Abstract
PurposeIn 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 designBlood 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.ResultsCTCs 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.ConclusionsOur 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.
Highlights
Ovarian cancer has the highest mortality rate of all gynecological cancers [1]
Baseline circulating tumor cell (CTC) indicated a higher risk of death in R0 patients with complete gross resection
Chromosomal gains at MDS1 And EVI1 Complex Locus (MECOM) and HERV-H LTR-Associating 1 (HHLA1) loci suggest that the observed cells were cancer cells and reflect pathophysiological decisive chromosomal aberrations of the primary and metastatic tumors
Summary
The standard of care for patients with advanced stage ovarian cancer consists of maximal cytoreductive or debulking surgery, and followed by a platinum-based adjuvant chemotherapy in combination with paclitaxel [2]. There is a major effort to identify biological markers of minimal residual disease (MRD), which remains inaccessible by clinically established staging procedures and measurement of the serum tumor marker CA-125. In this regard, circulating tumor cells (CTCs) have been actively investigated in a number of solid tumor types, predominantly using the FDA approved CellSearch assay (Janssen Diagnostic, USA) [5]. We hypothesized that CTCs may serve as indicators for tumor load at any time and for treatment response in ovarian cancer as well, and that CTCs could be used as surrogate markers of the risk of recurrence and metastasis
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