Comparison of CA-125 and HE4 in ovarian cancer recurrence detection

Purpose: This study aims to comprehensively evaluate CA-125 and HE4 as predictors of ovarian cancer (OC) recurrence in the same patient population. Methods: We systematically searched the WOS, PubMed, and Scopus databases on May 8, 2024, for studies investigating both tumor markers CA-125 and HE4 in the same patient population of ovarian cancer recurrence. We calculated pooled values of AUC, sensitivity, specificity, and univariate or multivariate hazard ratios (HR) for both tumor markers in serum using a random effects model and StataMP 17.0 software. Results: Thirteen articles comprising 1026 patients satisfied the inclusion criteria. Liquid-biopsy-based HE4 and CA-125 measurements were both proven to have high predictive value for detecting OC recurrence with comparable AUC values (AUCHE4:0.78, 95% CI=0.73-0.83; AUCCA125:0.80, 95% CI=0.73-0.88). While sensitivity of HE4 tests was higher than their specificity (SensitivityHE4=80.7%; 95% CI=73-88.4; I²=77.05%; p<0.001; SpecificityHE4=77.8%; 95% CI=68.9-86.6; I²=83.88%; p<0.001) in detecting OC recurrence, specificity was comparably higher for CA-125 analyses (SensitivityCA-125=71.4%; 95% CI=60.2-82.7; I²=85,67%; p<0.001; SpecificityCA-125=94.5%; 95% CI=91.9-97.1; I²=10.64%; p=0.34). Pooled HR values indicate that increased values of HE4 and CA125 increase the risk for worse progression-free survival by 3.1 (95% CI=1.3–5.0, I²=0.00 %, p=0.38) and 2.4-fold (95% CI=1.3–3.5, I²=0.00 %, p=0.93) respectively. HE4 indicates worse overall survival (HR=6.9, CI=0.8–12.6, I²=0.00 %, p=0.7). Conclusions: We suggest that HE4 is valuable as a recurrence tracker, with its higher sensitivity, while CA-125 can be used as a validator due to its higher specificity. Further prospective studies analyzing both biomarkers together are required for complete validation.