Influence of platinum-based chemotherapy on disseminated tumor cells in patients with primary ovarian cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5067-5067
Author(s):  
P. Wimberger ◽  
R. Kimmig ◽  
A. Schulte ◽  
M. E. Scheulen ◽  
S. Kasimir-Bauer
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Gradient Centrifugation ◽  
Prognostic Significance ◽  
Disseminated Tumor Cells ◽  
High Dose ◽  
Blood Samples ◽  
Primary Ovarian Cancer ◽  
Platinum Based Chemotherapy ◽  
The Impact

5067 Background: Recent studies in patients (pts) with breast cancer have demonstrated the prognostic significance of disseminated tumor cells (DTC) in the bone marrow (BM) which even can survive high-dose chemotherapy. For ovarian cancer, the impact of chemotherapy on DTC is unknown. Here we evaluated whether first-line chemotherapy with carboplatinum and paclitaxel can eliminate DTC in BM and peripheral blood (PB) of pts with primary ovarian cancer (OC, FIGO IC-IIIC). Methods: PB of 28 pts with OC and bilateral BM aspirates of 18/28 pts were assessed for DTC before and after chemotherapy using density gradient centrifugation and an immunocytochemical cytokeratin (CK) assay with the anti-CK antibody A45-B/B3. Results: We identified CK+ cells in 7/28 blood samples (25%) before therapy with a mean number of 2 cells/20 ml (range 1–3). After chemotherapy, CK+ cells were detected in 3/28 blood samples (11%) with a mean number of 9 cells/20 ml (range 1–18). In 5 out of these 7 CK+ patients prior to therapy, no CK+ cells were found after therapy, a no change and a reduction of DTC could be demonstrated in one patient each. CK+ cells were found in 10/18 BM samples (56%) before therapy with a mean number of 2 cells/9x10E6 BM cells (range 1–7) and in 8/18 BM samples (44%) after therapy with a mean number of 10 cells/9x10E6 BM cells (range 2–35). After chemotherapy, no CK+ cells were found in 6 pts, no change in DTC counts was documented in 2 pts and a significant enhancement of DTC was shown in 6 pts, including 4 pts who had no CK+ cells before chemotherapy. Conclusions: DTC are frequently present in the BM and PB of pts with OC and are not always successfully eliminated after platinum-based chemotherapy. It has to be considered, whether these pts might profit from an additive immunotherapy as already shown by the intraperitoneal application of a trifunctional antibody targeting EpCAM, CD3 and accessory cells (Proc Am Assoc Cancer Res 46: 4260, 2005). No significant financial relationships to disclose.

Persistence of EpCAM-positive disseminated tumor cells after platinum-based chemotherapy in the bone marrow of patients with primary ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 16023-16023
Author(s):  
P. Wimberger ◽  
M. Heubner ◽  
R. Kimmig ◽  
M. E. Scheulen ◽  
S. Kasimir-Bauer
Keyword(s):  
Ovarian Cancer ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Gradient Centrifugation ◽  
Progression Free Survival ◽  
Disseminated Tumor Cells ◽  
Rank Test ◽  
Primary Ovarian Cancer ◽  
Platinum Based Chemotherapy ◽  
The Impact

16023 Background: The impact of chemotherapy on disseminated tumor cells (DTC) in ovarian cancer is still unknown. Therefore we evaluated in 30 patients with primary ovarian cancer, undergoing radical tumor debulking surgery, (1) the influence of first-line chemotherapy with carboplatinum and paclitaxel on DTC elimination in bone marrow (BM) and peripheral blood (PB), (2) the coexpression of the epitelial antigen EpCAM on DTC and (3) the impact on progression free survival (PFS). Methods: DTC were detected in PB (20ml) and bilateral BM aspirates (10ml) using density gradient centrifugation and immunocytochemistry, applying the anti-cytokeratin antibody A45-B/B3. EpCAM-positive DTC were analyzed by using the antibodies HEA-125-FITC and Ber-EP4-FITC. PFS was estimated using the Kaplan-Meier method and statistically evaluated using a two-sided log-rank test. A significant increase or decrease of DTC was assessed if the difference was = 2 DTC. Results: Before chemotherapy, we identified DTC in 16% of PB samples with a mean number of 2 cells (range 1–3) and in 50% of BM samples with a mean number of 3 cells/9x10E6 BM cells (range 1–8). After chemotherapy, DTC were detected in PB in only one patient but still in 50% of BM samples with a with a mean number of 17 cells/9x10E6 BM cells (range 1–100). In BM, chemotherapy completely eliminated DTC in 30% of the patients, no significant change was documented in 47% and a significant enhancement of DTC was shown in 33%, including 8 patients (27%) who had no DTC before chemotherapy. In case of significant increase of DTC, patients showed a trend for reduced PFS (12.8 months ± 0.7; mean PFS ± SEM) in comparison to patients with no increase (19.3 months ± 1.4) or decrease of DTC (p=0.07). DTC, persisting after chemotherapy, co-expressed EpCAM. Conclusions: It has to be considered, whether these patients with persisting EpCAM-positive DTC in BM might profit from an additive immunotherapy e.g. by the intraperitoneal application of a trifunctional antibody targeting EpCAM, CD3 and accessory cells. No significant financial relationships to disclose.

scholarly journals Analysis of disseminated tumor cells before and after platinum based chemotherapy in primary ovarian cancer. Do stem cell like cells predict prognosis?

Oncotarget ◽  
2016 ◽  
Vol 7 (18) ◽  
pp. 26454-26464 ◽  
Author(s):  
Issam Chebouti ◽  
Christina Blassl ◽  
Pauline Wimberger ◽  
Hans Neubauer ◽  
Tanja Fehm ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Primary Ovarian Cancer ◽  
Platinum Based Chemotherapy ◽  
Before And After

Role of an EpCAM auto-antibody in ovarian cancer patients with special regard to disseminated tumor cells in bone marrow

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16557-e16557
Author(s):  
M. Heubner ◽  
S. Kasimir-Bauer ◽  
D. Errico ◽  
D. Herlyn ◽  
R. Kimmig ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Healthy Controls ◽  
Line Treatment ◽  
First Line ◽  
Platinum Based Chemotherapy ◽  
First Line Treatment

e16557 Background: EpCAM is a tumor associated antigen which is frequently expressed in ovarian cancer. Recently, an autoantibody (AAB) against EpCAM has been identified in ovarian cancer patients. Autoantibodies are immunogene factors and might be of prognostic importance. We showed that disseminated tumor cells (DTC) in bone marrow carry the EpCAM antigen on their surface and correlate with poorer progression free survival (PFS). Here, we evaluated whether EpCAM-AABs have an impact on clinical parameters or the presence of DTC in ovarian cancer patients. Methods: EpCAM-AABs were determined in sera of 28 healthy voluntary age matched females and 62 patients with primary epithelial ovarian cancer before and after platinum-based chemotherapy using a recombinant EpCAM-epitope for antibody- detection by ELISA technique. Mean follow up time was 13 months. DTC in BM were detected by immunocytochemistry applying the pan cytokeratin antibody A45-B/B3. All samples exceeding the mean antibody titer of healthy controls plus 2 standard deviations were considered positive. Results: The antibody titer of healthy controls was 0.061 + 0.015. Using a cut-off value of 0.091, we found 9/62 (15%) ovarian cancer patients to be positive for EpCAM-AABs after first-line treatment. Interestingly, no positive AAB-titers were seen before therapy. Using the paired T-Test, we noted a significant posttherapeutic increase of AABs (CI 0.95, p < 0.0001). Analysis of PFS, FIGO stage, resection status, grading, age, sensitivity to platinum based chemotherapy and DTC did not reveal significant associations with positive EpCAM-AAB titers. Conclusions: The clinical course of ovarian cancer patients and the prevalence of DTC were not altered by EpCAM-AABs. Interestingly, we observed an increase of antibody-levels after first-line treatment. For further validation, we intend to extend our patient collective. In future, it might also be interesting to investigate the impact of AABs on response to targeted therapies against EpCAM. No significant financial relationships to disclose.

Clinical relevance of VEGF-receptor status in primary ovarian cancer: A pilot study for future biomarker analyses.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5556-5556
Author(s):  
Pauline Wimberger ◽  
Issam Chebouti ◽  
Jan Dominik Kuhlmann ◽  
Rainer Kimmig ◽  
Eberhart Kuhlisch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Cancer Tissue ◽  
Vegf Receptor ◽  
Antiangiogenic Treatment ◽  
Primary Ovarian Cancer

5556 Background: Antiangiogenic treatment in addition to platinum/taxane based chemotherapy was shown to improve progression-free survival in first- and second-line chemotherapy in ovarian cancer patients. Predictive markers for antiangiogenic treatment are of high interest. Therefore we investigated VEGF-receptor (VEGFR) expression as possible biomarker candidate in primary ovarian cancer tissue and its clinical impact. Methods: A total of 82 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGFR1, VEGFR2 and VEGFR3 by immunhistochemistry. Moreover, the presence of circulating tumor cells (CTC) in the blood was detected by immunomagnetic enrichment and multiplex reverse transcriptase-polymerase chain reaction (Adnatest Ovarian Cancer, Adnagen). Disseminated tumor cells (DTC) in the BM were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and subsequent automatic detection based on staining and cytomorphology. Results: Positivity for at least one VEGFR was observed in 43% of cases. The positivity rates for VEGFR1, -2 and -3 were 34%, 17% and 27%, respectively. VEGFR-status of the primary tumor neither correlated with established clinicopathogical parameters (age, FIGO-stage, nodal status, grading, histological subtype) nor with the presence of CTC or DTC. In addition, VEGFR-status does not provide prognostic significance in regard to progression-free and overall survival (OS). Nevertheless, a trend was observed that patients, being positive for VEGFR3 at primary diagnosis, were more likely to experience suboptimal debulking (p = 0.074). CTC-positivity after adjuvant therapy significantly correlated with OS, but multivariable analysis showed only residual tumor as prognostic factor for OS. Conclusions: The VEGFR-family, albeit frequently expressed in our patient cohort, provided neither prognostic nor predictive relevance, but could probably be a predictor for debulking efficiency. The implementation of VEGFR-status into future biomarker studies should carefully be considered.

Abstract 2492: Do disseminated tumor cells with stem cell character after therapy predict prognosis in primary ovarian cancer

2016 ◽  
Author(s):  
Issam Chebouti ◽  
Christina Blassl ◽  
Pauline Wimberger ◽  
Hans Neubauer ◽  
Tanja Fehm ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Primary Ovarian Cancer

Influence of platinum-based chemotherapy on disseminated tumor cells in blood and bone marrow of patients with ovarian cancer

2007 ◽  
Vol 107 (2) ◽  
pp. 331-338 ◽  
Author(s):  
P WIMBERGER ◽  
M HEUBNER ◽  
F OTTERBACH ◽  
T FEHM ◽  
R KIMMIG ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Platinum Based Chemotherapy

Detection of disseminated tumor cells in bone marrow as an independent prognostic factor in primary ovarian cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5042-5042
Author(s):  
Pauline Wimberger ◽  
Malgorzata Banys ◽  
Sabine Kasimir-Bauer ◽  
Andreas D. Hartkopf ◽  
Natalia Krawczyk ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Prognostic Factor ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Stem Cell Marker ◽  
Primary Ovarian Cancer

5042 Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM)of breast cancer patients is associated with poor outcome. Recent studies demonstratedthat DTC may serve as a prognostic factor in ovarian cancer.The aim of our study was to evaluate the impact of BM status on survival in a large cohort of ovarian cancer patients. Methods: 365 patients with primary ovarian cancer were included into this three-center prospective study. BM aspirates were collected preoperatively from iliac crest. Disseminatedtumor cells were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and by cytomorphology. Patient outcomes were evaluated using a multivariable Cox regression model. Results: Disseminated tumor cells were detected in 28% of all BM aspirates. The number of CK-positive cells ranged from 1 to 42 per 2x106 mononuclear cells. DTC status did not correlate with any of the established clinicopathogical factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 mo, 95% CI: 35 – 67 mo versus 32 mo, 95% CI: 22 – 42 mo; p = 0.003). However, disease-free survival was not related to DTC-positivity. In the multivariable analysis, BM status, FIGO stage, nodal status, resection status and age were independent predictors of reduced overall survival. Interestingly, a subset of DTCs may have stem cell properties since a subset of these cells (128 out of 228 cases) were SOX2 positive, which is an embryonic stem cell marker. Conclusions: Tumor cell dissemination into bone marrow is a common phenomenon in ovarian cancer. DTC detection has the potential to become an important biomarker for prognostication and may be included as a therapeutic target in future concepts.

Impact of disseminated tumor cells in bone marrow on outcome of patients with primary ovarian cancer.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e15545-e15545
Author(s):  
M. L. Heubner ◽  
S. Kasimir-Bauer ◽  
R. Kimmig ◽  
P. Wimberger
Keyword(s):  
Ovarian Cancer ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Primary Ovarian Cancer
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