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A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma
Author(s) -
Court Colin M.,
Hou Shuang,
Winograd Paul,
Segel Nicholas H.,
Li Qingyu Wilda,
Zhu Yazhen,
Sadeghi Saeed,
Finn Richard S.,
Ganapathy Ekambaram,
Song Min,
French Samuel W.,
Naini Bita V.,
Sho Shonan,
Kaldas Fady M.,
Busuttil Ronald W.,
Tomlinson James S.,
Tseng HsianRong,
Agopian Vatche G.
Publication year - 2018
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.25062
Subject(s) - medicine , circulating tumor cell , hepatocellular carcinoma , epithelial cell adhesion molecule , oncology , hazard ratio , liquid biopsy , pathology , cancer research , cancer , metastasis , confidence interval
Current clinicopathologic staging systems and serum biomarkers poorly discriminate tumor biology in hepatocellular carcinoma (HCC), with high recurrence rates following curative‐intent surgical resection and liver transplantation (LT). Identification of accurate biomarkers for improved prognostication and treatment selection is a critical unmet need. We sought to develop a novel “liquid‐biopsy” assay capable of detecting HCC circulating tumor cells (CTCs) and characterizing phenotypic subpopulations with prognostic significance. Using HCC cell lines, a tissue microarray, and human blood samples, an antibody cocktail targeting the cell‐surface markers asialoglycoprotein receptor (ASGPR), glypican‐3, and epithelial cell adhesion molecule was optimized for HCC CTC capture using the NanoVelcro CTC Assay. The ability of HCC CTCs and vimentin (VIM)–positive CTCs (a subpopulation expressing an epithelial‐to‐mesenchymal phenotype) to accurately discriminate tumor stage, recurrence, progression, and overall survival (OS) was evaluated in a prospective study of 80 patients. Multimarker capture detected greater numbers of CTCs than any individual antibody alone for both cell line and patient samples ( P < 0.001). HCC CTCs were identified in 59/61 (97%) patients, and HCC (median, 6 CTCs) and non‐HCC patients (median, 1 CTC; area under the receiver operating characteristic curve [AUROC] = 0.92; P < 0.001; sensitivity = 84.2%; specificity = 88.5%) were accurately discriminated. VIM‐positive CTCs accurately discriminated early‐stage, LT eligible patients (median, 0 CTCs) from locally advanced/metastatic, LT ineligible patients (median, 6 CTCs; AUROC = 0.89; P = 0.001; sensitivity = 87.1%; specificity = 90.0%), and predicted OS for all patients (hazard ratio [HR], 2.21; P = 0.001), and faster recurrence after curative‐intent surgical or locoregional therapy in potentially curable early‐stage HCC (HR, 3.14; P = 0.002). In conclusion, we developed a novel multimarker CTC enrichment assay that detects HCC CTCs with high efficiency and accuracy. A phenotypic subpopulation of VIM‐positive CTCs appears to signify the presence of aggressive underlying disease and occult metastases and may have important implications for treatment selection. Liver Transplantation 24 946–960 2018 AASLD.