Kallikrein Markers In Blood Research Articles

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

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-β (MSP) adds predictive value. 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. 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. 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.

A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy

BackgroundA pre-specified model based on four kallikrein markers in blood, commercially available as 4Kscore, predicts Gleason Grade (GG) 3 + 4 or higher prostate cancer on biopsy. However, sampling error and variation in pathology reporting may miss aggressive disease.MethodsThe 4Kscore was measured in cryopreserved blood from 2330 men obtained before prostatectomy at a single institution between 2002 and 2010. Adverse surgical pathology and biochemical recurrence (BCR) were pre-specified to be assessed in all men, biopsy GG 3 + 3, and 3 + 4.ResultsAdjusted for established clinical predictors, the 4Kscore was significantly associated with adverse pathology (OR 1.49; 95% CI 1.32, 1.67; p < 0.0001). Adding 4Kscore increased discrimination from (AUC) 0.672 to 0.718 and 0.644 to 0.659 within biopsy GG 3 + 3 and 3 + 4, respectively. Higher 4Kscore was associated with higher risk of BCR (HR 1.16, 95% CI 1.06, 1.26; p = 0.001). Adding 4Kscore improved the prediction of BCR (C-index 0.630–0.660) within GG 3 + 3, but not GG 3 + 4.ConclusionsThe 4Kscore can help guide the clinical decision whether additional risk assessment—such as confirmatory biopsy—is needed to decide between active surveillance versus curative therapy. Evidence that the panel could influence management in biopsy GG 3 + 4 is less strong and requires further investigation.

Prespecified 4-Kallikrein Marker Model at Age 50 or 60 for Early Detection of Lethal Prostate Cancer in a Large Population Based Cohort of Asymptomatic Men Followed for 20 Years.

A prespecified statistical model based on 4 kallikrein markers in blood, commercially available as the 4Kscore®, has been shown to accurately detect high grade (greater than Grade Group 2) prostate cancer in men with moderately elevated prostate specific antigen. We assessed whether the model predicted prostate cancer metastasis or death in men not subject to prostate specific antigen screening. The cohort includes 43,692 unscreened prostate cancer-free men from a Swedish population based cohort with low rates of prostate specific antigen screening (Västerbotten Intervention Project). Using cryopreserved blood collected at ages 50 and 60 years from men in this cohort we analyzed the association between prostate specific antigen and other kallikrein marker levels in blood and risk of prostate cancer metastasis or death. There were 308 with metastases and 172 prostate cancer deaths. Baseline prostate specific antigen was strongly associated with 20-year risk of prostate cancer death (c-index at age 50, 0.859, 95% CI 0.799-0.916; age 60, 0.840, 95% CI 0.799-0.878). Men 60 years old with prostate specific antigen below median (less than 1.2 ng/ml) had 0.4% risk of prostate cancer death at 20 years. Among men with moderately elevated prostate specific antigen (2.0 ng/ml or greater) the 4Kscore markedly improved discrimination (c-index 0.767 vs 0.828 and 0.774 vs 0.862 in men age 50 and 60, respectively). Long-term risk of prostate cancer death or metastasis in men with low 4Kscores was very low. Screening should focus on men in top prostate specific antigen quartile at age 60 years. Men with elevated prostate specific antigen but a low 4Kscore can safely be monitored with repeated blood markers in place of immediate biopsy.

Abstract IA09: Early, highly specific risk stratification for lethal prostate cancer using a prespecified statistical model based on four kallikrein markers in blood

Abstract Prostate-specific antigen (PSA) and human kallikrein-related peptidase 2 (hK2) are 237-aa single chain glycoproteins with uniquely different serine proteinase activity and products of two highly homologous primate-lineage specific, androgen receptor-regulated genes (KLK3 and KLK2) with abundant prostate-restricted expression. In blood from healthy middle-aged men not subject to PSA testing, million-fold lower levels of multiple noncatalytic forms of PSA and hK2 are very strongly associated with 20+ year- risk of metastasis or death from prostate cancer (PC), whereas prospective randomized trials in Europe show that early detection by systematic PSA testing reduces PC-specific deaths but remains controversial due to harm from overdiagnosis and overtreatment. Population-based findings of longer lead time at Gleason Grade Group ≥2 (GGG2) versus GGG1 at PC diagnosis provide evidence of grade progression over time. However, our estimates of a ≤6% risk of ≥GGG2-PC by a predefined statistical model based on four kallikrein markers in blood in middle-aged men with modestly elevated PSA is strongly associated with 15-20-year risk of PC death or metastasis below population average. By contrast, a smaller subset of these middle-aged men with modestly elevated PSA and a ≥6% four kallikrein risk-score have 15-20-year risk of PC death or metastasis that is multiple folds higher than the population average. Although evidence exists that mutations in germline DNA are associated with PC-death or metastasis, it is currently unclear how we could integrate these findings in programs aimed at early specific detection of lethal PC. Citation Format: Hans Lilja. Early, highly specific risk stratification for lethal prostate cancer using a prespecified statistical model based on four kallikrein markers in blood [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA09.

A pre-specified statistical model based on four kallikrein markers in blood to predict advanced pathology on radical prostatectomy.

5073Background: Four kallikrein markers in blood – commercially available as the 4Kscore – has been shown to be highly predictive of Gleason Grade Group (GGG) 2 or higher prostate cancer at biopsy....

Serum markers in prostate cancer detection.

Prostate-specific antigen (PSA) testing provides significant benefits by reducing prostate cancer mortality, but also leads to important harms by detecting clinically insignificant cancers. Hence, there are urgent needs for complementary tools for middle-aged men with modest PSA elevations in blood. This review includes research on prostate cancer biomarkers in blood published from March 2013 through August 2014. Research progress has been made mainly on PSA as a predictive marker and in the field of kallikrein-based tests: [-2] proPSA, the prostate health index, and a panel of four kallikrein markers. As men with PSA levels below age-median are at very low 20-year risk of metastatic prostate cancer, individualized screening intervals, based on PSA levels, may help in reducing screening costs, prostate biopsies, and detection of insignificant cancer. Statistical models based on kallikrein-markers in blood improve the specificity at modestly elevated PSA (2-10 ng/ml), eliminate unnecessary biopsies, and help selecting men at risk of significant prostate cancer for biopsy or imaging. Individualized, risk-adapted PSA testing intervals and reflex-testing of kallikrein-markers for men with modestly increased PSA values may decrease the harms of screening. However, the clinical value of the proposed testing algorithms and additional tests awaits definitive confirmation in prospective trials.

The Kallikrein Panel for prostate cancer screening: Its economic impact

Current diagnostic testing for prostate cancer results in numerous unnecessary biopsy procedures and creates a substantial financial burden. A statistical prediction model for prostate cancer has been developed, based on four Kallikrein markers in blood. This systematic review and meta-analysis examines the aggregated results from published studies of the Kallikrein Panel. Literature searches to identify relevant studies were conducted. A meta-analysis of the results was performed using inverse variance, mean difference with corresponding 95% confidence intervals (CI). The results of the meta-analysis were used to assess the Kallikrein Panel's effect on healthcare costs. The Kallikrein Panel has been evaluated in more than 8,500 patients (2,780 with prostate cancer and 598 with high grade prostate cancer). Meta-analysis demonstrates a statistically significant improvement of 8-10% in predictive accuracy. In addition, 48% to 56% of current prostate biopsies could be avoided. Use of the Kallikrein Panel could result in annual US savings approaching $1 billion. The Kallikrein Panel has the potential to improve patient outcomes and reduce costs. The panel provides significantly improved specificity. Because the Kallikrein Panel has been studied in a range of clinical settings, it is a test that could be readily and widely used in practice.

Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam

BackgroundTreatment decisions can be difficult in men with low-risk prostate cancer (PCa). ObjectiveTo evaluate the ability of a panel of four kallikrein markers in blood—total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2—to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries. Design, setting, and participantsThe cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004. Outcome measurements and statistical analysisWe calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3–T4, extracapsular extension, tumor volume >0.5cm3, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood. Results and limitationsA total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model. ConclusionsOur study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.

850 A prediction based on levels of four kallikrein markers in blood improves preoperative prediction of indolent versus

850 A prediction based on levels of four kallikrein markers in blood improves preoperative prediction of indolent versus

Can one blood draw replace transrectal ultrasonography‐estimated prostate volume to predict prostate cancer risk?

To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting. The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (≥3 ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam (n = 2914) and Göteborg (n = 740). A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome. The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Göteborg. Adding digital rectal examination (DRE) or DRE plus transrectal ultrasonography (TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high-grade cancer. There was a strong correlation between the blood measurements and TRUS-estimated prostate volume (Spearman's correlation 0.60 in Rotterdam and 0.57 in Göteborg). In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to-day clinical practice. Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches.

A Four-Kallikrein Panel Predicts Prostate Cancer in Men with Recent Screening: Data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam

We have developed a statistical prediction model for prostate cancer based on four kallikrein markers in blood: total, free, and intact prostate-specific antigen (PSA), and kallikrein-related peptidase 2 (hK2). Although this model accurately predicts the result of biopsy in unscreened men, its properties for men with a history of PSA screening have not been fully characterized. A total of 1,501 previously screened men with elevated PSA underwent initial biopsy during rounds 2 and 3 of the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 388 cancers diagnosed. Biomarker levels were measured in serum samples taken before biopsy. The prediction model developed on the unscreened cohort was then applied and predictions compared with biopsy outcome. The previously developed four-kallikrein prediction model had much higher predictive accuracy than PSA and age alone (area under the curve of 0.711 versus 0.585, and 0.713 versus 0.557 with and without digital rectal exam, respectively; both P < 0.001). Similar statistically significant enhancements were seen for high-grade cancer. Applying the model with a cutoff of 20% cancer risk as the criterion for biopsy would reduce the biopsy rate by 362 for every 1,000 men with elevated PSA. Although diagnosis would be delayed for 47 cancers, these would be predominately low-stage and low-grade (83% Gleason 6 T(1c)). A panel of four kallikreins can help predict the result of initial biopsy in previously screened men with elevated PSA. Use of a statistical model based on the panel would substantially decrease rates of unnecessary biopsy.