Towards a Universal Ovarian Cancer Biomarker Model: Clinical Validation of Trx1 and CA125 Dual Strategy

Background Ovarian cancer is the fifth leading cause of cancer-related mortality in women, with early detection being critical for improving patient outcomes. Current diagnostic biomarkers, including Cancer antigen 125 (CA125), human epididymis protein 4 (HE4), and their combined Risk of Ovarian Malignancy Algorithm (ROMA), exhibit limited sensitivity and specificity, particularly in early-stage disease and premenopausal women. Thioredoxin-1 (Trx1) has emerged as a potential complementary biomarker. This study evaluates the diagnostic utility of Trx1 in combination with CA125 and HE4. Methods Serum levels of CA125, HE4, and Trx1 were measured in 80 ovarian cancer patients and 200 controls. The influence of age, menopausal status, obstetric history, pathological characteristics, and cancer stage on biomarker performance was analyzed. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) curve analysis, with sensitivity, specificity, and area under the curve (AUC) values calculated for individual biomarkers and their combinations. Performance comparisons were conducted across premenopausal and postmenopausal subgroups. Results Among individual biomarkers, CA125 demonstrated the highest diagnostic accuracy (AUC = 0.872), followed by HE4 (AUC = 0.815) and Trx1 (AUC = 0.588). The combination of Trx1 and CA125, termed the Dual-marker Ovarian Cancer Risk Algorithm (DORA), improved diagnostic performance (AUC = 0.852), while the addition of HE4 further enhanced accuracy (AUC = 0.878). Trx1 exhibited stable expression across demographic subgroups. ROMA demonstrated low sensitivity in premenopausal women (42.86%) despite high specificity (92.86%), whereas postmenopausal women showed slightly improved sensitivity (66.10%) with perfect specificity (100.00%). DORA was non-inferior to ROMA and achieved superior sensitivity in both premenopausal (76.19%) and postmenopausal (91.53%) patients, maintaining consistent performance across cancer stages. Conclusion DORA represents a promising alternative to ROMA, offering enhanced sensitivity and reliable diagnostic performance across diverse patient populations. Trx1 has the potential to improve ovarian cancer detection, particularly in early-stage and premenopausal cases where current diagnostic approaches remain inadequate.