous, which may reflect variability in their metastatic potential. CT changes the molecular characteristics of CTCs. Expression of TGFβ in EpCAM+ CTCs increases during CT. High ERCC1 expression in EpCAM+CK18+E-cadherin+ CTCs during CT is associated with decreased PFS in OC.