The Potential Clinical Implications of Circulating Tumor Cells and Circulating Tumor Microemboli in Gastric Cancer

Abstract

Background Gastric adenocarcinoma (GAC) is the third deadliest malignant neoplasm worldwide, mostly because of late disease diagnosis, low chemotherapy response rates, and an overall lack of tumor biology understanding. Therefore, tools for prognosis and prediction of treatment response are needed. Quantification of circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) and their expression of biomarkers has potential clinical relevance. Our aim was to evaluate CTCs and CTM and their expression of HER2 and plakoglobin in patients with nonmetastatic GAC, correlating the findings to clinicopathological data. Materials and Methods CTC enrichment was performed with isolation by size of epithelial tumor cells, and the analysis was performed with immunocytochemistry and microscopy. Two collections were made: one at diagnosis (55 samples before neoadjuvant treatment) and one after surgery and before adjuvant therapy (33 samples). Results A high detection rate of CTCs (90%) was observed at baseline. We evaluated HER2 expression in 45/55 biopsy samples and in 42/55 CTC samples, with an overlap of 36 subjects. Besides the good agreement observed for HER2 expression in primary tumors and paired CTCs for 36 cases (69.4%; κ = 0.272), the analysis of HER2 in CTCs showed higher positivity (43%) compared with primary tumors (11%); 3/5 patients with disease progression had HER2‐negative primary tumors but HER2‐positive CTCs. A significant CTC count drop in follow‐up was seen for CTC‐HER2‐positive cases (4.45 to 1.0 CTCs per mL) compared with CTC‐HER2‐negative cases (2.6 to 1.0 CTCs per mL). The same was observed for CTC‐plakoglobin‐positive cases (2.9 to 1.25 CTCs per mL). Conclusion CTC analysis, including their levels, plakoglobin, and HER2 expression, appears to be a promising tool in the understanding the biology and prognosis of GAC. Implications for Practice The analysis of circulating tumor cell levels from the blood of patients with gastric adenocarcinoma, before and after neoadjuvant treatment, is useful to better understand the behavior of the disease as well as the patients more likely to respond to treatment.

Emerging Role of Circulating Tumor Cells in Gastric Cancer

“…Those patients received clinical benefits from trastuzumab which were comparable to those from the trastuzumab in combination with chemotherapy of the ToGA clinical trial [90]. Similarly, as reported by Abdallah et al [67], three out of five nonmetastatic gastric adenocarcinoma patients with disease progression had HER2-negative primary tumors but HER2-positive CTCs. A significant CTC count drop in follow-up was seen for CTC-HER2-positive cases and CTC-plakoglobin-positive cases compared with CTC-HER2-negative cases and CTC-plakoglobin-negative cases.…”

Circulating Tumour Cells (CTCs) as Potential Biomarkers of Clinicopathological and Prognostic Significance in Gastric Cancer Patients: A Systematic Review and Meta-Analysis

“…Eighteen of the remaining 21 articles [16, 20, 21, 23, 24, 26, 29, 30, 32-34, 38, 40, 42, 48, 50-52] with 21 arms provided HRs for OS. Nine articles [12,16,20,21,23,24,29,30,40] with 11 arms provided HRs for PFS, and 3 articles [37,39,52] provided HRs for DFS.…”

Current progress in the clinical use of circulating tumor cells as prognostic biomarkers

“…The use of microemboli in addition to CTCs, and especially close examination of their expression of specific proteins, also recently has been shown to be promising for gastric cancer prognosis. 63…”

“…More specific biomarkers, such as EpCAM, which is known to be predictive of peritoneal metastasis in patients with gastric cancer, have potential as targets in liquid biopsies of CTCs for gastric cancer prognosis. The use of microemboli in addition to CTCs, and especially close examination of their expression of specific proteins, also recently has been shown to be promising for gastric cancer prognosis …”