Evaluation of CA-125, HE4, ROMA, and Copenhagen Index for Preoperative Risk Stratification of Adnexal Masses in Indian Women: A Prospective Cross-Sectional Study

Abstract Introduction Ovarian cancer causes ~ 207,000 deaths annually worldwide (GLOBOCAN 2022), with India bearing ~ 16% of the global burden. Despite screening advances, biomarkers remain essential for triage in low-resource settings. This study assessed CA-125, HE4, Risk of Ovarian Malignancy Algorithm (ROMA), and Copenhagen Index (CPH-I) for distinguishing benign from malignant adnexal masses in Indian women. Methodology: The study is a single-center, cross-sectional study enrolling participants prospectively conducted at a tertiary center. Serum CA-125 and HE-4 concentrations were measured, and used to calculate ROMA and CPH-I. The diagnostic accuracy was determined and the receiver operating characteristic curve was plotted. Univariable and multivariable analysis was undertaken to identify predictors of misclassification. Results Eighty-six participants were included in the final analysis, of whom 58 (67%) had benign masses, 23 (27%) had malignant tumors, and 5 (6%) had borderline ovarian tumors. Serum CA-125, HE-4, ROMA, and CPH-I values were significantly higher in malignant tumors than benign lesions. In premenopausal women, HE-4 and ROMA demonstrated the highest diagnostic accuracy with AUC values of 0.938 and 0.942, respectively, along with 75% sensitivity and 100% specificity. In postmenopausal women, the Copenhagen Index demonstrated the highest specificity (94.83%) and AUC (0.924). The predefined clinical cutoffs for CA-125, ROMA, and CPH-I were 35 U/mL, 12.5–14.4%, and 7%, respectively, while study-derived optimal cutoffs using Youden’s index were 29.6 U/mL for CA-125 and 5.3% for CPH-I. Endometriosis and tubercular masses were significant predictors of CA-125 discrepancies. Conclusion HE-4 and ROMA demonstrated improved specificity compared with CA-125 in premenopausal women. The Copenhagen Index demonstrated the highest specificity and AUC in postmenopausal women while offering the practical advantage of being independent of menopausal classification. These biomarkers may serve as useful adjunctive triage tools alongside imaging and clinical assessment to facilitate timely referral to gynecologic oncology services.