What is the 4Kscore?
The 4Kscore is a blood-based laboratory test that measures four kallikrein proteins (total PSA, free PSA, intact PSA, and human kallikrein 2) combined with clinical variables (age, digital rectal examination findings, and prior biopsy status) to calculate a patient's percent likelihood of harboring high-grade (Gleason ≥7) prostate cancer on biopsy. 1
Test Components and Methodology
The 4Kscore integrates the following elements:
- Four kallikrein biomarkers measured from serum: total PSA, free PSA, intact PSA, and human kallikrein 2 (hK2) 1
- Clinical variables: patient age, digital rectal examination results, and prior biopsy status 1
- Output: A percentage representing the probability of finding Gleason ≥7 cancer on prostate biopsy 1
The test is performed through a single CLIA-accredited laboratory in Nashville, Tennessee and is classified as a laboratory-developed test rather than an FDA-approved diagnostic 1.
Clinical Performance
The 4Kscore demonstrates strong discriminatory ability for detecting clinically significant prostate cancer:
- Area under the curve (AUC) of 0.82 in prospective multi-institutional U.S. trials 1, 2
- In a study of 1,012 patients, using a 15% risk threshold allowed 591 biopsies (58%) to be avoided while detecting 183 high-grade tumors and missing only 48 high-grade tumors (4.7% of participants) 1
- In a larger study of 6,129 men, using a 6% risk cutoff allowed 428 of 1,000 men to avoid biopsy, detecting 119 of 133 high-grade cancers while missing 14 1
The test performs equally well with or without digital rectal examination information (AUC 0.821 with DRE vs. 0.818 without DRE), making it useful in primary care settings where DRE may not be routinely performed 3.
Clinical Indications According to NCCN
The NCCN consensus recommends the 4Kscore can be considered for patients before initial biopsy and for those with prior negative biopsy who are thought to be at higher risk for clinically significant prostate cancer. 1
Specific scenarios where 4Kscore may be informative:
- Patients with PSA >3.0 ng/mL who meet criteria for biopsy consideration but wish to further define their probability of high-grade cancer 1
- Men with prior negative biopsy and persistently elevated PSA 1
- As an alternative to immediate biopsy to improve specificity of PSA testing 1
Critical Limitations and Caveats
No established cutoff threshold exists for the 4Kscore. 1 The NCCN emphasizes that if a 4Kscore test is performed, the patient and urologist must discuss the results together to decide whether to proceed with biopsy, as there is no universally accepted risk percentage that mandates or excludes biopsy 1.
Common thresholds used in clinical studies include:
- 6% risk cutoff (more conservative, fewer missed cancers) 1
- 7.5% cutoff (used in some clinical algorithms) 4
- 15% risk cutoff (more aggressive biopsy avoidance strategy) 1
Digital rectal examination timing: While DRE causes a statistically significant but clinically minimal decrease in 4Kscore (median 0.43% absolute decrease), blood should ideally be drawn before DRE or at least 96 hours after to avoid any potential confounding 4.
Relationship to Surgical Pathology
Higher 4Kscores correlate with more aggressive disease at radical prostatectomy:
- Median 4Kscore of 7% for Gleason ≥6 cancers in surgical specimens 5
- Median 4Kscore of 25% for Gleason 7 cancers 5
- Median 4Kscore of 47% for Gleason ≥8 cancers 5
- Median 4Kscore of 36% for non-organ-confined cancer versus 19% for organ-confined disease 5
Emerging Refinements
4K Density (4Kscore divided by prostate volume) is a novel metric that adjusts for prostate size and may improve risk stratification, particularly in men with benign prostatic hyperplasia and larger prostates where PSA elevation may be confounded 6. This metric achieved an AUC of 0.81 and outperformed both standard 4Kscore (AUC 0.76) and PSA density (AUC 0.76) in detecting Grade Group ≥2 cancer 6.