Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

Abstract

Breast cancer metastasis is the leading cause of cancer deaths in women and is difficult to combat due to the long periods in which disseminated cells retain a potential to be re-activated and start the relapse. Assessing the number and molecular profile of circulating tumor cells (CTCs) in breast cancer patients, especially in early breast cancer, should help in identifying the possibility of relapse in time for therapeutic intervention to prevent or delay recurrence. While metastatic breast cancer is considered incurable, molecular analysis of CTCs still have a potential to define particular susceptibilities of the cells representing the current tumor burden, which may differ considerably from the cells of the primary tumor, and offer more tailored therapy to the patients. In this review we inspect the routes to metastasis and how they can be linked to specific features of CTCs, how CTC analysis may be used in therapy, and what is the current status of the research and efforts to include CTC analysis in clinical practice.There are two main hypotheses describing cancer dissemination: linear progression, according to which, metastatic potential is gained gradually, and the whole process proceeds in steps and needs time, and parallel progression, according to which dissemination takes place early on, even before clinical manifestation of the tumor [6,7] (Figure 1). In the linear progression model, the evolving primary tumor gives rise to metastases due to increasingly aggressive and invasive phenotypes of the subclones of tumor cells. This model is in agreement with the postulated role of the epithelial-to-mesenchymal transition (EMT) in cancer and assumes active degradation of the stroma and migration into blood vessels by the motile, invasive single cells that broke loose from the epithelial monolayer. In contrast to that, parallel progression postulates intravasation by passive shedding, which may take place shortly after the angiogenic switch, occurring during the early, pre-invasive stage of tumor development [8,9].

The Role of Circulating Tumor Cells in Chemoresistant Metastatic Breast Cancer

“…One of the most important steps is epithelial-to-mesenchymal transition (EMT), a process in which tumor epithelial cells, which are immobile, lose their epithelial features and gain mesenchymal properties, including the ability to migrate, invade, and disseminate [ 6 ]. This is in accordance with linear progression [ 5 ].…”

“…Linear progression is a step-by-step process in which metastatic potential is achieved progressively. Parallel progression has been demonstrated so far in human epidermal growth factor receptor 2 (Her-2)-positive tumors and shows that dissemination of cancer cells occurs early on before the primary tumor becomes clinically evident (the first step of metastasis takes place at the same time the primary tumor develops) [ 5 ].…”

“…Because of all the changes mentioned above, CTCs found in peripheral blood can express different features, such as stem cell, epithelial, or mesenchymal features [ 6 ]. Circulating tumor cells result from either detaching from the primary tumor and moving via blood flow to distant sites where they will give rise to metastasis, or forming as a result of the CSC EMT [ 5 ]. CSCs have been identified between CTCs, showing their ability to spread to distant sites through the blood flow [ 6 ].…”

Slug and E-Cadherin: Stealth Accomplices?

“…In these contexts, the E-cadherin + cell may not be expressing high but still functionally relevant levels of E-cadherin. As hybrid E/M phenotypes in circulating tumor cells (CTCs) reveal strong association with tumor-initiation potential and metastasis (Fabisiewicz et al, 2020 ), Slug + /E-cadherin + cells are likely contributors to disseminating CTCs as well, perhaps in part through inhibition of anoikis or E-cadherin's potential to support stemness promoting signaling pathways.…”

Perspectives on liquid biopsy for label‐free detection of “circulating tumor cells” through intelligent lab‐on‐chips

“…In the last 10 years, scientific publications on CTCs triplicated, reaching more than 23.000 items by the end of 2019, 6 and pointing out to a growing interest in the clinical potential of their identification 7 . CTCs clinical trials are currently employed in breast, prostate, lung, and colorectal cancers 8‐11 . The challenge is the possibility to extend the clinical valence of CTCs analysis to other types of cancers.…”