2.1

PCA3

PCA3 is a prostate specific non-coding mRNA that is overexpressed (60-100 fold) in more than 90% of prostate tumors. PCA3 is quantified relative to prostate specific genes that are expressed at a constant rate in prostate cancer cells [ ]. Several studies have demonstrated superiority of PCA3 as compared to PSA alone for predicting outcomes of men undergoing first or repeat biopsy [ , ]. PCA3 achieved FDA approval in February 2012 for prostate cancer screening in men in the pre-biopsy or repeat biopsy setting.

One of the first prospective trials evaluating PCA3 involved 570 men presenting for a prostate biopsy due to serum PSA ≥2.5, abnormal digital rectal examination (DRE), family history of prostate cancer, or other risk factors such as race. All men had urine collected after a digital rectal examination (DRE) and specimens were analyzed for quantified PCA3 values [ ]. Men with a lower PCA3 value (<5) had a low rate of prostate cancer on final biopsy (14%), while those with higher volume of PCA3 (>100) tended to test positive more frequently for cancer (69%). Additionally, a rise in PCA3 correlated with progression from benign conditions to cancer. BPH and prostatitis specimens had values of 15 and 13 respectively, ASAP/PIN tested in the range of 24-27, and prostate cancer approximated 38 [ ]. When alternative variables such as prostate volume, DRE result, PSA and PCA3 were implemented together, the area under the ROC curve (AUC) improved to 0.752 compared to PCA3 alone (0.680), suggesting PCA3 can be most useful when combined with existing risk factors for prostate cancer.

There is some controversy surrounding the optimal threshold value for PCA3. The FDA stated a value of 25 indicated a high risk for prostate cancer, however, multiple studies have shown a cut-off value of 35 demonstrates superior sensitivity (69%), specificity (65%), and AUC (0.734) [ , , ]. Different thresholds have since been proposed depending on the statistical goal of the screening. Wei et al. suggested a cut-off of 100 improved PPV (80%) prior to initial biopsy and a cut-off of 20 improved NPV (88%) prior to repeat biopsy [ ]. However, in the same studies, patients with a PCA3 > 100 had a ∼50% positive biopsy rate, and this remained consistent even after a second biopsy, which indicates another 50% of patients had significantly elevated PCA3 without cancer [ , , ].

Nonetheless, PCA3 has shown promise in guiding initial biopsy decisions. A multicenter, prospective trial analyzed 516 men with a with a PSA between 2.5 and 10 ng/ml who underwent PCA3 testing followed by a prostate biopsy. They found that PCA3 demonstrated a sensitivity of 64% and a specificity of 76% for clinically significant prostate cancer (Gleason Grade ≥2). Using PCA3 in their cohort, 60% of unnecessary biopsies would have been avoided, missing 11% of clinically significant prostate cancer (Gleason Grade ≥2) [ ].

Identifying a consistent threshold value for PCA3 has been difficult, and there are varying results depending on which value is chosen. At its best, PCA3 demonstrates a sensitivity of 69%, a specificity of 76% and an AUC of 0.734 for detection of Grade Group ≥2 prostate cancer ( Table 1 ). Still, there is a large proportion (∼50%) of patients that will have elevated PCA3 (greater than 100) and not have cancer identified on biopsy.

As a standalone liquid biomarker, PCA3 is inconsistent. However, it seems to provide the most benefit as an adjunct data-point that can be used in a more comprehensive prediction tool with other variables.

2.2

MPS (my prostate score)

MPS or MyProstateScore was developed at the University of Michigan as a urine-based screening test that requires a DRE prior to collection. The test integrates PSA with 2 nontissue based prostate cancer specific biomarkers: PCA3 and TMPRSS2:ERG (T2:ERG), a prostate cancer-associated gene fusion protein.

TMPRSS2 (trans-membrane protease serine 2):ERG (v-ets erythroblastosis virus E26 oncogene homolog) gene fusion is present in >50% of PSA-screened prostate cancers [ ]. In a multi-center prospective trial, 1,312 men who underwent prostate biopsy for prostate cancer had a fluorescence in situ hybridization (FISH) analysis run on their biopsy to identify the T2:ERG fusion gene [ ]. The FISH test was positive 51% of the time. MPS testing was then performed on the urine from the same men who provided the biopsies with a positivity rate of 52% and 92% concordance with the FISH analysis. MPS was positive in 4% of the urine samples provided from men who had benign biopsies. Additionally, T2:ERG showed a positive association (higher score) with presence of cancer, clinically significant cancer, number of positive biopsies, percentage of biopsy cores with cancer, greater involvement of a single core and age [ ].

MPS was subsequently tested against PSA for detection of prostate cancer in a large study using pre-defined multivariate regression models for prostate cancer risk estimation. Urine was collected in men presenting for prostate biopsy and patients were stratified based on initial vs. repeat biopsy, normal vs. abnormal DRE, and serum PSA (<3 vs ≥3 – ≤10) [ ]. In 55 of 56 comparisons (98%) from fourteen stratified subsets and >55 patients, MPS had higher AUC than PSA based models. Importantly, in the group presenting for an initial biopsy, PSA ≥3-≤10 and normal DRE, AUC for MPS was 0.752 as compared to 0.637 for PSA alone ( P < 0.0004) [ ]. When compared to traditional prostate cancer screening markers (PSA, percent free PSA, prostate cancer risk factors), MPS has consistently outperformed them in terms of sensitivity, specificity, and AUC [ , ].

Some practices have suggested MPS as an important tool in “ruling out” clinically significant cancer. Using a threshold value of 10 in a large prospective trial of over 1,500 men presenting for a prostate biopsy, Tosoian et al., achieved a sensitivity of 95% and a NPV of 98% for Grade Group ≥2 cancer. Further, 387 (33%) unnecessary biopsies would have been avoided, with only 10 (3%) of clinically significant prostate cancer diagnoses missed [ , ].

Tosoian et al. expanded their use of MPS in a study investigating men who had a previous negative prostate biopsy presenting for a repeat biopsy. The primary cohort consisted of 422 men presenting at 3 academic centers and the external validation cohort included 268 men presenting to seven community centers. Using a “rule out” threshold of 15, they were able to achieve 90% sensitivity and with a “rule in” threshold of 40, a specificity of 80%. The prevalence of Grade Group ≥2 was 5.1% for MPS ≤ 15, 13% for MPS values 15–40, and 27% for MPS >40. In the external validation cohort, men with MPS 0-15 had no cases of Grade Group ≥2, with 19% and 11.2% found to have Grade Group 2 and 3 respectively in the >40 MPS group [ ].

MPS seems to be an effective measure for identification of men who are high risk for harboring Grade Group ≥2 prostate cancer, including men presenting for repeat biopsy. It should be noted that there are specific thresholds defined in the literature that change the sensitivity or specificity of the test which can be useful during a shared decision-making process.

2.3

ExoDX

ExoDx is a urine-based novel gene expression signature that was derived from erythroblastosis virus E26 oncogene homolog (ERG) RNA, PCA3 RNA, and SPDEF RNA. These 3 forms of RNA are known to be over-expressed in prostate cancer cells and have been associated with the propagation of prostate cancer [ ]. The ExoDx test does not require a DRE, allowing for patients to complete the test remotely using a collection kit mailed to their home.

In the initial development study, the ExoDx score was compared to PSA alone for prediction of prostate cancer in 499 men undergoing a prostate biopsy. The score was then subsequently validated in 1,064 patients from 22 community practices and academic sites. Men included in the study were 50 years or older, prostate cancer-free, and had a suspicious DRE or PSA 2-20 prompting a prostate biopsy [ ].

In the developmental cohort, a score cut-off of 15.6 demonstrated a negative predictive value (NPV) of 96%, a sensitivity of 91%, and a positive predictive value of 37% in detecting Grade Group ≥2 prostate cancer. Using the same threshold, 20% of unnecessary biopsies were avoided and only 2% of clinically significant cancer was missed (none that were primary Gleason pattern 4). In the validation stage, a cut-off score of 20 was utilized with similar results: NPV of 90%, sensitivity of 87% and avoidance of 36% of unnecessary biopsies with 12% of clinically significant cancer missed [ ].

In men being evaluated for a repeat biopsy after undergoing a prior negative biopsy, similar results were obtained (AUC = 0.660) using the previously validated cut-off of 15.6. Sensitivity was found to be 82% and NPV 92%, with 27% of unnecessary biopsies avoided and 2.1% of clinically significant prostate cancer missed [ , ]. The AUC for ExoDx has since been consistently shown to be superior to PSA screening alone in multiple trials with the added advantage that it does not require a DRE prior to collection [ , ].

A randomized controlled trial investigated whether ExoDx scores changed decision making and patient outcomes in clinical practice. There was a 30% increased rate of high-grade prostate cancer detected and an estimated 49% fewer high-grade cancers missed when compared to the control group (without an ExoDx score). About 68% of urologists claimed that it influenced their decision on whether to recommend a biopsy [ ].

Overall, ExoDx has shown utility in stratifying patients who may be harboring Grade Group ≥2 prior to initial biopsy or repeat biopsy. Both 15.6 and 20 have been identified as validated cut-offs, with higher cut-points leading to less unnecessary biopsies, but slightly higher rates of missed cancer diagnoses.

2.4

Select Mdx

Select Mdx is a urine-based screening tool that detects specific mRNA (HOXC6 and DLX1) that have been suggested as independent risk factors for clinically significant prostate cancer (Grade Group ≥2). It produces a score in combination with prostate size, PSA density (PSAD) and prior negative prostate biopsy that predicts the presence of Grade Group ≥2 prostate cancer. It is not FDA approved but does have College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) accreditation.

There have been two prospective, randomized controlled, multicenter studies that have described the efficacy of Select Mdx. Both trials involved men presenting for initial or repeat prostate biopsy based on elevated PSA (≥3 ng/ml), abnormal DRE, or a family history of prostate cancer [ , ]. Initially, there were four mRNA expression profiles detected: homeobox C6 (HOXC6), distal-less homeobox 1 (DLX1), tudor domain containing 1 (TDRD1), and homeobox C4 (HOXC4) as these were shown to have independent value in predicting high grade prostate cancer (Grade Group ≥2) on biopsy. The combination of HOXC6 and DLX1 eventually produced the most consistent and robust response with an AUC of 0.760. Using logistic regression models, the investigators were then able to determine which ‘traditional’ prostate cancer screening variables produced the best results when combined with HOXC6/DLX1. Ultimately, prostate size, PSA density and previous negative biopsies with HOXC6/DLX1 produced the best AUC at 0.870 [ , ].

In men who are traditionally difficult to risk stratify (PSA >2 – <10), the SelectMdx test produced an impressive AUC of 0.850 as compared to traditional risk factors alone (0.660) [ ]. Authors also used decision curve analysis (DCA), a statistical test that calculates the clinical “net benefit” of a diagnostic test when compared to default strategies of treating all or no patients, to evaluate SelectMDx. They found a NPV of 98% for Grade Group ≥2, a total reduction of biopsies by 42% and a decrease of unnecessary biopsies by 53% [ ].

Another randomized, prospective trial sought to test the generalizability of SelectMDx, as their cohort primarily consistent of men with PSA ≥2 – ≤10 presenting for their initial prostate biopsy [ ]. SelectMDx score was compared to the prostate cancer prevention trial risk calculator (PCPTRC) for detection of clinically significant prostate cancer. AUC for SelectMDx was 0.82 as compared to 0.70 for the PCPTRC test. Additionally, SelectMDx boasted 89% sensitivity, 53% specificity and 95% negative predictive value [ ].

Interestingly, there was no defined cut-off in the initial randomized studies. However, in a separate prospective, multicenter study, a cut-off of 2.8 was used to validate Select Mdx. About 599 biopsy-naive men with a PSA ≥3 were subjected to a SelectMDx test, a prostate multiparametric MRI (mpMRI), and a biopsy. Using SelectMDx, 35% of prostate biopsies could have been avoided and 10% of clinically significant prostate cancer would be missed. However, mpMRI alone avoided 49% of biopsies and missed only 4.9% of high-grade cancer. If a positive SelectMDx test led to initiation of a mpMRI, 60% of biopsies were avoided, 13% of high grade cancers were missed, and there was a reduction in 38% of mpMRI’s [ ]. These data suggest SelectMDx has a useful role in limiting expensive and unnecessary testing (mpMRI and/or prostate biopsy). However, when using SelectMDx as a decision maker in place of or prior to MRI, there was at minimum a 5.1% increased rate of missed high grade cancer.

The effect of SelectMDx on rate of biopsy and prostate cancer detection was evaluated in 5 clinical practices with 418 men prior to initial prostate biopsy. The time to prostate biopsy was significantly shorter in the positive SelectMDx group (2 months) as compared to the negative SelectMdx group (5 months). Further, of the 71 (43%) that underwent biopsy after a positive Select Mdx result, 27 (38%) were diagnosed with prostate cancer, with 10 patients harboring Grade Group 2 disease [ , ].

Overall, SelectMDx has shown promise in detection of clinically significant cancer prior to first or repeat biopsy. There is data, however, suggesting that mpMRI alone may be sufficient to screen patients prior to biopsy [ ] and that the rate of cancer on biopsy specimens after a positive SelectMDx test (38%) may not be as consistent as previously believed [ , ]. Regardless, there are data supporting it’s use as an adjunct to MRI, and it seems to be superior as a screening modality when compared to the ‘traditional’ modalities for prostate cancer screening.

2.5

miR- “Sentinel PCa Test”

The sentinel micro-RNA (miRNA) prostate cancer test is a urine-based PSA adjunct that analyzes various types of mRNA within prostate cancer cells. This RNA is contained within exosomes, small extracellular vesicles that originate in the endosomal component of the cell, which are found in blood, urine, semen, and CSF. Exosomes contain small non-coding (snRNA), miRNA, and small nucleolar RNA, which are derived from the cytoplasmic and nucleolar region of the cell. Exosomes and extracellular vesicles have been identified in the tumor microenvironment of prostate cancer and other urologic cancers [ , , ].

The sentinel prostate cancer test uses a proprietary selection and classification algorithm that identifies informative snRNA within prostate cancer cells. This snRNA is then used to create an interrogation mRNA OpenArray platform that forms the basis of the screening tool. The investigators identified particular snRNAs to differentiate cancer from no cancer (“Sentinel PCa test”), Grade Group 1 from Grade Group 2-5 (“Sentinel CS test”), and Grade Group 1-2 from 3-5 (“Sentinel HG test”) [ ].

The Sentinel miR test was validated in 1,436 men whose urine was sampled prior to prostate biopsy. This included patients from two New York based medical centers and retrospectively collected specimens that were part of the GUBIOBank network. All three screening tests had a sensitivity of at least 93% and a specificity of at least 90%. The false positive rate was approximately 10%, which the authors speculate could have been due to missed cancer on biopsy or a primary test failure [ ].

A follow-up study involved a validation cohort of 763 biopsy-naïve patients undergoing systematic or systematic plus targeted biopsies (after mpMRI). Sensitivity for the classification of clinically significant prostate cancer (Grade Group ≥ 2) was 92% with a negative predictive value of 96% and a false positive rate of 23%. However, when evaluating the 208 patients who underwent systematic plus targeted biopsies, Sentinel miR predicted the positive targeted biopsy outcome 93% of the time and positive systemic biopsy outcome 100% of the time. The authors concluded that the 23% disconcordance between negative biopsy results and positive test results were due to false negative biopsies [ ].

The mIR Sentinel test is a new assay that is in the early stages of introduction into the clinical marketplace, with validation data first reported in 2020. Therefore, long-term outcomes and prospective studies are necessary as the test becomes more widely used.

3.1

Percent Free PSA (% fPSA)

Percent free PSA (% fPSA) was one of the first blood-based PSA adjuncts to be introduced. The goal was to improve the specificity of PSA while maintaining a high sensitivity rate. The need for a more specific biomarker was especially pertinent in men with a PSA in the “gray zone” (PSA ≥2-≤10), where some studies had suggested just a 25% rate of prostate cancer [ ].

Percent free PSA is founded on the scientific notion that when prostate cancer is present, it precipitates PSA bound to alpha-1 chymotrypsin, which then correlates to lower levels of free PSA in the blood. The lower the percentage of free PSA, the more likely prostate cancer will be present on a prostate biopsy [ , ]. A % fPSA less than 25% has traditionally been the cut-off for increased likelihood of harboring prostate cancer. Many labs, including our own, report % fPSA results with a breakdown of risk based on a range of % fPSA values and age ( Table 2 ) [ ].

Published in 1996, one of the earlier investigations into free PSA was from Partin et al. who explored % fPSA values in 217 men with prior biopsy specimens. He found that patients with % fPSA < 10% had a higher (63%) chance of prostate cancer on biopsy than patients with % fPSA >26% (2%). Additionally, he noted that using % fPSA maintained sensitivity at 95%, increased specificity to 29% and led to avoidance of 29% of negative biopsies [ ].

Historic performance of % fPSA has since been investigated in a meta-analysis looking at the average AUC, which found it to be comparable to other prostate cancer screening tools at 0.70 [ ]. Interestingly, the likelihood ratio of finding prostate cancer on biopsy did not exceed 2, unless the percent free PSA cut off was set at 15% or less [ ].

The utility of % fPSA was expanded in a prospective, randomized study of 773 men where it demonstrated a 95% sensitivity and correlation with postprostatectomy pathologic stage and aggressiveness of disease (when % fPSA <15%), although it is not commonly used for that measure [ , ].

% fPSA has a multitude of data demonstrating its ability risk stratify patients who have a higher risk of prostate cancer on biopsy. Unlike other markers, it does not differentiate the risk of patients harboring clinically significant disease. This may be viewed as a major limitation of the test because a proportion of patients who are designated high risk on a % fPSA test might not harbor clinically significant disease necessitating a biopsy. % fPSA is one of the most widely implemented PSA adjuncts, likely due to the length of time on the market and cheaper price compared to other biomarkers.

3.2

PHI

The PHI score is a blood-based prostate cancer screening tool consisting of total PSA, free PSA, and 2proPSA (an incomplete form of a PSA precursor). A PHI score is created from a formula: ((–2)proPSA/fPSA) × √PSA. It achieved FDA approved in June 2012 for men with a PSA between 4 and 10 ng/mL; however, it can be used in men presenting with an abnormal DRE as well [ , ]. The score indicates that men with a higher total PSA, 2proPSA, and lower free PSA are more likely to have prostate cancer found on initial or repeat biopsy.

PHI was thought to be a superior predictor of prostate cancer as compared to free PSA or total PSA alone as it incorporated both elements into one score. Further, there are data suggesting the addition of 2proPSA leads to increased detection of clinically significant prostate cancer (Grade Group ≥2) when compared to a model consisting of just PSA and % fPSA [ , ]. PHI has outperformed free and total PSA in prediction of prostate cancer on biopsy (AUC 0.70), with improved detection of clinically significant prostate cancer (Grade Group ≥2) as well (AUC 0.698) [ ].

A challenging component of the PHI score is defining the optimal cut-off value where sensitivity and specificity are maximized. Loeb et al. investigated this notion in a study where 892 men with a PSA between 2-10 ng/ml underwent a serum PHI test followed by a prostate biopsy to determine the ability of PHI to detect Grade Group ≥ 2 prostate cancer. Sensitivities were set at pre-defined intervals (80%, 85%, 90%, 95%) using specific PHI cut-offs. Specificity for the detection of Grade Group ≥ 2 prostate cancer was determined for each cut-off. A PHI cut-off of 34.4 corresponded to a 80% sensitivity with a 46.4% specificity for Grade Group ≥ 2 prostate cancer. A PHI cut-off of 31.9, 28.9 and 28.1 corresponded to sensitivities of 85%, 90% and 95% with specificities of 38.9%, 29.7%, and 27.4% respectively. The author’s highlighted a cut-off value of 28.6 (90% sensitivity) spared 30.1% of men from an unnecessary biopsy, missing only 4.8% of Grade Group ≥ 2 prostate cancer [ ]. Similarly, de la Calle et. al. found a value of 24 produced a 95% sensitivity and 36% specificity with avoidance of 41% of unnecessary biopsies and only 5 men with false negative findings [ ].

In a prospective trial involving 4 large urology group practices, PHI showed a significant effect on physician decision making (73% of cases), with almost a 50% reduction in biopsies as compared to control (36.4% vs. 60.3%). There was no difference in percentage of positive biopsies although a modest reduction in detection of Gleason 6 disease was observed (9.9% vs 18.4%). 92% of physicians in the study reported that the PHI score was helpful, especially in alleviating patient concern regarding the potential for cancer when PHI score was low (28% of cases) [ ]. The study was subsequently criticized regarding the possibility of overlooking aggressive cancer as the omitted prostate cancer rate was ∼30% [ ]. In response, the authors stated that patients without biopsies were followed according to AUA and NCCN guidelines and due to the small number of high-grade cancers in their cohort, firm conclusions regarding biopsy omission should not be drawn [ , , ].

When directly compared to PCA3 in prostate biopsy-naive men, PHI consistently performed better with AUC’s of 0.70-0.77 as compared to 0.59-0.73 for PCA3 [ , ]. Additionally, multiple, large prospective studies have affirmed the superiority of PHI in the detection of prostate cancer and avoidance of unnecessary biopsies as compared to PSA alone or % fPSA alone [ , , , , , ].

As PHI continued to show promising results, Tosoian et al. sought to improve detection of cancer with the addition of PSA density to the traditional PHI formula, termed PHI-density (PHID). He found that in 118 men who underwent biopsy, a PHID threshold of 0.43 was 98% sensitive and 38% specific for clinically significant prostate cancer (Grade Group ≥2), with an AUC of 0.84. Further, he determined that using PHID, 38% of unnecessary biopsies could be avoided while missing only 2% of clinically significant cancers [ ]. Another study supported these data as they revealed use of PHID (cut-off >0.9) led to an avoidance of 20% of unnecessary biopsies while missing only 1 case of clinically significant disease [ ].

Critics have pointed out that physicians may miss clinically significant cancer when the decision to biopsy is made solely on PHI score [ ]. However, when used in conjunction with other traditional risk factors, such as MRI and DRE, it can serve as a useful clinical tool.

3.3

4K Score

The 4K score is a blood-based biomarker used to identify men harboring high grade prostate cancer who present with elevated PSA or abnormal DRE [ ]. It is not FDA approved but has accreditation from CAP and CLIA.

Total PSA, free PSA, intact PSA, and human kallikrein (hK2) comprise the four kallikreins, a family of blood-based proteins. The 4K score was validated in several European trials to identify men harboring pathologically indolent disease vs aggressive prostate cancer [ ].

The 4K score measures these 4 blood-based proteins and combines them with age, DRE findings, and history of prior negative biopsy (yes/no) to generate a risk-based assessment. During a validation trial in the United States, a large cohort of men from multiple institutions had a 4K score, PSA and DRE performed prior to undergoing a prostate biopsy. 4K score displayed excellent predictability with an AUC of 0.820. Post-hoc analysis revealed each kallikrein contributed significantly to prediction outcomes. On DCA analysis, a strategy where a biopsy would be performed for ≥ 9% probability of Grade Group ≥2 cancer, 43% of unnecessary biopsies would be avoided and only 2.4% of Grade Group ≥2 diagnoses would have been delayed. Additionally, among this group only 0.2% contained Gleason 4+3 disease. When the cut-off was increased to 15%, 58% percent of unnecessary biopsies were avoided with a higher rate (4.7%) of missed cancer [ , ].

After the initial, multicenter publication validating the 4K score [ ] was published, several follow-up studies sought to confirm these data. A meta-analysis examining the results of 12 clinical validation studies comprising a total of 11,134 patients demonstrated a pooled AUC of 0.810, almost perfectly aligning with the initial reported outcome. Even when the data was stratified based on use of the contemporary 4K score, the AUC was identical [ ].

Expansion of the diagnostic applicability of the 4K score was suggested in large population-based study examining its predictability of prostate cancer specific metastasis and death after 20 years. 43,692 patients who participated in the Vasterbotten Intervention Project, a Swedish cohort study where all men between 40 and 60 years old were invited to receive a free health examination including cryopreservation of blood, had 4K score markers measured in a retrospective fashion. Unsurprisingly, men within the top quartile of PSA encompassed nearly three quarters of prostate cancer deaths and were 10-fold higher to die of prostate cancer as compared to men with PSA below the median. 4K score outperformed both total PSA and free PSA in predicting prostate cancer specific death in men with moderately elevated PSA (≥2 ng/ml) with a c-index of 0.862. In men with a low 4K score (≤7.5%), the risk of metastasis and death was exceedingly low, reducing unnecessary biopsies by 40%-60%. Even in men with elevated PSA, if 4K score was low, the risk of metastasis and death was negligible (ex. 60 year old with a PSA ≥3 ng/ml and a 4K score <7.5% had 0.55% risk of prostate cancer death at 10 years) [ ].

Konety et al. investigated the impact of the 4K score in an academic and a community-practice setting. In the study, scores were stratified into low risk (<7.5%), intermediate (7.5%-19.9%) and high risk (≥20%). Test results influenced medical decision making 88.7% of the time, with biopsy avoidance in 94% (low risk), 52.9% (intermediate risk), and 19% (high risk) of cases. There were significantly higher rates of clinically significant prostate cancer found in the high risk group [ ].

Race and ethnicity increase or decrease a patient’s risk of clinically significant prostate cancer. 4K score has been validated in several studies on its effectiveness amongst multiple races, including African American, Hawaiian, Japanese, Latino, and Caucasian men. Multiple studies have confirmed that the AUC is the same (0.81) when stratified for race, indicating the widespread applicability of 4K score in patients with different race-based risk statuses [ , ].

Similar to the other biomarkers on the market, 4K score has shown that it can improve the detection of clinically significant cancer while avoiding unnecessary biopsies as compared to traditional prostate cancer screening methods. There are data also suggesting that it may correlate with prostate cancer specific death and metastasis [ ]. Further, it has been validated in multiple populations stratified by race, which increases the generalizability of the test [ , ].