4Kscore as a Pre-MRI Reflex Test for Men with PSA 1.80-2.99 ng/ml in the Göteborg-2 Prostate Cancer Screening Trial

Lowering the prostate-specific antigen (PSA) cut-off from 3.0 to 1.8 ng/ml in prostate cancer (PCa) screening would improve diagnostic yield but substantially increase the number of men undergoing diagnostic work-up.

To evaluate 4Kscore as a reflex test for pre-magnetic resonance imaging (MRI) risk stratification among men with PSA 1.80-2.99 ng/ml.

This diagnostic biomarker study was nested within the population-based Göteborg-2 PCa screening trial and included men with PSA ≥1.80 ng/ml who were referred for MRI and provided blood for biomarker research, followed by targeted biopsy if MRI-positive (Prostate Imaging Reporting and Data System [PI-RADS] ≥3). The analysis included 555 men (median age 59 yr) with PSA 1.80-2.99 ng/ml, pre-MRI 4Kscore, and assessable MRI.

The primary outcome was International Society of Urological Pathology (ISUP) grade ≥2. Diagnostic performance of 4Kscore as a pre-MRI reflex test was assessed using sensitivity, specificity, predictive values, and area under the receiver operating characteristic curve (AUC), with 95% confidence intervals (CI).

MRI was positive in 116/555 men (21%). Overall, PCa was detected in 52/555 men (9.3%), including 27/555 men (4.9%) with ISUP grade ≥2. A 4Kscore ≥7.5% would detect 56% of the ISUP grade ≥2 cancers and reduce detection of ISUP grade 1 by 64%. This approach would reduce MRI referrals by 71% and referrals to biopsy by 67% compared with performing MRI in all men with PSA ≥1.80 ng/ml and performing biopsies in all men with suspected lesions. With a 4Kscore cut-off of 7.5%, sensitivity and specificity for detecting ISUP grade ≥2 were 56% (95% CI = 35-74) and 72% (95% CI = 68-76), respectively. The AUC was 0.69 (95% CI = 0.58-0.79). The limited number of clinically significant PCa cases restricts generalizability.

Using a 4Kscore 7.5% cut-off as a reflex test before MRI in men with PSA 1.80-2.99 ng/ml could substantially reduce referrals to MRI and biopsy, reduce ISUP grade 1 cancer detection, and enable earlier detection of about half of ISUP grade ≥2 cancers. Many men with ISUP grade ≥2 cancers had 4Kscores <7.5%, and most men selected for MRI had PI-RADS <3. Evaluation of lower 4Kscore cut-offs, longer follow-up, and larger prospective studies is required before clinical implementation.