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. 2017 Nov 16;8(63):106415-106428.
doi: 10.18632/oncotarget.22468. eCollection 2017 Dec 5.

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

Eva Obermayr  1 , Natalia Bednarz-Knoll  2 , Beatrice Orsetti  3   4 , Heinz-Ulrich Weier  5 , Sandrina Lambrechts  6 , Dan Cacsire Castillo-Tong  1 , Alexander Reinthaller  1 , Elena Ioana Braicu  7 , Sven Mahner  8   9 , Jalid Sehouli  7 , Ignace Vergote  6 , Charles Theillet  3   4 , Robert Zeillinger  1 , Burkhard Brandt  10
Affiliations

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

Eva Obermayr et al. Oncotarget. .

Abstract

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1. Flow diagram depicting the sample processing according to protocol A and B, including basic results
Figure 2
Figure 2. Overall survival of optimally debulked ovarian cancer patients
The patients are stratified by presence (black line) or absence (grey line) of OvCa+/CD45– CTCs at diagnosis. All patients (n = 69) received primary surgery without any macroscopically visible tumor residue left. Differences in survival were compared using the log-rank test.
Figure 3
Figure 3. Copy Number Alterations (CNA) in 128 sporadic ovarian carcinomas and mapping of shortest regions of overlap (SRO) for gains at 3q26 and 8q24
(A) represents a whole genome CNA profile (gains blue, losses red). Regions at 3q26.2 and 8q24 were the most frequently gained (65.6 and 57% of the cases respectively). To select BAC best adapted BAC clones for FISH experiments, SROs were mapped (B and C) corresponding to blow up boxes showing profiles of all the tumors gained in the analyzed regions). BAC clones selected were RP11-250A4, at 3q26.2 covering the MECOM locus, and RP11-240B13, at 8q24 encompassing the HHLA1 gene.
See this image and copyright information in PMC

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