DIAGNOSTIC PERFORMANCE OF HE4, CA-125, AND ROMA SCORE IN EARLY DETECTION OF EPITHELIAL OVARIAN CANCER: A SYSTEMATIC REVIEWc

Abstract

Background: Epithelial ovarian cancer is one of the most lethal gynecological malignancies, largely because many cases are diagnosed at an advanced stage. Early detection remains a major clinical challenge. Cancer antigen 125 (CA-125) is the most widely used serum biomarker, but its diagnostic accuracy is limited, especially in early-stage disease and premenopausal women. 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 between benign and malignant ovarian disease.

Objective: This systematic review aimed to evaluate the diagnostic performance of HE4, CA-125, and ROMA score in the early detection and risk stratification of epithelial ovarian cancer.

Methods: A systematic literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and Cochrane Library using terms related to HE4, CA-125, ROMA score, epithelial ovarian cancer, early detection, diagnostic accuracy, sensitivity, specificity, and adnexal mass. Studies were eligible if they assessed the diagnostic performance of HE4, CA-125, ROMA, or combinations of these markers in women with suspected ovarian malignancy or adnexal masses. Data were extracted regarding study design, population, menopausal status, biomarker cutoffs, sensitivity, specificity, area under the curve, and diagnostic conclusions. The review was structured according to PRISMA 2020 principles.

Results: The initial search identified 1,246 records. After removal of 318 duplicates, 928 records were screened by title and abstract. Of these, 812 records were excluded. One hundred and sixteen full-text articles were assessed for eligibility, and 78 were excluded for predefined reasons. Finally, 38 studies were included in the systematic review. Across studies, CA-125 showed good sensitivity in advanced epithelial ovarian cancer but reduced accuracy in early-stage disease and lower specificity in premenopausal women due to elevations in benign gynecological and inflammatory conditions. HE4 demonstrated higher specificity than CA-125 in most studies and was less frequently elevated in benign conditions such as endometriosis. ROMA generally provided better overall discrimination than either biomarker alone, particularly for differentiating epithelial ovarian cancer from benign adnexal masses. However, performance varied according to menopausal status, histological subtype, disease stage, assay platform, cutoff values, and study population.

Conclusion: HE4 and ROMA improve diagnostic specificity and overall risk stratification compared with CA-125 alone, particularly in women with adnexal masses. CA-125 remains clinically useful but is limited as a standalone early detection marker. ROMA may support preoperative triage and referral decisions, but no biomarker strategy is sufficiently accurate for population-based screening of asymptomatic average-risk women. Future studies should standardize cutoff values, assay platforms, menopausal stratification, and early-stage epithelial ovarian cancer reporting.