Beyond Total <scp>PSA</scp> : Clinical Significance of <scp>S2</scp> , <scp>3PSA</scp> % in Reducing Unnecessary Prostate Biopsies

Prostate-specific antigen (PSA) testing has long been central to prostate cancer detection but is limited by poor specificity, resulting in overdiagnosis and unnecessary prostate biopsies. Although PSA derivatives such as percentage free PSA and the Prostate Health Index (PHI) have improved diagnostic performance, substantial uncertainty persists, particularly in patients with equivocal magnetic resonance imaging (MRI) findings. Cancer-associated alterations in PSA glycosylation have emerged as a promising strategy to address these limitations. Percentage α2,3-linked sialylated PSA (S2,3PSA%) reflects tumor-associated glycoform changes that differ from those observed in benign prostatic conditions. This review summarizes the biological basis, analytical development, and clinical evidence supporting S2,3PSA% as a novel biomarker for prostate cancer diagnosis. We highlight key studies demonstrating that S2,3PSA% improves discrimination of clinically significant prostate cancer and provides complementary information when combined with PHI and MRI. Recent data further indicate that integrated diagnostic approaches incorporating S2,3PSA%, PHI, and PI-RADS scoring can meaningfully reduce unnecessary prostate biopsies without compromising detection of clinically significant disease. Beyond diagnostic accuracy, emerging evidence suggests that S2,3PSA%-guided risk stratification in screening settings may also reduce the number of unnecessary MRI examinations and biopsies, thereby contributing to more efficient use of healthcare resources and potential cost savings. We also discuss the potential role of S2,3PSA% in prostate cancer screening and active surveillance. Collectively, current evidence supports S2,3PSA% as a biologically informed biomarker that helps reduce diagnostic uncertainty inherent to PSA-based decision-making and facilitates more individualized and resource-conscious prostate cancer care.