Evaluation of S100A4, CA-12, CA-9, Annexin A1/A2, and Galectin-3 in Prostate Cancer: Diagnostic and Prognostic Implications

Objective: The limited specificity of prostate-specific antigen (PSA) increases the risk of unnecessary biopsies and overtreatment. This study aimed to evaluate the diagnostic and prognostic value of serum S100A4, along with CA-9, CA-12, Annexin A1/A2, and Galectin-3, in prostate cancer. Methods: This prospective case-control study, conducted between July 2024 and September 2025, included 80 patients with histopathologically confirmed prostate cancer and 40 age-matched healthy controls. Patients were stratified into low-risk (ISUP grades 1-2) and high-risk (ISUP ≥ 3) groups. Serum biomarker levels were measured using ELISA. Diagnostic and prognostic performance was assessed by receiver operating characteristic (ROC) analysis, with cut-off values determined using the Youden index. Logistic regression analyses were performed to identify independent biomarkers. Results: Serum CA-12 and CA-9 levels were significantly higher in prostate cancer patients than in controls (p = 0.004 and p = 0.032, respectively). Although S100A4 levels were lower in prostate cancer patients compared with controls, they were significantly higher in high-risk patients within the cancer cohort (p = 0.002). Logistic regression identified S100A4 (p = 0.032) and CA-12 (p = 0.004) as independent predictors of prostate cancer diagnosis. ROC analysis demonstrated excellent diagnostic accuracy for CA-12 (>52.9 ng/mL; AUC = 0.99) and S100A4 (<9.96 ng/mL; AUC = 0.98). For prognostic stratification, S100A4 (>8.27 ng/mL; AUC = 0.97) and CA-12 (>72.8 ng/mL; AUC = 0.91) effectively distinguished high-risk from low-risk disease. Conclusion: S100A4 and CA-12 exhibit strong diagnostic and prognostic performance in prostate cancer. When used alongside PSA, S100A4 and CA-12 may improve risk stratification in patients with suspected prostate cancer and help reduce unnecessary prostate biopsies. This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License.