Among women, BC is the most prevalent cancer and is influenced by lifestyle factors, hormonal factors, reproductive factors, and iatrogenic factors. Furthermore, recent data from 185 countries reported 2.3 million new cases (more than 10% of all cancers) of breast cancer and a mortality rate of 6.9%, and BC ranked the second leading cause of death from cancer among women globally (1, 2). During the past few decades, the morbidity of BC has continued to increase around the world (3). Furthermore, a study showed a significant increase in breast cancer mortality rate in low-income regions, while the decreasing rate mostly belongs to Western Europe, with 37.57 in 1990 to 36.00 in 2015 (4). Due to advances in screening methods and breakthroughs in early diagnosis and treatment, BC survival rates have improved. The conventional diagnostic methodologies of BC include breast biopsy, which is regarded as the gold standard, and imaging methods without high sensitivity to detect BC in the early stage (5). In addition, molecular markers, including CA15-3 and CEA, are common markers for monitoring and follow-up of patients by testing BC patient blood samples, but they have low SEN and SPE (6–8). Thus, it was not suitable for the detection of BC. To improve BC cure rates and reduce BC mortality, early diagnosis remains essential. Thus, it is necessary to explore a new test with high SEN and SPE to diagnose BC in the early stage. Recently, a hot research topic about tumors has been the clinical application of CTCs. CTCs, a subset of tumor cells that circulate within the body due to tumor tissue instability or external physical stimulation, participate in the body’s circulation and then integrate into the peripheral blood circulation (9, 10). The Fourth Edition of the National Comprehensive Cancer Network (NCCN) guidelines has added a new M0 (i+) category, which is defined as “no clinical or radiographic evidence of distant metastases, but the presence of detected tumor cells in the circulation fluids” (11). In addition, CTCs have demonstrated efficacy in the screening of malignant cancers such as prostate, lung, and colorectal cancers (9). In a recent study, CTCs were found to be 76.56% sensitive and 95.4% specific for diagnosing breast cancer using the CytoSorter^® (12). Nonetheless, several studies have been conducted on CTCs to diagnose BC with varied results by testing peripheral blood. In addition, current studies have shown that CTC detection positive rates (≥ 1 CTC/7.5 ml) range from 11%~54% for early breast cancer, while ≥1 CTC can be detected in approximately 70% of stage IV BC patients. Thus, a meta-analysis was performed to determine whether CTCs are particularly useful as a diagnostic tool in patients with BC.

This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (13).

Breast ultrasound and mammography are currently the main methods for screening BC, but with low SEN, they are easily influenced by breast density, and the incidence of false negatives and false positives is high (22). Serological markers such as carbohydrate antigen CA153 and carcinoembryonic antigen (CEA) have the characteristics of noninvasiveness, nonradiation, and low price but still have low SEN and SPE. Thus, they are not suitable for the early diagnosis of BC (23). CTCs are cancer cells that contain unique biomarkers and are commonly found in blood samples from individuals with solid tumors but often not in healthy populations. The prognostic relevance of CTCs in many types of metastatic cancer has already been demonstrated (24–26). According to the eighth AJCC cancer staging manual, BC patients with CTCs are at a greater risk for poor outcomes (27). In recent years, CTC detection has been proven to be helpful in the diagnosis of lung cancer (28), bladder cancer, urothelial cancer (29), pancreatic cancer (30), and so on. Furthermore, CTCs in peripheral blood have been used to diagnose BC in a limited number of studies, with varying results. Consequently, we conducted the first meta-analysis to assess the diagnostic value of CTC detection in the peripheral blood of BC patients.

The results of the study, including 2014 individuals from 8 diagnostic accuracy studies, proved that CTCs had high clinical utility in the diagnosis of breast cancer, with a pooled SEN of 0.69 (0.55-0.80), a pooled SPE of 0.93 (0.60-0.99), a pooled LNR of 9.5 (1.4-65.9), a pooled NLR of 0.33 (0.23-0.48), and a total AUC of the SROC curve of 0.81. These results show that the overall accuracy of CTCS in the early diagnosis of BC is relatively good. After sensitivity analysis, the results of the literature we included were stable, indicating that our meta-analysis results are of reference significance. By using the DOR, a diagnostic test evaluation indicator, we could compare the likelihood of positive results between patients with and without the condition. In the present analysis, the pooled DOR was 29 (95% CI, 4–205), indicating that in comparison to patients who do not test positive for CTCs, those who test positive have 29 times the likelihood of developing BC. Based on the above results, CTCs might be helpful as a diagnostic method for BC screening, which is in accordance with a prior study (12). However, the included studies have different CTC detection methodologies, as well as different sensitivity levels, resulting in a varying CTC cutoff value for the same clinical application (31). To date, CellSearch^® has been the only CTC system approved by the Food and Drug Administration (FDA). However, CellSearch^® had low rates of CTC detection in BC, approximately 40–50% in metastatic BC and just under 30% in early-stage BC (32). There was only one study (21) using CellSearch^® in our meta-analysis. Another study (12) reported the CytoSorter^® CTC detection system. CytoSorter^® was shown to be superior to CellSearch^® in detecting CTCs in BC patients at stages II and III, with a detection rate of over 90% (32). Due to the lack of uniform detection standards for CTCs, clinical practice does not consider CTCs to be a standard routine diagnostic tool. Thus, more research is required to determine the criteria for CTC detection. Based on the use of different threshold values in the included studies, we used Spearman’s correlation coefficient to analyze threshold effects and found that there was no connection between thresholds and heterogeneity.

This study has some limitations. First, on account of the relatively small number of cases in this study, we failed to determine the potential source of this study due to the relatively high heterogeneity of this study. Second, in various studies, cutoff values differ, which has an impact on our results, and there is a need for further research on CTCS’s optimal cutoff point. In addition, seven out of eight studies were conducted in Asia, and the electronic databases included regional databases, which could cause bias in the results. It would be beneficial to conduct more international prospective multicenter research on this topic.

This meta-analysis showed that CTCs can be used as a helpful tool in BC screening and early diagnosis, with better sensitivity and specificity. To clarify the accuracy of CTCs as BC diagnostic indicators, more high-quality prospective studies are needed.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by TJ, YC and J-QY. The first draft of the manuscript was written by TJ, and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.