Prospective validation of microseminoprotein-ß added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort.

OBJECTIVES: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-ß (MSP) adds predictive value. PATIENTS AND METHODS: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. RESULTS: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014-0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. CONCLUSION: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.

Prostate Cancer in Older Adults: Risk of Clinically Meaningful Disease, the Role of Screening and Special Considerations.

PURPOSE OF REVIEW: Prostate cancer is the second most common cancer in men in the USA and several studies suggest more aggressive disease in older patients. However, screening remains controversial, especially in the older patient population. RECENT FINDINGS: Aggressive prostate cancers are more common in older men. Screening trial results are conflicting but data suggest an improvement in prostate cancer mortality and increased detection of metastatic disease with screening. When PSA is utilized with multiparametric MRI and biomarker assays, patients at significant risk of clinically meaningful prostate cancer can be appropriately selected for biopsy. A thoughtful and individualized approach is central when considering prostate cancer screening in older men. This approach includes life expectancy estimation, use of appropriate geriatric assessment tools, use of multiparametric MRI and biomarkers in addition to PSA, and most importantly shared decision-making with patients.

Using biomarkers in patients with positive multiparametric magnetic resonance imaging: 4Kscore predicts the presence of cancer outside the index lesion.

OBJECTIVES: To evaluate if the blood biomarker, 4Kscore, in addition to multiparametric magnetic resonance imaging information could identify patients who would benefit from undergoing only a targeted biopsy. METHODS: We retrospectively analyzed a population of 256 men with positive multiparametric magnetic resonance imaging who underwent standard + targeted biopsy at Mount Sinai Hospital, New York, NY, USA. 4Kscore (OPKO Health, Miami, FL, USA) was sampled from all patients before biopsy. Uni- and multivariable binary logistic regression analyses were carried out to predict clinically significant prostate cancer, defined as International Society of Urological Pathology grade group ≥2, in standard biopsy cores. The model with the best area under the curve was selected and internal validation was carried out using the leave-one-out cross-validation. RESULTS: The developed model showed an area under the curve of 0.86. Carrying out only targeted biopsy in patients with a model-derived probability <12.5% resulted in 39.5% (n = 101) fewer standard biopsies and a 33.9% (n = 20) reduction of detecting grade group 1 disease, while missing grade group ≥2 in 5.2% (n = 4) using standard biopsy only and 1.1% (n = 1) using standard biopsy + targeted biopsy. CONCLUSIONS: 4Kscore in combination with multiparametric magnetic resonance imaging can help to reduce unnecessary standard biopsy and decrease detection of clinically insignificant prostate cancer.

Prostate Cancer Markers.

Diagnostic biomarkers derived from blood, urine, or prostate tissue provide additional information beyond clinical calculators to determine the risk of detecting high-grade prostate cancer. Once diagnosed, multiple markers leverage prostate cancer biopsy tissue to prognosticate clinical outcomes, including adverse pathology at radical prostatectomy, disease recurrence, and prostate cancer mortality; however the clinical utility of some outcomes to patient decision making is unclear. Markers using tissue from radical prostatectomy specimens provide additional information about the risk of biochemical recurrence, development of metastatic disease, and subsequent mortality beyond existing multivariable clinical calculators (the use of a marker to simply sub-stratify risk groups such as the NCCN groups is of minimal value). No biomarkers currently available for prostate cancer have been prospectively validated to be predict an improved clinical outcome for a specific therapy based on the test result; however, further research and development of these tests may produce a truly predictive biomarker for prostate cancer treatment.

Novel Biomarkers for Prostate Cancer Detection and Prognosis.

Prostate cancer (PCa) remains as one of the most controversial issues in health care because of the dilemmas related to screening using Prostate Specific Antigen (PSA). A high number of false positive biopsies and an elevated rate of overdiagnosis are the main problems associated with PSA. New PCa biomarkers have been recently proposed to increase the predictive value of PSA. The published results showed that PCA3 score, Prostate Health Index and 4Kscore can reduce the number of unnecessary biopsies, outperforming better than PSA and the percentage of free PSA. Furthermore, 4Kscore provides with high accuracy an individual risk for high-grade PCa. High values of PHI are also associated with tumor aggressiveness. In contrast, the relationship of PCA3 score with aggressiveness remains controversial, with studies showing opposite conclusions. Finally, the development of molecular biology has opened the study of genes, among them TMPRSS2:ERG fusion gene and miRNAs, in PCa detection and prognosis.

Prostate Cancer Detection and Prognosis: From Prostate Specific Antigen (PSA) to Exosomal Biomarkers.

Prostate specific antigen (PSA) remains the most used biomarker in the management of early prostate cancer (PCa), in spite of the problems related to false positive results and overdiagnosis. New biomarkers have been proposed in recent years with the aim of increasing specificity and distinguishing aggressive from non-aggressive PCa. The emerging role of the prostate health index and the 4Kscore is reviewed in this article. Both are blood-based tests related to the aggressiveness of the tumor, which provide the risk of suffering PCa and avoiding negative biopsies. Furthermore, the use of urine has emerged as a non-invasive way to identify new biomarkers in recent years, including the PCA3 and TMPRSS2:ERG fusion gene. Available results about the PCA3 score showed its usefulness to decide the repetition of biopsy in patients with a previous negative result, although its relationship with the aggressiveness of the tumor is controversial. More recently, aberrant microRNA expression in PCa has been reported by different authors. Preliminary results suggest the utility of circulating and urinary microRNAs in the detection and prognosis of PCa. Although several of these new biomarkers have been recommended by different guidelines, large prospective and comparative studies are necessary to establish their value in PCa detection and prognosis.

Molecular and diffusion features for identification of clinically significant prostate cancer in PI-RADS 3 lesions.

BACKGROUND: The recommendation to perform biopsy of PIRADS 3 lesions has not been adopted with strength as compared to higher scored lesions on multiparametric MRI. This represents a challenging scenario and an unmet need for clinicians to apply a risk adapted approach in these cases. In the present study, we examined clinical and radiologic characteristics in men with PI-RADS 3 index lesions that can predict csPCa on mpMRI-target biopsy. METHODS: Revision of a prospective database with patients who underwent targeted and systematic biopsies from 2015 to 2023 for PI-RADS 3 lesions identified on mpMRI. Baseline variables were collected, such as PSA density (PSAd), 4Kscore, prostate size, and the apparent diffusion coefficient (ADC) value of the lesion on mpMRI. Logistic regression, receiver operating characteristic (ROC) and decision curve analyses (DCA) assessing the association between clinic-radiologic factors and csPCa were performed. RESULTS: Overall, 230 patients were included in the study and the median age was 65 years. The median prostate size and PSA were 50 g and 6.26 ng/mL, respectively. 17.4% of patients had csPCa, while 27.5% had Gleason group 1. In univariable logistic analyses, we found that age, BMI, prostate size, PSAd, ADC, and 4Kscore were significant csPCa predictors (P < 0.05). PSAd showed the best prediction performance in terms of AUC (= 0.679). On multivariable analysis, PSAd and 4Kscore were associated with csPCa. The net benefit of PSAd combined with clinical features was superior to those of other parameters. Within patients with PSAd < 0.15, 4Kscore was a statistically significant predictor of csPCa (OR = 3.25, P = 0.032). CONCLUSION: PSAd and 4Kscore are better predictors of csPCa in patients with PIRADS 3 lesions compared to ADC. The predictive role of 4Kscore is higher in patients with low PSAd. These results can assist practitioners in the risk stratification of patients with equivocal lesions to determine the need of biopsy.

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

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. PATIENT SUMMARY: In this study, 4Kscore, a blood-based biomarker, as a reflex test for men with elevated prostate-specific antigen (PSA), reduces the need for magnetic resonance imaging and biopsy. These results support the inclusion of new blood-based biomarkers in addition to PSA.

Optimum threshold of the 4Kscore for biopsy in men with negative or indeterminate multiparametric magnetic resonance imaging.

Objective: The study aims to identify the optimal 4Kscore thresholds to determine the need for a prostate biopsy when multiparametric magnetic resonance imaging (MRI) (mpMRI) is negative or indeterminate. Materials and methods: We analysed retrospective data from men in eight different institutions who underwent an mpMRI, 4Kscore and prostate biopsy for evaluation of prostate cancer. We selected men with a negative (PIRADS ≤2) or indeterminate (PIRADS 3) mpMRI. 4Kscore values were categorized into ranges of 1-7, 8-19, 20-32 and greater than 32. We evaluated the proportion of men with grade group 2 or higher (GG2+) cancer in groups defined by PIRADS and 4Kscore. We also evaluated the number of biopsies avoided and GG2+ cancer missed in each group reported depend on 4Kscore cutoff points. Results: Among 1111 men who had an mpMRI, 4Kscore and biopsy, 625 of them had PIRADS ≤3 on mpMRI: 374 negative (PIRADS ≤2) and 251 indeterminate (PIRADS 3). In men with a negative mpMRI, we found a 4Kscore cut-point of 33 resulted in an increased risk of GG2+ cancer on biopsy. In patients with an equivocal lesion on mpMRI, men with a 4Kscore cutoff ≥8 had a greater risk of GG2+ cancer on biopsy. Decision curve analysis supported the proposed cut-points in each mpMRI group. Conclusions: In men with negative and indeterminate mpMRI, we found the best 4Kscore threshold to determine the need for biopsy to be 33 and 8 respectively. Future prospective studies in independent populations are needed to confirm these findings.

Implementation of 4Kscore as a Secondary Test Before Prostate Biopsy: Impact on US Population Trends for Prostate Cancer.

Prostate cancer screening using prostate-specific antigen (PSA) reduces prostate cancer mortality at the cost of unnecessary prostate biopsy, overdiagnosis, and overtreatment. Several secondary tests have been developed to restrict biopsy to men at the greatest risk of high-grade disease. 4Kscore is a widely used secondary test that has been shown to reduce biopsy rates by approximately two-thirds in routine clinical practice. We estimated how 4Kscore implementation has affected cancer trends in the US population. We combined data from the US validation study of 4Kscore with data from the diagnostic test impact study, using a basis of 70 000 on-label 4Kscore tests performed annually. We estimate that each year, 4Kscore leads to 45 200 fewer biopsies and 9400 fewer overdiagnoses of low-grade cancer, at the cost of delayed diagnosis of high-grade prostate cancer for 3450 patients, of whom two-thirds have International Society of Urological Pathology grade group 2 disease. These findings need to be taken into consideration when studying epidemiologic trends in prostate cancer. They also suggest that high levels of overdiagnosis and overtreatment are not inevitable characteristics of PSA screening, but can be mitigated by additional tests. Patient summary: We estimate that use of a test called 4Kscore to predict the probability that a patient has high-grade prostate cancer has significantly reduced the number of unnecessary biopsies and overdiagnosis of low-grade cancer in the USA. These decisions may result in delayed diagnosis of high-grade cancer in some patients. 4Kscore is a useful additional test in the management of prostate cancer.

4Kscore diagnostic value in patients with high-grade prostate cancer using cutoff values of 7.5% to 10%: A meta-analysis.

BACKGROUND: Reported 4Kscore thresholds used to differentiate between patients with and without high-grade prostate cancer (CaP) were variable. Patients with 4Kscore results <7.5% have been proven to be at low risk of carrying high-grade CaP. This study employed a meta-analysis approach in order to assess the diagnostic accuracy of the 4Kscore as a means of detecting high-grade CaP in prostate biopsy samples using cutoff values of 7.5% to 10%. METHODS: Relevant studies published as of December 2019 were identified via searching PubMed, Embase, and Cochrane Library. Data pertaining to 4Kscore diagnostic accuracy were then extracted from these studies and utilized for the calculation of pooled sensitivity , specificity , diagnostic odds ratio , and area under the curve values relating to high-grade CaP diagnosis. RESULTS: In total, 9 studies incorporating 1,689 high-grade CaP patients were included in our meta-analysis. Following the exclusion of 1 outlier study, the pooled sensitivity, specificity , diagnostic odds ratio , and area under the curve values for 4Kscore diagnostic accuracy with corresponding 95% confidence intervals (CIs) were 0.90 (95%CI: 0.86-0.92), 0.44 (95%CI: 0.36-0.52), 7 (95%CI: 5-8), and 0.81 (95%CI: 0.77-0.84), respectively. CONCLUSION: These findings indicate that 4Kscore can be used as a model for the diagnosis of high-grade CaP. However, we detected significant heterogeneity among studies that was not explained by subgroup or meta-regression analysis, thus lowering our confidence in these results. It is therefore essential that future large, well-designed studies be conducted so as to confirm whether the 4Kscore can be used with cutoff values of 7.5% to 10% to reliably detect high-grade CaP.

Towards personalized prostate cancer screening.

The value of the prostate-specific antigen (PSA) in prostate cancer (PCa) screening is controversial. Contradictory results have been reported in the literature as to whether PSA-based screening reduces mortality. Also, some of the studies published are methodologically flawed. However, evidence consistently demonstrates that screening programs results in the identification of patients with indolent prostatic tumors which rate has increased. Controversy is not only about the value of PSA-based screening, but also about the age range for screening, risk groups based on baseline PSA, PSA ranges, or the use of other biomarkers (PHI, 4Kscore). At present, PCa screening in the general population is not recommended by most scientific societies, although it can be used after discussing the risks and benefits with the patient. When discussing the need to perform a screening, the risks of using screening (lack of specificity of PSA, overdiagnosis) must be weighed against the risks of not performing it (increased rate of patients with initial diagnosis of metastasis). In the recent years, a number of authors have advocated the use of personalized screening, which could change the risk/benefit evaluation, thereby making screening necessary on the basis of a set of individual factors.

PSA Based Biomarkers, Imagistic Techniques and Combined Tests for a Better Diagnostic of Localized Prostate Cancer.

Prostate cancer represents the most encountered urinary malignancy in males over 50 years old, and the second most diagnosed after lung cancer globally. Digital rectal examination and prostatic specific antigen were the long-time standard tools for diagnosis but with a significant risk of overdiagnosis and overtreatment. Magnetic resonance imaging recently entered the diagnosis process, but to this date, there is no specific biomarker that accurately indicates whether to proceed with the prostate biopsy. Research in this area has gone towards this direction, and recently, serum, urine, imagistic, tissue biomarkers, and Risk Calculators promise to help better diagnose and stratify prostate cancer. In order to eliminate the comorbidities that appear along with the diagnosis and treatment of this disease, there is a constant need to implement new diagnostic strategies. Important uro-oncology associations recommend the use of novel biomarkers in the grey area of prostate cancer, to better distinguish the next step in the diagnostic process. Although it is not that simple, they should be integrated according to the clinical policies, and it should be considered that statistical significance does not always equal clinical significance. In this review, we analyzed the contribution of prostate-specific antigen (PSA)-based biomarkers (PHI, PHID, 4Kscore, STHLM3), imagistic techniques (mp-MRI and mp-US), and combined tests in the early diagnosis process of localized prostate cancer.

Avoiding Unnecessary Magnetic Resonance Imaging (MRI) and Biopsies: Negative and Positive Predictive Value of MRI According to Prostate-specific Antigen Density, 4Kscore and Risk Calculators.

The 2019 European Association of Urology guidelines recommend multiparametric magnetic resonance imaging (mpMRI) for biopsy-naïve patients with clinical suspicion of prostate cancer (PC) and avoiding biopsy in patients with negative mpMRI and low clinical suspicion. However, consensus on the optimal definition of low clinical suspicion is lacking. We evaluated 266 biopsy-naïve patients who underwent mpMRI, the 4Kscore test, and prostate biopsy to define the best strategy to avoid unnecessary testing and biopsies. The European Randomized Study of Screening for Prostate Cancer risk calculator (ERSPC-RC) and prostate-specific antigen density (PSAd) were also considered. For men with Prostate Imaging-Reporting and Data System v2.0 (PI-RADS) 1â¿¿2 lesions, the highest negative predictive value was observed for those with low or intermediate 4Kscore risk (96.9% and 97.1%), PSAd <0.10ng/ml/cm3 (98.7%), and ERSPC-RC <2% (98.7%). For men with PI-RADS 3â¿¿5 lesions the lowest positive predictive value was observed for those with low 4Kscore risk (0%), PSAd <0.10ng/ml/cm3 (13.2%), and ERSPC-RC <2% (12.3%). The best biopsy strategy was an initial 4Kscore followed by mpMRI if the 4Kscore was>7.5% and a subsequent biopsy if the mpMRI was positive (PI-RADS 3â¿¿5) or the 4Kscore was â¿¥18%. This would result in missing 2.7% (2/74) of clinically significant PCs (csPCs) and avoiding 34.2% of biopsies. Initial mpMRI followed by biopsy for negative mpMRI (PI-RADS 1â¿¿2) if the 4Kscore was â¿¥18% or PSAd was â¿¥0.10ng/ml/cm3 resulted in a similar percentage of csPC missed (2.7% [2/74] and 1.3% [1/74]) but slightly fewer biopsies avoided (25.2% and 28.1%). Physicians should consider clinical risk screening tools when ordering and interpreting mpMRI results to avoid unnecessary testing and diagnostic errors. PATIENT SUMMARY: Performing the 4Kscore test in conjunction with multiparametric magnetic resonance imaging for men with a clinical suspicion of prostate cancer may help to reduce unnecessary biopsies.

A Four-kallikrein Panel and ß-Microseminoprotein in Predicting High-grade Prostate Cancer on Biopsy: An Independent Replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™. OBJECTIVE: To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether ß-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. DESIGN, SETTING, AND PARTICIPANTS: Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The predictive accuracy of prespecified prediction models was compared with biopsy outcomes. RESULTS AND LIMITATIONS: Among men with PSA of 4.0-25ng/ml, 1111 had prostate cancer, 318 of whom had high-grade disease. Total PSA and age predicted high-grade cancer with an area under the curve of 0.648 (95% confidence interval [CI] 0.614-0.681) and the four-kallikrein panel increased discrimination to 0.746 (95% CI 0.717-0.774). Adding MSP to the four-kallikrein panel led to a significant (Wald test; p=0.015) but small increase (0.003) in discrimination. Limitations include a risk of verification bias among men with PSA of 3.0-3.99ng/ml and the absence of digital rectal examination results. CONCLUSIONS: These findings provide additional evidence that kallikrein markers can be used to inform biopsy decision-making. Further studies are needed to define the role of MSP. PATIENT SUMMARY: Four kallikrein markers and ß-microseminoprotein in blood improve discrimination of high-grade prostate cancer at biopsy in men with elevated prostate-specific antigen.

Developing an effective strategy to improve the detection of significant prostate cancer by combining the 4Kscore and multiparametric MRI.

OBJECTIVES: Recent years have seen the development of biomarkers and imaging technologies designed to improve the specificity of PSA. Widespread implementation of imaging technologies, such as mp-MRI raises considerable logistical challenges. Our objective was to evaluate a biopsy strategy that utilizes selective mp-MRI as a follow-up test to biomarkers to improve the detection of significant prostate cancer. METHODS AND MATERIALS: We developed a conceptual approach based on the risk calculated from the 4Kscore using results from the US prospective validation study, multiplied by the likelihood ratio of mp-MRI from the PROMIS trial. The primary outcome was Gleason grade ≥ 7 (grade group ≥ 2) cancer on biopsy. Using decision curve analysis, the net benefit was determined for our model and compared with the use of the 4Kscore and mp-MRI independently at various thresholds for biopsy. RESULTS: For a cut-point of 7.5% risk of high-grade disease, patients with <5% risk from a blood marker would not have risk of significant prostate cancer sufficiently increased by a positive mp-MRI to warrant biopsy; comparably, patients with a risk >23% would not have risk sufficiently reduced by a negative imaging study to forgo biopsy. From the 4Kscore validation study, 46% of men considered for biopsy in the US have risks 5% to 23%. Net benefit was highest for the combined strategy, followed by 4Kscore alone. CONCLUSIONS: Selective mp-MRI in men with intermediate scores on a secondary blood test results in a biopsy strategy that is more scalable than mp-MRI for all men with elevated PSA. Prospective validation is required to demonstrate if the predicted properties of combined blood and imaging testing are empirically confirmed.

Genomic biomarkers in prostate cancer.

Prostate cancer is the most common non-cutaneous cancer among men in the United States. In the last decade there has been a rapid expansion in the field of biomarker assays for diagnosis, prognosis, and treatment prediction in prostate cancer. The evidence base for these assays is rapidly evolving. With several commercial assays available at each stage of the disease, deciding which genomic assays are appropriate for which patients can be nuanced for physicians. In an effort to help guide these decisions in clinical practice, we aim to give an update on the current status of the biomarker field of prostate cancer.

Use of the 4Kscore test to predict the risk of aggressive prostate cancer prior to prostate biopsy: Overall cost savings and improved quality of care to the us healthcare system.

The 4Kscore® Test (BioReference Laboratories, Elmwood Park, NJ) is a blood test that accurately determines the risk of aggressive prostate cancer and significantly reduces prostate biopsies and associated overdiagnosis and overtreatment of indolent cancer. A budget impact model was developed to test the hypothesis that the 4Kscore Test can improve quality of care and deliver cost savings for patients who are suspected of having prostate cancer and would otherwise undergo prostate biopsy under the current standard of care (SOC) in the United States. The direct costs (diagnosis plus treatment) utilized in the model are based on Medicare payment data and were calculated over a 1-year time horizon. The model compares SOC, in which all patients have prostate biopsy, to a "4Kscore strategy," in which the 4Kscore Test is used to guide the decision to biopsy the prostate. A set of one-way sensitivity analyses was conducted to examine the robustness of the findings. Savings of more than $169 million (15.6% of total SOC costs) were realized in the 4Kscore strategy versus SOC ($917 M versus $1,086 M, respectively) in a cohort of 100,000 patients. Sensitivity analyses demonstrated that the findings are robust. Most cost savings for the 4Kscore strategy were realized in patients who, when managed by SOC, are found to have no prostate cancer or Gleason score 6 pathology. The patients with Gleason score 6 exhibited the greatest benefits from the 4Kscore strategy, avoiding both an unnecessary prostate biopsy and subsequent overtreatment. The 4Kscore Test was shown to significantly reduce costs to the healthcare system while improving patients' quality of care. Providers and their patients suspected of having prostate cancer should consider using the 4Kscore Test prior to proceeding with prostate biopsy.

Clinical performance of the 4Kscore Test to predict high-grade prostate cancer at biopsy: A meta-analysis of us and European clinical validation study results.

The 4Kscore® Test (OPKO Diagnostics, Woburn, MA) is a blood test utilized prior to a prostate biopsy to determine a patient's risk of high-grade prostate cancer (PCa) should the biopsy be performed, thus providing critical information in the clinical management of men with a suspicious prostate-specific antigen value or digital rectal examination result. Multiple US and European clinical studies confirmed that a prebiopsy 4Kscore Test has a high degree of discrimination for a subsequent discovery of high-grade (Gleason score ≥7) PCa. The aim of this study was to evaluate the predictive accuracy of the 4Kscore Test to discriminate between patients with and without high-grade PCa based on published clinical validation studies. A systematic review and meta-analysis of the eligible 4Kscore Test clinical validation studies was conducted. The pooled area under the curve (AUC) of the 4Kscore Test as reported from all the studies, and the heterogeneity among these studies were analyzed and repeated for subgroups of the studies. Twelve clinical validation studies were included in the meta-analysis, comprising a total of 11,134 patients. The pooled AUC to discriminate for high-grade PCa for all 12 studies was 0.81 (fixed effects 95% CI, 0.80-0.83). Restricting the analysis to the six publications that used the contemporary 4Kscore Test algorithm led to very similar results (AUC 0.81; 95% CI, 0.79-0.83). Heterogeneity was high among all of the 12 studies, as well as among the six publications that used the contemporary 4Kscore Test (Cochrane's Q test, p = 0.001 for both); however, in both cases, after exclusion of a single outlying study with a much lower AUC, heterogeneity was no longer significant (p = 0.08 and p = 0.21). The pooled estimate of 4Kscore Test discrimination (AUC) for high-grade PCa is >0.80, and is consistent across multiple US and European clinical validation studies.

The Use of Biomarkers in Prostate Cancer Screening and Treatment.

Prostate cancer screening and diagnosis has been guided by prostate-specific antigen levels for the past 25 years, but with the most recent US Preventive Services Task Force screening recommendations, as well as concerns regarding overdiagnosis and overtreatment, a new wave of prostate cancer biomarkers has recently emerged. These assays allow the testing of urine, serum, or prostate tissue for molecular signs of prostate cancer, and provide information regarding both diagnosis and prognosis. In this review, we discuss 12 commercially available biomarker assays approved for the diagnosis and treatment of prostate cancer. The results of clinical validation studies and clinical decision-making studies are presented. This information is designed to assist urologists in making clinical decisions with respect to ordering and interpreting these tests for different patients. There are numerous fluid and biopsy-based genomic tests available for prostate cancer patients that provide the physician and patient with different information about risk of future disease and treatment outcomes. It is important that providers be able to recommend the appropriate test for each individual patient; this decision is based on tissue availability and prognostic information desired. Future studies will continue to emphasize the important role of genomic biomarkers in making individualized treatment decisions for prostate cancer patients.