ASSESSMENT OF HE4, CA-125, AND ROMA SCORE IN THE EARLY DIAGNOSIS OF EPITHELIAL OVARIAN CANCER: A SYSTEMATIC REVIEW

Abstract

Background: Epithelial ovarian cancer remains one of the most lethal gynecologic malignancies because most patients are diagnosed at an advanced stage. Early detection is clinically important but remains difficult due to non-specific symptoms and limited accuracy of single serum biomarkers. Cancer antigen 125 (CA-125) is widely used but has suboptimal specificity, particularly in premenopausal women and benign gynecologic conditions. Human epididymis protein 4 (HE4) and the Risk of Ovarian Malignancy Algorithm (ROMA), which combines HE4, CA-125, and menopausal status, have been proposed to improve diagnostic discrimination. Objective: This systematic review aimed to evaluate the diagnostic performance of HE4, CA-125, and ROMA score in the early detection of epithelial ovarian cancer, with emphasis on sensitivity, specificity, area under the curve, menopausal status, early-stage disease, and clinical applicability. Materials and Methods: A systematic literature search was conducted using PubMed/MEDLINE, Scopus, Web of Science, Embase, Google Scholar, and manual reference screening. Studies evaluating HE4, CA-125, ROMA score, or their combinations for detection or preoperative discrimination of epithelial ovarian cancer were included. Diagnostic accuracy studies, prospective and retrospective observational studies, and case-control studies were considered. Reviews, editorials, case reports, studies without histopathological confirmation, non-epithelial ovarian tumors alone, and studies without extractable diagnostic data were excluded. Data were synthesized descriptively because of heterogeneity in assay platforms, cut-off values, menopausal status, disease stage, and study design. Results: A total of 34 studies involving 9,486 women were included, comprising 2,918 epithelial ovarian cancer cases and 6,568 benign or non-malignant controls. Among cancer cases, 1,184 were early-stage and 1,734 were advanced-stage. Overall, CA-125 showed pooled sensitivity of 82.6%, specificity of 73.8%, and AUC of 0.84. HE4 showed sensitivity of 78.4%, specificity of 89.1%, and AUC of 0.90. ROMA showed the highest overall diagnostic performance, with sensitivity of 87.5%, specificity of 85.3%, and AUC of 0.93. In early-stage epithelial ovarian cancer, ROMA and HE4 demonstrated better diagnostic balance than CA-125 alone. CA-125 remained sensitive but less specific, especially in premenopausal women and benign inflammatory or endometriotic conditions. Conclusion: HE4 and ROMA improve diagnostic discrimination for epithelial ovarian cancer compared with CA-125 alone, particularly by increasing specificity. ROMA showed the best overall performance, while HE4 was valuable for reducing false-positive results. However, none of the markers alone is sufficient as a population-level screening test for early ovarian cancer. Their greatest clinical utility lies in risk stratification of women with adnexal masses and in combination with imaging, menopausal status, clinical assessment, and histopathological confirmation.