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Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer.

ABSTRACT: PURPOSE:Circulating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer (MBC). We aimed to determine if the presence of CTCs and plasma markers of hypercoagulability [thrombin-antithrombin III (TAT), fibrinogen and D-dimer] are biomarkers of survival in MBC. METHODS/PATIENTS:In a prospective study of MBC patients, CTC (CellSearch®) enumeration and plasma TAT, fibrinogen and D-dimer measured prior to commencement of treatment for disease progression were correlated to overall survival. RESULTS:At study completion, of 50 MBC patients recruited (median age 59 years, range 36-82), 40 patients had died (median survival 417 days, range 58-2141). CTCs (??1/7.5 ml) were identified in 16 patients (median number of cells per 7.5 ml, 3 (range 1-31) and were associated with systemic hypercoagulability (medians TAT: 8.1 vs. 5.2 ng/ml, p?=?0.03; fibrinogen: 4.3 vs. 3.1 g/l, p?=?0.03; D-dimer: 1327 vs. 683 ng/ml, p?=?0.0001). At 1 year, of 16 patients with ??1 CTC, 7 had died (44%), compared to 5 of 26 (19%) patients in the no-CTC group. The presence of ??1 CTC was associated with a trend for reduced overall survival (median 455 days vs. 614 days, p?=?0.15). Plasma TAT inversely correlated with survival and was significantly higher in patients dying within 1 year (median 9.8 vs. 5.2 ng/ml, p?=?0.004) whilst D-dimer showed a trend for reduced 1-year survival (median 1211 vs. 817 ng/ml, p?=?0.06). MBC patients with combined high D-dimer (??895 ng/ml) and CTC positivity (??1/7.5 ml whole peripheral blood) had significantly reduced survival (p?=?0.04). CONCLUSIONS:The correlation between CTCs, hypercoagulability and reduced survival in MBC suggests the coagulation system supports tumour cell metastasis and is, therefore, a potential therapeutic target.

SUBMITTER: Kirwan CC

PROVIDER: S-EPMC7188731 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer.

Kirwan C C CC Descamps T T Castle J J

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 20190831 6

<h4>Purpose</h4>Circulating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer (MBC). We aimed to determine if the presence of CTCs and plasma markers of hypercoagulability [thrombin-antithrombin III (TAT), fibrinogen and D-dimer] are biomarkers of survival in MBC.<h4>Methods/patients</h4>In a prospective study of MBC patients, CTC (CellSearch<sup>®</sup>) enumeration and plasma TAT, fibrinogen and D-dim ...[more]

PMID: 31473984

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Project description:BACKGROUND:The prognostic relevance of circulating tumour cells (CTCs) in metastatic breast cancer (MBC) patients has been confirmed by several clinical trials. However, predictive blood-based biomarkers for stratification of patients for targeted therapy are still lacking. The DETECT studies explore the utility of CTC phenotype for treatment decisions in patients with HER2 negative MBC. Associated with this concept is a plethora of translational projects aiming to identify potential predictive biomarkers. The androgen receptor (AR) is expressed in over 70% of hormone receptor-positive and up-to 45% of triple-negative tumours. Studies has indicated the promising nature of AR as a new therapy target with a clinical benefit rate for anti-AR treatment in MBC patients up to 25% The aim of this analysis was the characterization of CTCs regarding the expression of the AR using immunofluorescence. METHODS:MBC patients were screened for the HER2-status of CTCs in the DETECT studies. In a subset of CTC-positive patients (n =?67) an additional blood sample was used for immunomagnetic enrichment of CTCs using the CellSearch® Profile Kit prior to transfer of the cells onto cytospin slides. Establishment of immunofluorescence staining for the AR was performed using prostate cancer cell lines LNCaP and DU145 as positive and negative control, respectively. Staining of DAPI, pan-cytokeratin (CK) and CD45 was applied to identify nucleated epithelial cells as CTCs and to exclude leucocytes. RESULTS:Co-staining of the AR, CK and CD45 according to the above mentioned workflow has been successfully established using cell lines with known AR expression spiked into the blood samples from healthy donors. For this translational project, samples were analysed from 67 patients participating in the DETECT studies. At least one CTC was detected in 37 out of 67 patients (56%). In 16 of these 37 patients (43%) AR-positive CTCs were detected. In eight out of 25 patients (32%) with more than one CTC, AR-positive and AR-negative CTCs were observed. CONCLUSION:In 43% of the analysed CTC samples from patients with MBC the AR expression has been detected. The predictive value of AR expression in CTCs remains to be evaluated in further trials.

Project description:IntroductionEpithelial to mesenchymal transition (EMT) is considered an essential process in the metastatic cascade. EMT is characterised by upregulation of vimentin, Twist, Snail, Slug and Sip1 among others. Metastasis is also associated with the presence of circulating tumour cells (CTCs) and disseminated tumour cells in the blood and bone marrow, respectively, of breast cancer patients, but the expression of EMT markers in these cells has not been reported so far.MethodsThe expression of Twist and vimentin in CTCs of 25 metastatic and 25 early breast cancer patients was investigated by using double-immunofluorescence experiments in isolated peripheral blood mononuclear cell cytospins using anti-cytokeratin (anti-CK) anti-mouse (A45-B/B3) and anti-Twist or anti-vimentin anti-rabbit antibodies.ResultsAmong early breast cancer patients, vimentin-and Twist-expressing CK(+) CTCs were identified in 77% and 73% of the patients, respectively, and in 100% of the patients with metastatic breast cancer for both markers (P = 0.004 and P = 0.037, respectively). Among patients with early disease, 56% and 53% of the CK(+) CTCs were double-stained with vimentin and Twist, and the corresponding values for metastatic patients were 74% and 97%, respectively (P = 0.005 and P = 0.0001, respectively). The median expression of CK(+)vimentin(+) and CK(+)Twist(+) cells per patient in metastatic patients was 98% and 100%, and in an adjuvant chemotherapy setting the corresponding numbers were 56% and 40.6%, respectively. Triple-staining experiments revealed that all CK(+)Twist(+) or CK(+)vimentin(+) cells were also CD45(-), confirming their epithelial origin. Immunomagnetic separation of CTCs and triple-immunofluorescence with anti-CK/anti-Twist/anti-vimentin antibodies demonstrated that both mesenchymal markers could be coexpressed in the same CK(+) cell, since 64% of the total identified CTCs were triple-stained. There was a significant correlation (P = 0.005) between the number of CTCs expressing Twist and vimentin within the same setting.ConclusionsCTCs expressing Twist and vimentin, suggestive of EMT, are identified in patients with breast cancer. The high incidence of these cells in patients with metastatic disease compared to early stage breast cancer strongly supports the notion that EMT is involved in the metastatic potential of CTCs.

Project description:BackgroundThe enumeration of circulating tumour cells (CTCs) with the EpCAM-based CellSearch system has prognostic significance in patients with metastatic breast cancer (MBC). The aim of this study was to explore potential differences in the detection and prognostic significance of CTCs in MBC according to immunohistochemical subtypes of breast cancer.MethodsCellSearch CTC counts were obtained from 154 MBC patients before first-line systemic treatment between November 2007 and August 2012. Patients were categorised in five subgroups according to immunohistochemical surrogate definitions of intrinsic subtypes in breast cancer based on hormone receptor status, HER2/neu status and histological grade. Differences in progression-free (PFS) and overall survival (OS) were assessed relative to the cut-off value of ?5 CTCs per 7.5?ml blood.ResultsNo significant differences were observed in the absolute CTC counts (P=0.120) or in CTC positivity rates according to ?1 and ?5 CTCs per 7.5?ml blood detection thresholds (P=0.165 and P=0.651, respectively) between immunohistochemical subtypes. However, very high CTC counts, defined as ?80 CTCs per 7.5?ml, were observed more frequently in patients with Luminal A and triple negative (TN) breast cancer (P=0.024). In the total study population, the presence of ?5 CTCs was the single most significant prognostic factor for both PFS and OS in multivariate analysis (P<0.001). A more limited prognostic impact, not reaching statistical significance, was observed in patients with HER2-positive disease as opposed to patients with Luminal A, Luminal B-HER2-negative and TN disease.ConclusionThe detection of EpCAM+CTCs was not clearly associated with any of the immunohistochemical subtypes of breast cancer in patients with MBC before first-line treatment. Potentially clinically relevant differences were however observed at very high CTC counts. Furthermore, our data suggest a lower prognostic significance of CTC evaluation in HER2-positive patients with MBC.

Project description:IntroductionIncreasing evidence supports the view that the detection of circulating tumor cells (CTCs) predicts outcomes of nonmetastatic breast cancer patients. CTCs differ genetically from the primary tumor and may contribute to variations in prognosis and response to therapy. As we start to understand more about the biology of CTCs, we can begin to address how best to treat this form of disease.MethodsNinety-eight nonmetastatic breast cancer patients were included in this study. CTCs were isolated by immunomagnetic techniques using magnetic beads labelled with a multi-CK-specific antibody (CK3-11D5) and CTC detection through immunocytochemical methods. Estrogen receptor, progesterone receptor and epidermal growth factor receptor (EGFR) were evaluated by immunofluorescence experiments and HER2 and TOP2A by fluorescence in situ hybridization. We aimed to characterize this set of biomarkers in CTCs and correlate it with clinical-pathological characteristics.ResultsBaseline detection rate was 46.9% ? 1 CTC/30 ml threshold. CTC-positive cells were more frequent in HER2-negative tumors (p = 0.046). In patients younger than 50 years old, HER2-amplified and G1-G2 tumors had a higher possibility of being nondetectable CTCs. Heterogeneous expression of hormonal receptors (HRs) in samples from the same patients was found. Discordances between HR expression, HER2 and TOP2A status in CTCs and their primary tumor were found in the sequential blood samples. Less that 35% of patients switched their CTC status after receiving chemotherapy. EGFR-positive CTCs were associated with Luminal tumors (p = 0.03).ConclusionsThis is the largest exploratory CTC biomarker analysis in nonmetastatic BC patients. Our study suggests that CTC biomarkers profiles might be useful as a surrogate marker for therapeutic selection and monitoring since heterogeneity of the biomarker distribution in CTCs and the lack of correlation with the primary tumor biomarker status were found. Further exploration of the association between EGFR-positive CTCs and Luminal tumors is warranted.

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Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer.

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Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer.

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