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because EPISPOT detects only CXCR4-positive CTCs, analysis of the heterogeneity of CTCs captured is
limited.

While these developments can make CTC isolation accurate, further research on molecular characterization
is necessary to confirm the significance of CTCs. Thus, the number of validation studies focusing on the
characterization of CTCs has increased in recent years.

CLINICAL UTILITY OF CTCS IN GASTRIC CANCER
There have been many previous studies of CTCs in gastric cancer, as summarized in Table 2. Although there
are various methodologies of CTCs identification (e.g., RT-PCR, FACS, CellSearch System), determining the
most appropriate detection method and marker of CTCs in gastric cancer remains controversial. Several
meta-analyses have demonstrated that the presence of CTC is associated with advanced clinicopathological
[39]
features and poor survival in gastric cancer [37,38] . Huang et al. indicated that CTCs was associated with
advanced stage, undifferentiated histological type, lymphatic invasion positive, and poorer survival.

Furthermore, CTC detection has been suggested to be a useful biomarker of diagnosis. Although previous
meta-analysis showed that CTC cannot be recommended as a screening test of gastric cancer owing to lower
and inconsistent sensitivity estimates for CTCs, a recent study demonstrated that CTC detection based on
FAST technique, in contrast to previous studies mainly based on RT-PCR, can be an available biomarker
[40]
for early diagnosis of gastric cancer with high sensitivity and specificity . In addition to diagnosis and
prediction of prognosis, recent studies reported that monitoring changes of CTCs during treatment may
[41]
be a predictive marker of response to treatment. Li et al. demonstrated that elevated CTCs (≥ 3) during
treatment were significantly associated with poor response rates and shorter survival. Notably, conversion
to CTCs less than 3 after therapy improved the prognosis, while change to CTCs 3 or higher exhibited
[42]
significantly worse prognosis. Shimazu et al. reported that gastric cancer with diffuse bone metastases
might have a very high CTC count (> 200) in a small cohort. In cases with decrease of CTC count after
treatment, tumor was sensitive to chemotherapy. They suggested that the change of CTC counts during
[42]
treatment could be a predictive biomarker .

HER2 has become a significant molecule for targeted therapy in gastric cancer. Trastuzumab (anti-HER2
monoclonal antibody) improved survival for patients with HER2 overexpressing gastric cancer. Although
the assessment of HER2 status is usually performed on biopsy tissues from primary site, it has been reported
that a discrepancy of HER2 status between the primary and the metastatic site was observed in some
[43]
cases . There has been an attempt to use CTCs for reassessment of HER2 status in recurrence or metastatic
[44]
[45]
sites . Mishima et al. found a number of patients whose primary tumors were HER2 protein negative but
who had HER2 gene positive CTCs by using 3D-FISH in gastric cancer. Furthermore, those patients had a
favorable response to trastuzumab, and the second stage of the phase 2 trial is ongoing.

FUTURE PERSPECTIVES
Heterogeneity of CTCs
Tumor heterogeneity has been well-known to show genetic and phenotypic diversities between different
tumor types, and within the same tumor and the same patient. It has been reported that heterogeneity
[46]
was associated with the response and resistance to treatment . Since the tumor heterogeneity changes
throughout treatment, the serial profiling of disease is needed. However, there have been no diagnostic
modalities or biomarkers available for timely and accurate assessment of heterogeneity. Therefore, much
attention has been paid to monitoring dynamic changes of tumor heterogeneity during treatment by
detecting CTCs, which is a minimally invasive and repeatable procedure, and may allow for reassessing the
[47]
biology even in recurrence or metastasis. Scher et al. demonstrated that the degree of heterogeneity could