Enrichment and Detection Method for the Prognostic Value of Circulating Tumor Cells in Ovarian Cancer: A Meta-analysis

In part due to a lack of early symptoms and robust screening strategies, ovarian cancer is often diagnosed in later stages and has the highest worldwide mortality among gynecologic malignancies. Tumor markers CA125 and HE4 are effective in the diagnosis of ovarian cancer; however, there is a need for prognostic tumor markers for ovarian cancer. Circulating tumor cells (CTCs) detected in liquid biopsy may correlate with prognosis of several cancers and can be used in early evaluation of recurrence. Despite numerous studies, there is conflicting evidence in the prognostic significance of CTCs in ovarian cancer. This meta-analysis aimed to evaluate whether detection of CTCs in patients with ovarian cancer had adverse survival outcomes with consideration of sampling time, treatment, enrichment method, and detection method. A literature search across the electronic databases of Embase, PubMed, and Cochrane Library was conducted in July 2020, and clinical trials that analyzed CTCs in ovarian cancer patients along with survival outcomes including progression-free survival (PFS) and overall survival (OS) were included. Techniques used for CTC enrichment and detection involve various enrichment approaches (physical and immunological methods) and detection approaches (immunocytological and molecular biological techniques). Protocol and clinicopathological characteristics were extracted along with survival outcomes from relevant articles. In the case that an included study did not have survival outcomes with hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS, statistical analyses were run on the Kaplan-Meier survival curves to obtain this information for analysis. A total of 15 studies, 2 clinical trials and 13 prospective studies, including 1285 patients with ovarian cancer were included in the final analysis. The results showed CTCs were not significantly associated with grades, stages, and lymph node metastasis (odds ratio [OR], 1.17; 95% CI, 0.72-1.88; P = 0.52; OR, 2.69; 95% CI, 0.45-15.90; P = 0.28; OR, 1.94; 95% CI, 0.96-3.92; P = 0.07, respectively). Two studies investigated the relationship between CTCs and chemosensitivity, finding a significant association between platinum sensitivity and the presence of CTCs (OR, 0.49; 95% CI, 0.25-0.97; P = 0.04). Pooled HR for OS from 14 studies found the presence of CTCs to be significantly correlated with OS (HR, 1.77; 95% CI, 1.42-2.21; P < 0.00001) and PFS (HR, 1.53; 95% CI, 1.26-1.86; P < 0.0001). Subgroup analysis revealed that CTCs obtained before treatment (HR, 1.79; 95% CI, 1.43-2.24; P < 0.00001), detected in the cohort of patients being treated with surgery (HR, 1.82; 95% CI, 1.42-2.33; P < 0.00001), detected in the "physical method" subgroup (HR, 1.94 [1.21-3.09]; P = 0.006), detected in the "immunological method" subgroup (HR, 1.84 [1.37-2.48]; P < 0.0001), and detected through reverse transcription polymerase chain reaction (RT-PCR) (HR, 2.29; 95% CI, 1.53-3.42; P < 0.0001) were significantly associated with OS. This meta-analysis revealed that CTCs carry a prognostic value for OS and PFS in ovarian cancer patients and could serve as a new noninvasive marker. Importantly, CTCs detected by RT-PCR and collected before the initiation of treatment could suggest a more insidious disease.