Presence of EpCAM‐positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma

Abstract

Current imaging technologies do not sufficiently detect micrometastasis and therefore do not allow adequate stratification of patients with hepatocellular carcinoma (HCC) for curative or systemic therapy. In HCC, presence of stem cell-like, epithelial cell adhesion molecule (EpCAM)-positive cells correlates with tumor aggressiveness and formation of metastasis. Therefore, we investigated the prognostic relevance of EpCAM-positive circulating tumor cells (CTCs) in patients with HCC. Blood from 78 patients (19 patients in the control cohort and 59 patients with HCC) was tested for CTCs with the CellSearch TM system. Correlation analysis to overall survival (OS), the Barcelona Clinic Liver Cancer (BCLC) staging system, macroscopic and microscopic vascular invasion and alpha-fetoprotein (AFP) levels were performed. We detected 1 CTC in 18=59 HCC patients and in 1=19 patients with cirrhosis or benign hepatic tumor (p 5 0.026). OS was significantly shorter (460 vs. 746 days) in the CTC-positive cohort (p 5 0.017). Comparing BCLC stages, significant differences in CTC detection rates were also observed: BCLC stages A 1=9, B 6=31 and C 11=19 (p 5 0.006). Ten of 18 patients with macroscopic and 10=16 patients with microscopic vascular invasion exhibited positive findings in CTC testing (p 5 0.004 and p 5 0.006). Furthermore, CTC results correlated to AFP (cutoff > 400 ng=mL) levels (p 5 0.050). Our study demonstrates frequent presence of EpCAM-positive CTC in patients with intermediate or advanced HCC and its prognostic value for OS with possible implications for future treatment stratification.Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, has a rising incidence in Western countries, and is ranked third in global cancer-related mortality. 1-7 Most cases result from cirrhosis of the liver or chronic viral hepatitis. It is believed that alcoholic liver disease and nonalcoholic steatohepatitis (NASH) will play a dominant role as underlying etiology in Western countries in the near future. 4 Treatment of patients with confirmed HCC is based on the Barcelona Clinic Liver Cancer (BCLC) staging system. Patients with early-stage HCC (BCLC stage A) are selected for curative resection, local ablative therapy or orthotopic liver transplantation. Unfortunately, most patients in Western countries are diagnosed in an advanced stage (BCLC stage C), characterized by vascular invasion, metastases and an impaired performance status (PS 1-2). 8,9 The key problem in curative treatment in HCC (BCLC stage A) is recurrence after curative therapy. This might be owing to undetectable micrometastasis at initial staging. Therefore, it would be pivotal to rule out a possible metastatic dissemination at the time of diagnosis, including micrometastasis or potential "metastasis-initiating" circulating tumor cells (CTCs) in order to evaluate the true benefit of curative treatment. Furthermore, it is important to determine to what extent BCLC stage B patients (HCC limited to the liver) without CTC might benefit from curative th...

Prognostic impact of circulating tumor cells in patients with ampullary cancer

“…A similar result was obtained in a large prospective trial using the CellSearch system in patients with breast cancer (Rack et al, 2014). Studies have also evaluated the prognostic significance of CTC in hepatocellular carcinoma (HCC); a study using the CellSearch system showed that ≥1 CTC per sample was associated with shorter OS on univariate analysis of 59 patients with HCC ( p  = 0.02) (Schulze et al, 2013). A landmark study of CTC using the CellSearch system showed that CTCs were independent predictors of OS in patients with cholangiocarcinoma (Yang et al, 2016).…”

Gene Knockdown by EpCAM Aptamer–siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells

“…In one study, about 2/3 of TNBCs, presumably the basal-like subtype, stained strongly for EpCAM (25). The number of EpCAM þ circulating cells is linked to poor prognosis in breast cancer (32)(33)(34)(35)(36). An EpCAM antibody has been evaluated clinically for epithelial cancers, but had limited effectiveness on its own (37)(38)(39).…”

“…An EpCAM antibody has been evaluated clinically for epithelial cancers, but had limited effectiveness on its own (37)(38)(39). EpCAM expression identifies circulating tumor cells in an FDA-approved method for monitoring metastatic breast, colon, and prostate cancer treatment (32)(33)(34)(35)(36). Moreover, about 97% of human breast cancers and virtually 100% of other common epithelial cancers, including lung, colon, pancreas, and prostate, stain brightly for EpCAM (23), suggesting that the platform developed here could be adapted for RNAi-based therapy of common solid tumors.…”

Squamous cell carcinoma of the oral cavity and circulating tumour cells

“…OSCC is characterised by specific expression patterns for different keratins, capable of being detected in CTCs/DTCs [77] , leading to technical limitations that must be considered. The detection methods have been optimised for CTCs or DTCs derived from adenocarcinomas such as breast, prostate, colorectal or hepatocellular carcinomas, as reported by Schulze et al [78] in the latter case. Therefore, an adaption to the unique biology of OSCC may be required.…”