ERCC1-expressing circulating tumor cells as a potential diagnostic tool for monitoring response to platinum-based chemotherapy and for predicting post-therapeutic outcome of ovarian cancer
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Issam Chebouti1,6, Jan Dominik Kuhlmann2,5,6, Paul Buderath1,6, Stephan Weber3, Pauline Wimberger2,5,6, Yvonne Bokeloh4, Siegfried Hauch4, Rainer Kimmig1,6, Sabine Kasimir-Bauer1,6
1Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
2Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3ACOMED Statistik, Department of Biostatics, Magdeburg, Germany
4QIAGEN Hannover GmbH, Langenhagen, Germany
5National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
6German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
Issam Chebouti, email: [email protected]
Keywords: circulating tumor cells, ERCC1, platinum-resistance, ovarian cancer, prognosis
Received: June 30, 2016 Accepted: October 13, 2016 Published: November 11, 2016
Background: We recently showed that the presence of ERCC1+CTCs is an independent predictive biomarker for platinum-resistance and poor prognosis of ovarian cancer. The goal of our current research was to determine how the auxiliary assessment of ERCC1-transcripts influences overall CTC-detection rate. We extended this investigation from an initially predictive setting to paired pre- and post-therapeutic blood analysis in order to see, whether ERCC1+CTCs dynamics mirror response to chemotherapy.
Methods: 65 Paired blood samples (10ml) of primary ovarian cancer patients at primary diagnosis and after chemotherapy were studied for CTCs with the AdnaTest Ovarian Cancer (QIAGEN Hannover GmbH). We analyzed the tumor-associated transcripts EpCAM, MUC-1 and CA-125. ERCC1-transcripts were investigated in a separate approach by singleplex RT-PCR.
Results: Auxiliary assessment of ERCC1-transcripts enhanced the overall CTC-detection rate up to 17%. ERCC1+CTCs (defined as positive for one of the AdnaTest markers plus ERCC1-positivity) were detected in 15% of patients at primary diagnosis and in 12% after chemotherapy. The presence of ERCC1+CTCs after chemotherapy correlated with platinum-resistance (P=0.01), reduced PFS (P=0.0293) and OS (P=0.0008) and their persistence indicated poor post-therapeutic outcome (PFS: P=0.005; OS: P=0.0058). Interestingly, the assessment of ERCC1-transcripts alone was sufficient for the detection of prognostic relevant ERCC1-expressing CTCs.
Conclusion: Auxiliary assessment of ERCC1-transcripts expands the phenotypic spectrum of CTC detection and defines an additional overlapping fraction of ERCC1-expressing CTCs, which are potentially selected by platinum-based chemotherapy. Specifically, we suggest that ERCC1+CTCs could additionally be useful as a surrogate for monitoring platinum-based chemotherapy and to assess the post-therapeutic outcome of ovarian cancer.
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