Research Papers:

Circulating tumor cells: potential markers of minimal residual disease in ovarian cancer? a study of the OVCAD consortium

Eva Obermayr, Natalia Bednarz-Knoll, Beatrice Orsetti, Heinz-Ulrich Weier, Sandrina Lambrechts, Dan Cacsire Castillo-Tong, Alexander Reinthaller, Elena Ioana Braicu, Sven Mahner, Jalid Sehouli, Ignace Vergote, Charles Theillet, Robert Zeillinger and Burkhard Brandt _

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Oncotarget. 2017; 8:106415-106428. https://doi.org/10.18632/oncotarget.22468

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Eva Obermayr1, Natalia Bednarz-Knoll2, Beatrice Orsetti3,4, Heinz-Ulrich Weier5, Sandrina Lambrechts6, Dan Cacsire Castillo-Tong1, Alexander Reinthaller1, Elena Ioana Braicu7, Sven Mahner8,10, Jalid Sehouli7, Ignace Vergote6, Charles Theillet3,4, Robert Zeillinger1,* and Burkhard Brandt9,*

1Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria

2Institute of Tumor Biology, University Medical Center Eppendorf, Hamburg, Germany

3INSERM U1194, IRCM, Université de Montpellier, Montpellier, France

4Institut du Cancer de Montpellier, Montpellier, France

5Department of Cancer and DNA Damage Responses, Life Sciences Division, University of California, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

6Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium

7Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany

8Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

9Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

10Department of Gynecology and Obstetrics, University of Munich, Munich, Germany

*These authors contributed equally to this work

Correspondence to:

Burkhard Brandt, email: [email protected]

Keywords: circulating tumour cells; minimal residual disease; ovarian cancer; multi-marker analysis; FISH on CTCs

Received: November 01, 2016     Accepted: October 11, 2017     Published: November 16, 2017


Purpose: In 75% of ovarian cancer patients the tumor mass is completely eradicated by established surgical and cytotoxic treatment; however, the majority of the tumors recur within 24 months. Here we investigated the role of circulating tumor cells (CTCs) indicating occult tumor load, which remains inaccessible by established diagnostics.

Experimental design: Blood was taken at diagnosis (baseline samples, n = 102) and six months after completion of adjuvant first-line chemotherapy (follow-up samples; n = 78). CTCs were enriched by density gradient centrifugation. A multi-marker immunostaining was established and further complemented by FISH on CTCs and tumor/metastasis tissues using probes for stem-cell like fusion genes MECOM and HHLA1.

Results: CTCs were observed in 26.5% baseline and 7.7% follow-up blood samples at a mean number of 12.4 and 2.8 CTCs per ml blood, respectively. Baseline CTCs indicated a higher risk of death in R0 patients with complete gross resection (univariate: HR 2.158, 95% CI 1.111–4.191, p = 0.023; multivariate: HR 2.720, 95% CI 1.340–5.522, p = 0.006). At follow-up, the presence of CTCs was associated with response to primary treatment as assessed using RECIST criteria. Chromosomal gains at MECOM and HHLA1 loci suggest that the observed cells were cancer cells and reflect pathophysiological decisive chromosomal aberrations of the primary and metastatic tumors.

Conclusions: Our data suggest that CTCs detected by the multi-marker protein panel and/or MECOM/HHLA1 FISH represent minimal residual disease in optimally debulked ovarian cancer patients. The role of CTCs cells especially for clinical therapy stratification of the patients has to be validated in consecutive larger studies applying standardized treatment schemes.

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