Current laboratory diagnostic tools for epithelial ovarian cancer (EOC) primarily rely on cancer antigen 125 (CA125) and human epididymis protein 4 (HE4). However, their effectiveness is suboptimal for early disease diagnosis and triage of adnexal masses. The evidence reviewed on the topic of tissue and circulating circular RNAs (circRNAs) as diagnostic, prognostic, and treatment-response biomarkers in EOC and what is needed to implement circRNA assays in clinical laboratory practice are summarized herein. Several circRNAs identified in plasma/serum (such as circBNC2, hsacirc0003972, hsacirc0007288, and circN4BP2L2) have diagnostic potential (area under the receiver operating characteristic curve [AUC] between the typical range of 0.79–0.95) and can be used to enhance multimarker algorithms with CA125 and HE4. In addition to biomarker performance, we are interested in laboratory medicine challenges that can define clinical usability, such as Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE)-compatible assay design to detect back-splice junction, specimen-specific pre-analytical variables (e.g., hemolysis, clotting time, and exosome isolation workflows), normalization strategies of liquid biopsy, analytical validation, reference intervals/decision limits, and external quality assessment. Although published accuracies are encouraging, the majority of studies have small cohorts and lack external validation, and preanalytical handling and reporting heterogeneity are significant. Thus, strong standardization and regulatory level validation are necessary for circRNA testing to be established as a routine EOC diagnosis, risk stratification, or treatment monitoring tool.
