Abstract CN3-1: Detection, clinical relevance, and molecular characteristics of circulating tumor cells
Authors: Pantel Klaus 
Published: January 2011

Abstract
Early spread of tumor cells is usually undetected even by high-resolution imaging technologies, which prevents effective early intervention. However, sensitive immunocytochemical and molecular assays have become available and enable now the specific detection of 'occult' metastatic tumor cells even at the single-cell stage. These technologies provide the potential to track systemic tumor cell dissemination in cancer patients.
Disseminated tumor cells (DTC) have been frequently detected in the bone marrow (BM) of patients with diverse types of solid tumors, suggesting that the BM might be a preferred reservoir for blood-borne DTC. Whether DTC use this environment as niche to persist in a dormant state over many years before they disseminate into other organs or grow out in the BM into overt metastases is subject of current investigations. To understand this stage of dormancy and the conditions enabling DTC to reactivate growth as well as to identify the founder cells of overt metastases (“metastatic stem cells”) are some of the most important and challenging research areas. The observed correlation between DTC in BM and local relapse in breast cancer support the recent experimental findings in mice that these cells might re-circulate back to their primary organ site. If BM is a particular reservoir for DTC, drugs targeting the BM-tumor interaction (e.g., bisphosphonates or antibodies to the RANK ligand) may be efficient to prevent metastatic or even local relapse.
In clinical practice, peripheral blood drawings are more acceptable than BM aspirations in solid tumor patients. Many research groups are therefore assessing the clinical value of circulating tumor cells (CTC) for therapy monitoring, which has provided significant prognostic information in metastatic breast cancer, and seems to be superior over conventional imaging methods for response evaluation. The clinical utility of these findings are now being prospectively addressed in a randomized trial SWOG S0500 led by the Southwest Oncology group (www.cancer.gov/clinicaltrials/SWOG-S0500). While the prognostic significance of CTC could be demonstrated for metastatic breast, colorectal or prostate cancer patients, studies on the impact of CTC in early stage cancer patients are still ongoing. Thus far, encouraging results on monitoring of CTC during primary systemic or adjuvant chemotherapy in breast cancer patients were obtained.
Phenotypical and molecular characterization of DTC/CTC will be essential to identify new diagnostic and therapeutic targets and contribute to more “tailored” and personalized anti-metastatic therapies (www.dismal-project.eu). The identification of therapeutically relevant targets may contribute to a better selection of cancer patients for targeted therapies. In breast cancer, HER2 has become the most prominent target for biological therapy with a humanized anti-HER2 monoclonal antibody. Currently, all patients are stratified to trastuzumab therapy by primary tumor analysis only. However, recent reports have shown that HER2-positive DTC/CTC can be detected also in patients with HER2-negative primary tumors (Pantel et al NRC 2008), suggesting that additional patients could benefit from HER2-directed therapies. Ongoing clinical studies will reveal whether the HER2 status of CTC may predict response to trastuzumab or other HER2-directed therapies. These results may have also an important impact on the future design of clinical trials testing other promising targets expressed on micrometastatic cancer cells.
In conclusion, information obtained from DTC/CTC analyses might be useful to obtain prognostic information, monitor the efficacy of anti-cancer therapies, identify therapeutic targets on metastatic cells and provide new insights into the biology of metastatic progression in cancer patients.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN3-1