Preoperative Folate Receptor-Positive Circulating Tumor Cells Are Associated With Occult Peritoneal Metastasis and Early Recurrence in Gastric Cancer Patients: A Prospective Cohort Study

Abstract

BackgroundThe aim of this study is to explore the clinical feasibility of detecting folate receptor-positive circulating tumor cells (FR+ CTCs) for predicting peritoneal metastasis and short-term outcome in gastric cancer patients.MethodsThis is a prospective, single-center, observational study. We applied ligand-targeted enzyme-linked polymerization method to detect preoperative FR+ CTC levels in peripheral blood. We evaluated the diagnostic value of FR+ CTCs and other biomarkers in predicting peritoneal metastasis. Prognostic factors for recurrence-free survival (RFS) were investigated in univariate and multivariate analyses.ResultsA total of 132 patients with gastric cancer and 9 patients with benign disease were recruited. Gastric cancer patients had a significantly higher CTC level compared to that of patients with benign disease (p < 0.01). Combined model including CTC level and other biomarkers presented high sensitivity (100%) and moderate specificity (59.3%) in predicting peritoneal metastasis. Univariate analysis revealed that decreased serum prealbumin, decreased peripheral lymphocyte count, FR+ CTCs, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and lymph node metastasis were significantly associated with shorter RFS. FR+ CTC level [≥12.6 folate units (FU)/3 ml, hazard ratio (HR) = 6.957, p = 0.005] and CA19-9 (>34 ng/ml, HR = 3.855, p = 0.037) were independent prognostic factors in multivariate analysis.ConclusionsOur findings for the first time suggested the diagnostic value of preoperative CTC levels in predicting peritoneal metastasis in gastric cancer. Moreover, the FR+ CTC level could be a novel and promising prognostic factor for the recurrence of gastric cancer in patients who underwent surgery.Clinical Trial RegistrationChinese Clinic Trial Registry, identifier ChiCTR2100050514.

Association between circulating tumor cells in the peripheral blood and the prognosis of gastric cancer patients: a meta-analysis

“…In all, 28 eligible studies 19 , 20 , 27 – 52 containing 2383 patients were enrolled for analysis ( Figure 1 ). Table 1 shows the basic characteristics and experimental design variables of all included studies.…”

Folate receptor-positive circulating tumor cells predict survival and recurrence patterns in patients undergoing resection for pancreatic cancer

“…In addition, FR + CTCs have been shown to serve as prognostic markers in several cancer types, including gastric, breast and lung cancers (38)(39)(40). In a prospective cohort study including 132 gastric cancer patients, combined model including FR + CTC level and other biomarkers (CA19-9, prealbumin and peripheral lymphocyte count) presented high sensitivity (100%) and moderate specificity (59.3%) in predicting peritoneal metastasis, the preoperative FR + CTC level could also predict short-term recurrence after surgery (38). In another prospective study to investigate the prognostic and predictive significance of FR + CTC in non-small cell lung cancer patients who underwent surgery, patients with lower preoperative CTC level had longer relapse-free FIGURE 2 survival (RFS) and OS, CTC level (HR = 4.10) and pathological stage (HR = 3.16) were independent prognostic factors of RFS (40).…”

“…As FRs are also highly expressed in PC, our previous study has shown that FR + CTCs have potential as a biomarker for the diagnosis of PC and LT-PCR is feasible and reliable for detecting FR + CTCs in patients with PC ( 32 ). In addition, FR + CTCs have been shown to serve as prognostic markers in several cancer types, including gastric, breast and lung cancers ( 38 – 40 ). In a prospective cohort study including 132 gastric cancer patients, combined model including FR + CTC level and other biomarkers (CA19-9, prealbumin and peripheral lymphocyte count) presented high sensitivity (100%) and moderate specificity (59.3%) in predicting peritoneal metastasis, the preoperative FR + CTC level could also predict short-term recurrence after surgery ( 38 ).…”

Clinical application and detection techniques of liquid biopsy in gastric cancer

“…This approach includes positive selection with antibodies against tumor-associated antigens such as EpCAM, CKs, mucin-1, human epidermal growth factor receptor 2, or epithelial growth factor receptor [50][51][52] and negative selection with antibodies against the common leukocyte antigen CD45 [53]. The CellSearch system (Veridex) is the most widely used antibody-based isolation technique and the only one approved by the Food and Drug Administration (FDA) for the detection of CTCs in the blood of some tumor patients [54][55][56], which has a greater benefit as a diagnostic and prognostic indicator for patients with metastatic disease [34,37]. However, imposing EpCAM bias on the enriched CTCs population is an obvious drawback of immunocapture methods, including CellSearch [57].…”

“…In this study, the authors also found that the number of CTCs in stage III GC patients was higher than that in stage I GC patients and that the overall survival rate of patients with more than 5 CTCs was lower. Dan Zeng et al [ 37 ] used ligand‐targeted polymerase chain reaction to detect the levels of folate receptor-positive CTCs in blood samples from GC patients and found that preoperative CTCs levels have a diagnostic value in predicting peritoneal metastases in GC. Furthermore, Huang et al [ 30 ] found CTCs in 10.8% of the resected group with a high recurrence rate and 60.2% of the unresectable group, but not in the healthy control group.…”