Performance of 4Kscore as a Reflex Test to Prostate-specific Antigen in the GÖTEBORG-2 Prostate Cancer Screening Trial

Abstract

Background and objective: We investigated whether adding 4Kscore as a reflex test to prostate-specific antigen (PSA) could improve the screening algorithm for prostate cancer (PC).

Methods: In the GÖTEBORG-2 PC screening trial, 38 000men (50-60 yr) were invited to PSA testing and, if elevated, followed by magnetic resonance imaging (MRI). For 571 men with PSA ≥3.0 ng/ml and evaluable outcomes, 4Kscore was calculated. The performance using a prespecified 4Kscore cutoff of 7.5% was evaluated.

Key findings and limitations: The area under the curve for 4Kscore to identify intermediate- and high-risk PC was 0.84 (95% confidence interval 0.79-0.89), and the positive predictive value, and negative predictive value were 15% (0.12-0.20) and 99% (97-100%), respectively. Of the 54 men diagnosed with intermediate- or high-grade PC, two had a 4Kscore cutoff below 7.5%, both with organ-confined intermediate-risk PC. Per 1000 men with elevated PSA, adding 4Kscore would have resulted in avoidance of MRI for 408 (41%) men, biopsies for 95 (28% reduction) men, and diagnosis of 23 low-grade cancers (23% reduction) while delaying the diagnosis of four men with intermediate-grade cancers (4%).

Conclusions and clinical implications: Including 4Kscore as a reflex test for men with elevated PSA reduces the need for MRI and biopsy markedly, and results in less overdiagnosis of low-grade PC at the cost of delaying the diagnosis of intermediate-grade PC in a few men. These results add further evidence for including new blood-based biomarkers in addition to PSA to improve the harm and benefit ratio of PC screening and reduce the need for resource-demanding MRI and biopsies.

Keywords: 4Kscore; GOTEBORG-2 study; Magnetic resonance imaging; Prostate cancer; Prostate-specific antigen; Screening.

Fig. 1 –

Study flow. G2 study = GÖTEBORG-2 randomized screening study; G2B = biomarker study within G2 study; ISUP = International Society of Urological Pathology; MRI = magnetic resonance imaging; PSA = prostate-specific antigen.

Fig. 2 –

Box-dot plots of 4Kscore distribution by MRI and biopsy outcome. MRI = magnetic resonance imaging; ISUP = International Society of Urological Pathology; MRI = magnetic resonance imaging.

Fig. 3 –

Sensitivity, specificity, PPV, and NPV by different cutoffs of 4Kscore for the diagnosis of intermediate- to high-grade prostate cancer (ISUP ≥2). ISUP = International Society of Urological Pathology; NPV = negative predictive value; PPV = positive predictive value.