Clinical Implications of Circulating Tumor Cells of Breast Cancer Patients: Role of Epithelial–Mesenchymal Plasticity

Abstract

There is increasing interest in circulating tumor cells (CTCs) due to their purported role in breast cancer metastasis, and their potential as a “liquid biopsy” tool in breast cancer diagnosis and management. There are, however, questions with regards to the reliability and consistency of CTC detection and to the relationship between CTCs and prognosis, which is limiting their clinical utility. There is increasing acceptance that the ability of CTCs to alter from an epithelial to mesenchymal phenotype plays an important role in determining the metastatic potential of these cells. This review examines the phenotypic and genetic variation, which has been reported within CTC populations. Importantly, we discuss how the detection and characterization of CTCs provides additional and often differing information from that obtained from the primary tumor, and how this may be utilized in determining prognosis and treatment options. It has been shown for example that hormone receptor status often differs between the primary tumor and CTCs, which may help to explain failure of endocrine treatment. We examine how CTC status may introduce alternative treatment options and also how they may be used to monitor treatment. Finally, we discuss the most interesting current clinical trials involving CTC analysis and note further research that is required before the breast cancer “liquid biopsy” can be realized.

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

“…EMT indeed provides epithelial tumor cells with enhanced migratory, invasive, and survival abilities that participate in the liberation of CTCs into the circulation (1,2,4,5). A variety of EMT-inducing extracellular signals and signaling pathways have been shown to converge on the expression of EMT transcription factors including the Snail and ZEB families, Twist, and E47 (6)(7)(8).…”

“…The contribution of epithelial-to-mesenchymal transitions (EMT) to CTCs biology has generated much interest (1)(2)(3)(4)(5). EMT indeed provides epithelial tumor cells with enhanced migratory, invasive, and survival abilities that participate in the liberation of CTCs into the circulation (1,2,4,5).…”

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

“…The development of highly sensitive methods for detecting ctDNA is responsible for its emergence in the clinic and synergizes with tumor biopsy genomic analysis, because monitoring for tumor-specific DNA enhances the technique's sensitivity. Analyzing CTCs is another promising diagnostic approach because these cells contain a wealth of information about a patient's tumor biology (92,93,98). Creating a CTC diagnostic is challenging from many reasons-CTCs are extremely rare as well as heterogeneous.…”

“…More recently, direct methods of CTC detection are emerging (ISET, RareCells CO; ScreenCell, Co.). To date, a universal approach to detect CTCs is elusive but many new methodologies are being assessed in the clinic (92,98). The next frontier for the noninvasive biopsy approach is for surveillance in the adjuvant and posttreatment settings.…”

Circulating tumor cells in breast cancer

“…It may also acquire the characteristics of quiescence and self-renewal, thus behaving as a cancer stem cell (most commonly identified by CD44+/CD24− or ALDH1 expression). [13] Now, DTCs are also recognized as a subtype of CTC.…”