Abstract
BackgroundAssuming 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.ResultsBefore 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 MethodsBlood 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.ConclusionsPlatinum-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.
Highlights
Epithelial ovarian cancer is the fifth leading cause of cancer death among women in Europe and the United States and the second most common gynecological malignancy [1]
PI3K+ EMT-like circulating tumor cells (CTCs) in combination with epithelial CTCs indicated decreased overall survival (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)
Epithelial CTCs alone significantly correlated with decreased progression free survival (PFS) and OS (p = 0.02, p = 0.002), supported by an additional inclusion of PI3K+ CTCs (OS, p = 0.001)
Summary
Epithelial ovarian cancer is the fifth leading cause of cancer death among women in Europe and the United States and the second most common gynecological malignancy [1]. Standard treatment of advanced ovarian cancer is primary surgery aiming at complete resection followed by platinum and paclitaxel based chemotherapy, which has been shown to prolong progression free survival (PFS) as www.impactjournals.com/oncotarget well as overall survival (OS) [2]. Postoperative residual tumor is one of the most important prognostic factors in advanced ovarian cancer [3,4,5]. The identification of innovative therapeutic targets and the identification of predicitive and prognostic biomarker concepts are highly desirable. Assuming that tumor cell dissemination requires a shift to a mesenchymal phenotype, we analyzed the incidence of epithelial-to-mesenchymaltransition (EMT)-like circulating tumor cells (CTCs) in ovarian cancer patients and inquired, how their molecular phenotypes respond to platinum-based chemotherapy and influence outcome
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