EMT-like circulating tumor cells in ovarian cancer patients are enriched by platinum-based chemotherapy

Background:

Assuming that tumor cell dissemination requires a shift to a mesenchymal phenotype, we analyzed the incidence of epithelial-to-mesenchymal-transition (EMT)-like circulating tumor cells (CTCs) in ovarian cancer patients and inquired, how their molecular phenotypes respond to platinum-based chemotherapy and influence outcome.

Methods:

Blood samples of 91 ovarian cancer patients before surgery and 31 matched samples after adjuvant chemotherapy were evaluated for CTCs with the AdnaTest OvarianCancer and EMT1/StemCell, analyzing the epithelial-associated transcripts EpCAM, MUC-1 and CA125 and the EMT-associated transcripts PI3Kα, Akt-2 and Twist.

Results:

Before surgery, overall detection rate for epithelial CTCs was 18%. EMT-like CTCs were more frequently observed (30%) and the majority of patients (82%) had either exclusively EMT-like or exclusively epithelial CTCs in their blood. After chemotherapy, EMT-like CTCs increased to 52%, accompanied by the “de novo” emergence of PI3Kα⁺/Twist⁺ EMT-like CTCs. Before surgery, PI3K⁺ EMT-like CTCs in combination with epithelial CTCs indicated decreased OS (p = 0.02) and FIGO III patients with residual tumor burden after surgery were more likely to be positive for EMT-like CTCs after chemotherapy (p = 0.02). In the latter group, epithelial CTCs alone significantly correlated with decreased PFS and OS (p = 0.02, p = 0.002), supported by an additional inclusion of PI3K⁺ CTCs (OS, p = 0.001).

Conclusion:

Platinum-based chemotherapy seems to select for EMT-like CTCs in ovarian cancer patients and provokes a shift towards PI3Kα and Twist expressing CTCs, which may reflect clonal tumor evolution towards therapy resistance. It has to be determined, whether this CTC subgroup may serve as a biomarker to identify patients at high risk.