circulating tumor cells in breast cancer
Saturday 25 February 2012
CTCs in breast cancer
Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis.
CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease.
Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential.
Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation.
Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment.
CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis. (24240660)
In breast cancer, the majority of patients present with local disease, and the primary lesions are generally removed by surgery prior to the development of clinically detectable metastases.
Circulating tumor cells (CTCs) represent cells that have already escaped the primary tumor site and thus may be an appropriate candidate as biomarkers. These cells have a high level of agreement (82%–89%) at the level of HER2 status with the primary tumor; however, concordances for ER and PR status are lower (41% and 45%, respectively). These observations suggest that CTCs may act as a proxy for the subset of cells within the primary tumor capable of leading to disease recurrence.
Interestingly, characterization of CTCs shows that subpopulations of these cells are enriched for stem cell and EMT markers, suggesting that they arise from specific subgroups within the tumor. Further investigations of the correlation between markers of CTCs and those of distant metastases are expected to clarify the origin of CTCs and how their features influence disease course.
Brain metastatic breast cancer (BMBC) is uniformly fatal and increasing in frequency. Despite its devastating outcome, mechanisms causing BMBC remain largely unknown. The mechanisms that implicate circulating tumor cells (CTCs) in metastatic disease, notably in BMBC, remain elusive.
In epithelial cell adhesion molecule (EpCAM)–negative CTCs, it has been identified a potential signature of brain metastasis comprising “brain metastasis selected markers (BMSM)” HER2+/EGFR+/HPSE+/Notch1+. (23576814)
These CTCs—which are not captured by the CellSearch platform because of their EpCAM negativity—were analyzed for cell invasiveness and metastatic competency in vivo. CTC lines expressing the BMSM signature were highly invasive and capable of generating brain and lung metastases when xenografted in nude mice. (23576814)
Notably, increased brain metastatic capabilities, frequency, and quantitation were detected in EpCAM− CTCs overexpressing the BMSM signature. The presence of proteins of the BMSM CTC signature was also detected in the metastatic lesions of animals. (23576814)
HER2 - ERBB2
In breast cancer, ERBB2 is one of the most prominent targets for systemic therapy (Wan et al, 2013). Currently, all patients are stratified to trastuzumab (or other anti-ERBB2 therapies) by primary tumor tissue analysis only.
Recent reports, however, have shown that ERBB2-positive CTCs can be detected also in patients with ERBB2-negative primary tumors (Riethdorf et al, 2010; Ignatiadis et al, 2011; Hartkopf et al, 2012), suggesting that there might exist additional patients that could benefit from ERBB2-directed therapies.
Ongoing clinical studies (e.g., DETECT III (NCT01619111) trial in Germany and CTC-TREAT (NCT01548677) trial in Europe) will reveal whether the ERBB2 status of CTCs may predict response to ERBB2-directed therapies (Bidard et al, 2013a,b).
Another example for the use of CTCs as predictive biomarkers is the presence of ER-negative CTCs in breast cancer patients with ER-positive primary tumors (Babayan et al, 2013).
ER is the most common therapeutic target in breast cancer, and 70–80% of patients have ER-positive primary tumors. However, ER-negative CTCs that may have escaped hormonal therapy to block ER-mediated growth frequently occur in these patients.
Pantel K, 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309663/
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