Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients

Austrup, Frank; Uciechowski, Peter; Eder, Claudine; Böckmann, Beatrix; Suchy, Bernhard; Driesel, Gerhard; Jäckel, Sven; Kusiak, I; Grill, H. J.; Giesing, Michael

doi:10.1054/bjoc.2000.1501

Cited by 41 publications

(26 citation statements)

References 30 publications

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“…Cancer cell fractions were isolated from 7.5 mL blood, and molecular analysis was carried out in two populations of circulating disease cells, namely EPCAM + CECs and CCCs. Both classes of circulating tumour cells have been enriched from mononucleated cells (MNCs) as described recently [ 4,7,8 ] . As published by our laboratory in 2000 [ 8 ] , spiking experiments in blood with aggregates or individual, dispersed EPCAM + epithelial cells from SW480 cultures have shown that the two cell types to be isolated represent two different classes of circulating disease cells.…”

Section: Methodsmentioning

confidence: 99%

“…2 ). The methods were published by our laboratory in detail in 2000 [ 8 ] . Briefl y, clusters were captured in the fi ltrate matrix whereas individual cells would pass through the matrix and appear in the fi ltrate; therefore, scattered non-aggregated SW 480 cells were applied to determine their presence in CCCs ( Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…Patients at the metastatic stage were compared with patients without tumour relapse ( n = 77). [ 8 ] .…”

Section: Methodsmentioning

confidence: 99%

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Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

Giesing¹,

Driesel²,

Molitor³

et al. 2012

BJU International

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What's known on the subject? and What does the study add?The role of circulating cancer cells in metastogenesis is generally accepted. Two forms of these cells have been reported in a number of studies, cancer cell clusters (CCCs) and individual epithelial cancer cells. Clusters appear at higher frequencies in the blood. CCCs have been reported to be rich in vimentin and poor in E‐cadherin expression The resulting epithelial to mesenchymal transition, a prerequisite for metastasis formation, occurs in CCCs. We have developed a new set of biomarkers, namely the antioxidant genes GPX1, SOD2 and TXNRD1, specific to cell trafficking in the blood.Firstly, the study shows that diagnosis of distant metastases is feasible by applying molecular phenotyping with a five gene test that has 94% sensitivity and 81% accuracy. Again SOD2 and GPX1 showed the highest sensitivities. Secondly, the study shows the efficacy of palliative chemotherapy in clearing the blood of CCCs overexpressing diagnostic genes. Clinically the overall lifespan ranged from 5 to 99 months under taxotere. We aimed to investigate the molecular reasons and found that MDR1 overexpression worsened survival by 31%. To the best of our knowledge, this is the first study to show the clinical impact of drug targeting and the counter‐effect of drug resistance in CCCs on overall survival. The findings may, therefore, add a novel tool for clinicians in tailoring therapies individually.OBJECTIVES To find the molecular phenotype in circulating cancer cells from patients with prostate cancer (PCa) in order to predict distant metastases. To determine genes affecting the study endpoints of overall survival and time to progression. PATIENTS AND METHODS Twenty‐five urologists in several clinics participated in the study, with 51 patients with metastatic and 77 with non‐metastatic PCa. Molecular analysis was carried out in two forms of circulating cancer cells, cancer cell clusters (CCCs) and individual epithelial cancer cells (CECs). Gene expression was studied using real‐time reverse‐transcriptase PCR. Cycle threshold values were normalized with glyceraldehyde 3‐phosphate dehydrogenase in cancer cells and mononucleated cells, yielding comparative specific expression values from the relative quantification method with the help of the standard curve method for each patient and each gene locus. RESULTS Preclinical validation was performed using aggregated and non‐aggregated SW480 cells showing the independence of CCCs and CECs. Prediction of metastases was achieved with five genes showing the highest sensitivity, SOD2, GPX1, AR, cyclin B and bFGF. The following results were obtained: 94% sensitivity, 65% specificity, 76% positive predictive value and 89% negative predictive value. The prevalence was 63%. Test accuracy was 81% with an odds ratio of 32 (P < 0.001). Overall survival was worsened by preceding chemotherapies when leaving insufficient GPX1 clearance in blood. Drug resistance genes were found to worsen the endpoints, among them MDR1 (P = 0.003; hazard ratio: 1.31; 95% CI: 1.09–1.58). CONCLUSIONS SOD2, GPX1 and AR represent a novel biomarker set for circulating cancer cells (clusters and scattered individual cells) in PCa. The clinical usefulness of these biomarkers ranges from the prediction of clinical tumours to disease prognostication, therapy monitoring and therapy outcome prediction (hormonal therapies, chemotherapies). The presence of CCCs and CECs after batch isolation allows the addition of genes for intensive studies, e.g. drug resistance.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

Giesing¹,

Driesel²,

Molitor³

et al. 2012

BJU International

View full text Add to dashboard Cite

show abstract

“…Furthermore, a better understanding CTC biology is likely to reveal previously unavailable information about the mechanisms of metastasis. For example, genetic changes can be detected in CTCs, including abnormal telomerase activity (Soria et al, 1999), allelic loss and/or amplification of multiple oncogenes not seen in normal control populations (Austrup et al, 2000), and aneuploid changes in cellular chromosome content based upon FISH analysis similar to those seen in the primary tumour (Fehm et al, 2002). Additionally, cancer-associated protein expression by CTCs can be detected, such as HER2 (Figure 2) (Hayes et al, 2002).…”

Section: Future Directionsmentioning

confidence: 99%

The measurement and therapeutic implications of circulating tumour cells in breast cancer

2005

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Circulating tumours cells (CTCs) represent an important biologic link in the spread of breast cancer from primary to metastatic disease. CTCs are strong predictors of prognosis in patients with metastatic breast cancer. Research to date has focused on development of methods with adequate sensitivity and specificity to reproducibly identify these rare events. Future research will focus on the biologic phenotypes of these cells with goals to understand mechanisms of metastasis, to identify novel therapeutic targets, and to monitor response to therapy.

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“…the detection of circulating tumor cells (ctcs) in the peripheral blood of patients with different neoplastic diseases has been used as an early potential marker of the metastatic spread of malignant cells in the bloodstream (2)(3)(4)(5)(6), and is, therefore, considered a sign of poor prognosis (7)(8)(9)(10)(11). In fact, the malignant nature of ctcs has been established in previous studies by the identification of tumor-specific chromosomal aberrations (2) and other genetic changes (12,13), as well as by their in vitro growth with cancer cell-like behaviour (14). In addition, in several studies the number of ctcs detected seems to correlate with the aggressiveness of different advanced malignancies, such as breast (9,15,16), prostate (17,18) and colorectal cancer (19).…”

Section: Introductionmentioning

confidence: 99%

Comparison of three distinct methods for the detection of circulating tumor cells in colorectal cancer patients

et al. 2011

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Abstract. the detection of circulating tumor cells (ctcs) has considerable utility in the clinical management of patients with solid cancers. However, the phenotypic heterogeneity of ctcs and their low numbers in the bloodstream of patients means that no standardized detection method currently exists for these cells. this, together with differences in pre-analytical sample processing, has led to the collection and accumulation of inconsistent data among independent studies. Here, we compare the ability of three methods to detect ctcs in the blood of colorectal cancer patients. specifically, different aliquots of the same blood sample were screened for the presence of ctcs by a multimarker rt-pcr assay, the standardized cellsearch assay and dHplc-based gene mutation analysis. In the population tested, none of the blood samples analysed appeared to be positive by all three methods. of the samples, 75% were positive for the presence of ctcs by the rt-pcr method. only 20% were positive by the cellsearch assay, while 14.3% of samples displayed gene mutations consistent with the presence of ctcs when the dHplc method was applied. the samples which were positive for ctcs by the cellsearch assay did not overlap with those that were positive by dHplc. Interestingly, however, all of these samples were positive when assessed by rt-pcr. conversely, of the samples that resulted negative by rt-pcr analysis, none appeared to be positive by either of the other methods. these data, therefore, indicate that of the three methods tested, the multimarker rt-pcr assay provides maximal probability of ctc detection. Here, we present the preliminary results of an ongoing clinical study. Future follow-up involving detection of ctcs in the blood of colorectal cancer patients using these three distinct methods will allow us to verify whether either a single method, or a combination of different assays, is necessary to uncover further prognostic significance of circulating tumor cells.

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Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients

Cited by 41 publications

References 30 publications

Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

The measurement and therapeutic implications of circulating tumour cells in breast cancer

Comparison of three distinct methods for the detection of circulating tumor cells in colorectal cancer patients

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