Abstract
The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial–mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively.
Highlights
Breast cancer is the most common cancer in women and metastasis is the major cause of the mortality of patients [1]
epithelial cell adhesion molecule (EpCAM)-based assay is unable to detect circulating tumor cells (CTCs) with low or absent EpCAM expression and other circulating tumor associated cells, including stem cell-like tumor cells and CTCs undergoing epithelial–mesenchymal transition (EMT), which were identified by stem cell and EMT markers in early and metastatic breast cancer patients [11,12,13]; and cancer associated macrophage-like cells (CAMLs), which are specialized phagocytic myeloid cells found in the peripheral blood of patients with solid tumors including breast cancer, but not in healthy individuals [14]
Recent studies showed that CAMLs were found in blood of cancer patient and their presence was associated with the stage of disease as a blood based biomarker [14]
Summary
Breast cancer is the most common cancer in women and metastasis is the major cause of the mortality of patients [1]. The treatment for aggressive metastatic breast cancer (MBC) remains challenging as the intrinsic clinical subtypes, biological features of the metastases, and tumor heterogeneity including circulating tumor cells (CTCs) all contribute to the resistance to current standard strategies [2]. Current treatments mainly rely on expression profiles of the primary tumor or metastatic tumor biopsy. The expression profiles may change during or after adjuvant treatments or targeted therapies. A real-time tumor assay using a liquid biopsy that focuses on the analysis of CTCs and circulating tumor DNA (ctDNA) has been actively investigated as new therapeutic targets and drug resistance mechanisms in cancer patients [3,4]. Blood-based testing using a non-invasive and complementary approach has the potential to enhance therapeutic efficacy and improve the outcome of MBC patients
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