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

// Issam Chebouti 1, 4 , Sabine Kasimir-Bauer 1, 4 , Paul Buderath 1, 4 , Pauline Wimberger 2, 3, 4 , Siegfried Hauch 5 , Rainer Kimmig 1, 4 and Jan Dominik Kuhlmann 2, 3, 4 1 Department of Gynecology and Obstetrics, University Hospital Essen, 45147 Essen, Germany 2 Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany 3 National Center for Tumor Diseases (NCT), Partner Site Dresden, 69120 Heidelberg, Germany 4 German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 5 QIAGEN, 40724 Hilden, Germany Correspondence to: Jan Dominik Kuhlmann, email: jan.kuhlmann@uniklinikum-dresden.de Keywords: ovarian cancer, circulating tumor cells, epithelial-to-mesenchymal-transition, PI3Kα, Akt-2 Received: January 06, 2017 Accepted: February 27, 2017 Published: March 14, 2017 ABSTRACT 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. Results: Before surgery, overall detection rate for epithelial CTCs was 18%. EMT-like CTCs were more frequently observed (30%) and were mutually exclusive to epithelial CTCs in the majority of patients (82%). After chemotherapy, EMT-like CTCs increased up 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 I-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). Materials and Methods: Blood samples of 91 ovarian cancer patients before surgery and 31 matched samples after adjuvant chemotherapy were evaluated for CTCs with the AdnaTest ovarian cancer and EMT-1 , analyzing the epithelial-associated transcripts EpCAM, Muc-1 and CA125 and the EMT-associated transcripts PI3Kα, Akt-2 and Twist. Conclusions: 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.