Schwarzenbach H et al. (FEB 2009)
Clinical cancer research : an official journal of the American Association for Cancer Research 15 3 1032--8
Cell-free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer.
PURPOSE: Circulating cell-free DNA in the blood of cancer patients harbors tumor-specific aberrations. Here, we investigated whether this DNA might also reflect the presence of circulating tumor cells (CTC). EXPERIMENTAL DESIGN: To identify the source of cell-free DNA in blood, plasma derived from 81 patients with prostate cancer was examined for CTCs and cell-free DNA. An epithelial immunospot assay was applied for detection of CTCs, and a PCR-based fluorescence microsatellite analysis with a panel of 14 polymorphic markers was used for detection of allelic imbalances (AI). RESULTS: The plasma DNA levels significantly correlated with the diagnosis subgroups of localized (stage M0, n = 69) and metastasized prostate cancer (stage M1, n = 12; P = 0.03) and with the tumor stage of these patients (P textless 0.005). AI was found on cell-free DNA in plasma from 45.0% and 58.5% of M0 and M1 patients, respectively. Detection of CTCs showed that 71.0% or 92.0% of the M0 and M1 patients harbored 1 to 40 CTCs in their blood, respectively. The occurrence of CTCs correlated with tumor stage (P textless 0.03) and increasing Gleason scores (P = 0.04). Notably, significant associations of the number of CTCs with the AI frequencies at the markers D8S137 (P = 0.03), D9S171 (P = 0.04), and D17S855 (P = 0.02) encoding the cytoskeletal protein dematin, the inhibitor of the cyclin-dependent kinase CDKN2/p16 and BRCA1, respectively, were observed. CONCLUSIONS: These findings show, for the first time, a relationship between the occurrence of CTCs and circulating tumor-associated DNA in blood, which, therefore, might become a valuable new source for monitoring metastatic progression in cancer patients.
Gerges N et al. (JAN 2010)
British medical bulletin 94 49--64
New technologies for the detection of circulating tumour cells.
The vast majority of cancer-related death is due to the metastatic spread of the primary tumour. Circulating tumour cells (CTC) are essential for establishing metastasis and their detection has long been considered as a possible tool to assess the aggressiveness of a given tumour and its potential of subsequent growth at distant organs. Conventional markers are not reliable in detecting occult metastasis and, for example, fail to identify approximately 40% of cancer patients in need of more aggressive or better adjusted therapies. Recent studies in metastatic breast cancer have shown that CTC detection can be used as a marker for overall survival and assessment of the therapeutic response. The benefits of CTC detection in early breast cancer and other solid tumours need further validation. Moreover, optimal CTC detection techniques are the subject of controversy as several lack reproducibility, sensitivity and/or specificity. Recent technical advances allow CTC detection and characterization at the single-cell level in the blood or in the bone marrow. Their reproducibility propels the use of CTC in cancer staging and real-time monitoring of systemic anticancer therapies in several large clinical trials. CTC assays are being integrated in large clinical trials to establish their potential in the management of cancer patients and improve our understanding of metastasis biology. This review will focus on the techniques currently used, the technical advancements made, the limitations of CTC detection and future perspectives in this field.
Mostert B et al. (AUG 2009)
Cancer treatment reviews 35 5 463--74
Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer.
The enumeration of circulating tumor cells has long been regarded as an attractive diagnostic tool, as circulating tumor cells are thought to reflect aggressiveness of the tumor and may assist in therapeutic decisions in patients with solid malignancies. However, implementation of this assay into clinical routine has been cumbersome, as a validated test was not available until recently. Circulating tumor cells are rare events which can be detected specifically only by using a combination of surface and intracellular markers, and only recently a number of technical advances have made their reliable detection possible. Most of these new techniques rely on a combination of an enrichment and a detection step. This review addresses the assays that have been described so far in the literature, including the enrichment and detection steps and the markers used in these assays. We have focused on breast cancer as most clinical studies on CTC detection so far have been done in these patients.
V. Appierto et al. (APR 2017)
Seminars in cancer biology
How to study and overcome tumor heterogeneity with circulating biomarkers: The breast cancer case.
Breast cancer ranks first among female cancer-related deaths in Western countries. As the primary tumor can often be controlled by surgical resection, the survival of women with breast cancer is closely linked to the incidence of distant metastases. Molecular screening by next generation sequencing highlighted the spatial and temporal heterogeneity of solid tumors as well as the clonal evolution of cancer cells during progression and under treatment pressure. Such findings question whether an optimal assessment of disease progression and a screening for druggable mutations should be based on molecular features of primary or recurrent/metastatic lesions and therefore represent a crucial element for failure or success of personalized medicine. In fact, new targeted therapies may induce only short-term benefit annulled by the emergence of resistant clones with new driver mutations which would need to be rapidly and reliably identified. Serial tissue sampling is therefore essential but, unfortunately, also represents a problem since biopsies from solid lesions, which are invasive and potentially painful and risky, cannot be easily repeatedly sampled, are inaccessible or may not fully reflect tumor heterogeneity. The need to early detect and strike this moving target" is now directing the scientific community towards liquid biopsy-based biomarkers which include circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA) can be repeatedly assessed through non-invasive and easy-to-perform procedures and may act as reliable read-outs of functional and molecular features of recurrent/metastatic lesions. In this review we summarize the outcome of CTCs and ctDNA in breast cancer with special reference on their role on unveiling and overcoming tumor heterogeneity on their potential relevance for tumor surveillance and monitoring and for the selection of therapeutic options. Finally we propose integration between blood-based molecular and clinical approaches for monitoring disease progression according to the specific pattern of recurrence of the most aggressive breast cancer molecular subtypes."