Establishment of an optimized CTC detection model consisting of EpCAM, MUC1 and WT1 in epithelial ovarian cancer and its correlation with clinical characteristics

Abstract

Objective Emerging studies have demonstrated the promising clinical value of circulating tumor cells (CTCs) for diagnosis, disease assessment, treatment monitoring and prognosis in epithelial ovarian cancer. However, the clinical application of CTC remains restricted due to diverse detection techniques with variable sensitivity and specificity and a lack of common standards. Methods We enrolled 160 patients with epithelial ovarian cancer as the experimental group, and 90 patients including 50 patients with benign ovarian tumor and 40 healthy females as the control group. We enriched CTCs with immunomagnetic beads targeting two epithelial cell surface antigens (EpCAM and MUC1), and used multiple reverse transcription-polymerase chain reaction (RT-PCR) detecting three markers (EpCAM, MUC1 and WT1) for quantification. And then we used a binary logistic regression analysis and focused on EpCAM, MUC1 and WT1 to establish an optimized CTC detection model. Results The sensitivity and specificity of the optimized model is 79.4% and 92.2%, respectively. The specificity of the CTC detection model is significantly higher than CA125 (92.2% vs . 82.2%, P=0.044), and the detection rate of CTCs was higher than the positive rate of CA125 (74.5% vs. 58.2%, P=0.069) in early-stage patients (stage I and II). The detection rate of CTCs was significantly higher in patients with ascitic volume ≥500 mL, suboptimal cytoreductive surgery and elevated serum CA125 level after 2 courses of chemotherapy (P<0.05). The detection rate of CTC EpCAM + and CTC MUC1+ was significantly higher in chemo-resistant patients (26.3% vs . 11.9%; 26.4% vs . 13.4%, P<0.05). The median progression-free survival time for CTC MUC1+ patients trended to be longer than CTC MUC1− patients, and overall survival was shorter in CTC MUC1+ patients (P=0.043). Conclusions Our study presents an optimized detection model for CTCs, which consists of the expression levels of three markers (EpCAM, MUC1 and WT1). In comparison with CA125, our model has high specificity and demonstrates better diagnostic values, especially for early-stage ovarian cancer. Detection of CTC EpCAM+ and CTC MUC1+ had predictive value for chemotherapy resistance, and the detection of CTC MUC1+ suggested poor prognosis.

Metastatic Melanoma: Liquid Biopsy as a New Precision Medicine Approach

“…The EPithelialImmunoSPOT (EPISPOT) assay (which exploits tumor expression of specific molecules) allows blood detection of even a single cell and has produced significant results in terms of cell concentration assessment in several solid tumors [ 68 , 69 ]. The assay discriminates tumor cells from “normal” cells by selectively recognizing the expression of the epithelial cell adhesion molecule (EpCAM) [ 70 ]. Unlike other solid tumors, such as adenocarcinomas of the colon and pancreas and hormone-refractory adenocarcinomas of the prostate, melanoma has non-high levels of EPCAM protein [ 71 , 72 ].…”

The Role of Circulating Tumor Cells in Ovarian Cancer Dissemination

“…Haematogenous spread of cancer cells in ovarian carcinomas is believed to be a rather rare event. Still, this phenomenon is well documented [ 7 , 8 , 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 23 , 24 , 26 , 32 , 43 , 50 , 69 , 70 , 71 ], and the presence of CTCs in blood was recently shown to correlate with tumor stage, presence of ascites, tumor debulking, disease recurrence, shorter OS and PFS [ 7 , 18 , 23 , 24 , 43 , 50 , 69 ].…”

“…A number of studies have also evaluated the utility of CTCs as a biomarker of chemotherapy response in OC [ 7 , 11 , 12 , 18 , 43 , 69 , 71 ]. It has been demonstrated that chemotherapy leads to a rapid decline in CTCs count.…”

“…Other researchers focus on the expression of markers, including EpCAM, MUC-1, HER-2, and WT1, and claim that such CTCs’ gene expression profiling makes it possible to predict the likelihood of chemotherapy resistance and evaluate prognosis as well as the potential to develop novel molecular targets for specific biological therapies. Zhang et al also prove that using this methodology, CTCs may be detected in the blood of patients in all stages of EOC disease, while Aktas et al and Wang et al document that the occurrence of CTCs significantly correlates with shorter OS before surgery but also after chemotherapy [ 43 , 47 , 71 ].…”

Purification of Circulating Tumor Cells Based on Multiantibody-Modified Magnetic Nanoparticles and Molecular Analysis toward Epithelial Ovarian Cancer Detection

“…The significant heterogeneity of EOC primary tumors makes it more challenging to isolate CTCs from EOC patients’ blood, especially since EOC CTCs are highly heterogeneous with variable expression levels of epithelial cell adhesion molecule (EpCAM). , Moreover, CTCs that undergo the epithelial-to-mesenchymal transition (EMT) progress may lose EpCAM expression, − further complicating the isolation of EOC CTCs by traditional EpCAM-dependent methods. To overcome the issue, our group , and others − have developed a multimarker capture strategy targeting multiple surface proteins for EOC CTC isolation, including N-cadherin ,, and other epithelial cell surface antigens, e.g., MUC1 . N-cadherin is a marker of mesenchymal phenotype associated with the EMT, which is known to play a critical role in tumor invasion in several cancer types, including ovarian cancer …”