Towards a universal ovarian cancer biomarker model: clinical validation of Trx1 and CA125 dual strategy

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Abstract 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 exploratory 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 297 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 performance (AUC = 0.832), followed by HE4 (AUC = 0.812) and Trx1 (AUC = 0.768). The combination of Trx1 and CA125, termed the Dual-marker Ovarian Cancer Risk Algorithm (DORA), demonstrated diagnostic performance comparable to ROMA (AUC, 0.864 vs. 0.853) while showing higher sensitivity (87.5% vs. 57.5%). Trx1 concentrations showed minimal associations with age and menopausal status. In subgroup analyses, DORA demonstrated higher sensitivity than ROMA in premenopausal women (76.2% vs. 42.9%) and in patients with early-stage ovarian cancer (82.2% vs. 36.8–46.2%), while maintaining acceptable overall diagnostic performance. Conclusion DORA demonstrated diagnostic performance comparable to that of ROMA while showing higher sensitivity in clinically relevant subgroups, including premenopausal women and patients with early-stage ovarian cancer. These findings suggest that incorporation of Trx1 may provide complementary diagnostic information in women undergoing evaluation for suspected ovarian malignancy.