Mesenchymal phenotype of circulating tumor cells is associated with distant metastasis in breast cancer patients

Abstract

In this study, we investigated the relationship between the epithelial–mesenchymal transition phenotype of circulating tumor cells (CTCs) and distant metastasis in breast cancer patients. We analyzed the expression of epithelial (epithelial cell adhesion molecule, cytokeratin [CK]8, CK18 and CK19) and mesenchymal (vimentin and TWIST1) markers in CTCs from a large cohort of Chinese breast cancer patients (N=1083) using Canpatrol™ CTC assays. We identified CTCs in 84.9% (920/1083) of the breast cancer patients enrolled in this study. Among these 920 patients, 547 showed epithelial CTCs, 793 showed biphenotypic CTCs and 516 showed mesenchymal CTCs. Receiver operating characteristic (ROC) curves demonstrated circulation of both biphenotypic and mesenchymal CTCs (area under ROC curve value: 0.728; sensitivity: 68.7% and specificity: 71.6%) in patients was associated with distant metastasis. These findings demonstrate that the epithelial–mesenchymal transition phenotype of CTCs is a potential biomarker predictive of distant metastasis in breast cancer.

Prospective study of the relevance of circulating tumor cell status and neoadjuvant chemotherapy effectiveness in early breast cancer

“… CTC assessments have been applied in multiple steps of tumor treatment throughout early relapse, therapeutic efficacy, resistance occurrence, and selection of targeted drugs . Being regarded as the pre‐stadium to initiate metastases in distant organs, CTC populations in the blood of carcinoma patients contain cells with a clonal capacity . Enumeration of CTCs during BC treatment has been used as a biomarker to reflect effective doses of antitumor agents, and CTCs may also serve as a monitor of drug susceptibility as tumors acquire mutations accompanying treatment in genes such as PIK3CA and estrogen receptor gene (ESR1) .…”

A disintegrin and metalloprotease 23 hypermethylation predicts decreased disease‐free survival in low‐risk breast cancer patients

“…CTC with mesenchymal phenotype can be detected in the peripheral circulation of BC patients through mRNA expression of EMT‐inducing transcription factors . Their presence in BC patient peripheral blood was associated with worse prognosis (Mego et al, in preparation). Herein, we have shown an association between ADAM23 promoter methylation and mesenchymal CTC, detected by the above‐mentioned method.…”

“…47 CTC with mesenchymal phenotype can be detected in the peripheral circulation of BC patients through mRNA expression of EMT-inducing transcription factors. 42,48,49 Their presence in BC patient peripheral blood was associated with worse prognosis 25,26 (Mego et al, in preparation). Herein, we have…”

“…Therefore, commonly used CTC identification strategies exclusively based on epithelial marker detection omit patients who have the most aggressive CTC subpopulations with the mesenchymal phenotype in their peripheral blood . It has been shown in several studies that mesenchymal CTC presence strongly correlates with worse prognosis and risk of developing distant metastases compared to epithelial CTC …”

“…24 It has been shown in several studies that mesenchymal CTC presence strongly correlates with worse prognosis and risk of developing distant metastases compared to epithelial CTC. 25,26 A Disintegrin And Metalloprotease (ADAM) proteins, consisting of multiple domains, operate in various processes such as ectodomain shedding of growth factors, cytokines or receptors, cleavage and remodeling of extracellular matrix proteins and adhesive activities through their disintegrin and cysteine-rich domains. 27 Among 21 human ADAM proteins, ADAM23 belongs to a non-catalytic group because of its inactive metalloprotease domain.…”