Development and evaluation of the MiCheck® Prostate test for clinically significant prostate cancer.

BACKGROUND: There is a clinical need to identify patients with an elevated PSA who would benefit from prostate biopsy due to the presence of clinically significant prostate cancer (CSCaP). We have previously reported the development of the MiCheck® Test for clinically significant prostate cancer. Here, we report MiCheck's further development and incorporation of the Roche Cobas standard clinical chemistry analyzer. OBJECTIVES: To further develop and adapt the MiCheck® Prostate test so it can be performed using a standard clinical chemistry analyzer and characterize its performance using the MiCheck-01 clinical trial sample set. DESIGN, SETTINGS, AND PARTICIPANTS: About 358 patient samples from the MiCheck-01 US clinical trial were used for the development of the MiCheck® Prostate test. These consisted of 46 controls, 137 non-CaP, 62 non-CSCaP, and 113 CSCaP. METHODS: Serum analyte concentrations for cellular growth factors were determined using custom-made Luminex-based R&D Systems multi-analyte kits. Analytes that can also be measured using standard chemistry analyzers were examined for their ability to contribute to an algorithm with high sensitivity for the detection of clinically significant prostate cancer. Samples were then re-measured using a Roche Cobas analyzer for development of the final algorithm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression modeling with Monte Carlo cross-validation was used to identify Human Epidydimal Protein 4 (HE4) as an analyte able to significantly improve the algorithm specificity at 95% sensitivity. A final model was developed using analyte measurements from the Cobas analzyer. RESULTS: The MiCheck® logistic regression model was developed and consisted of PSA, %free PSA, DRE, and HE4. The model differentiated clinically significant cancer from no cancer or not-clinically significant cancer with AUC of 0.85, sensitivity of 95%, and specificity of 50%. Applying the MiCheck® test to all evaluable 358 patients from the MiCheck-01 study demonstrated that up to 50% of unnecessary biopsies could be avoided while delaying diagnosis of only 5.3% of Gleason Score (GS) ≥3+4 cancers, 1.8% of GS≥4+3 cancers and no cancers of GS 8 to 10. CONCLUSIONS: The MiCheck® Prostate test identifies clinically significant prostate cancer with high sensitivity and negative predictive value (NPV). It can be performed in a clinical laboratory using a Roche Cobas clinical chemistry analyzer. The MiCheck® Prostate test could assist in reducing unnecessary prostate biopsies with a marginal number of patients experiencing a delayed diagnosis.

A comparison of prostate health index, total PSA, %free PSA, and proPSA in a contemporary US population-The MiCheck-01 prospective trial.

BACKGROUND: Increasing numbers of patients are presenting with aggressive prostate cancer (CaP); therefore, there exists a need to optimally identify these patients pre-biopsy. OBJECTIVES: To compare the accuracy of total prostate specific antigen (PSA), %free PSA, and prostate health index (PHI) to differentiate between patients without CaP, with non-aggressive (Gleason 3 + 3, non-AgCaP) and with aggressive (Gleason ≥ 3 + 4, AgCaP) in a contemporary US population. DESIGN, SETTINGS, AND PARTICIPANTS: Serum samples were collected from 332 US patients scheduled for biopsy due to an elevated age-adjusted PSA. Site and Central biopsy pathologic assessment were performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Testing of PSA, free PSA, proPSA, and PHI was performed along with central pathology review. Test performance using logistic regression analysis for differentiating CaP from non-CaP as well as non-AgCaP from AgCaP was evaluated. RESULTS AND LIMITATIONS: Central pathology review resulted in 32 upgrades including 14 Gleason 3 + 3 scores being upgraded to AgCaP with final distribution of 148 no-CaP, 64 non-AgCaP, and 120 AgCaP patients. Receiver operator curve (ROC) analysis of the different tests showed that PHI performed best at differentiating CaP from no-CaP subjects (area under the receiver operator curve 0.79). In contrast, the different tests were essentially equivalent in differentiating AgCaP vs. non-AgCaP. CONCLUSIONS: In this recent US study of prebiopsy patients we observed a high proportion of AgCaP patients consistent with previous studies in contemporary US populations. Central Gleason review is recommended for multi-institutional studies comparing biomarkers. PHI was superior to PSA, free PSA, %free PSA, and proPSA in detecting CaP in this population but was not superior at differentiating AgCaP from non-AgCaP.

Development and evaluation of the MiCheck test for aggressive prostate cancer.

BACKGROUND: A clinical need exists for a biomarker test to accurately delineate aggressive prostate cancer (AgCaP), and thus better assist clinicians and patients decision-making on whether to proceed to prostate biopsy. OBJECTIVES: To develop a blood test for AgCaP and compare to PSA, %free PSA, proPSA, and prostate health index (PHI) tests. DESIGN, SETTINGS AND PARTICIPANTS: Patient samples from the MiCheck-01 trial were used for development of the MiCheck test. METHODS: Serum analyte concentrations for cellular growth factors were determined using a custom-made Luminex-based R&D Systems multianalyte kit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bayesian model averaging and random forest approaches were used to identify clinical factors and growth factors able to distinguish between men with AgCaP (Gleason Score [GS] ≥3+4) from those with non-AgCaP (GS 3+3). Logistic regression and Monte Carlo cross-validation identified variable combinations in order to able to maximize differentiation of AgCaP from non-AgCaP. RESULTS: The MiCheck logistic regression model was developed and comprises the following variables: serum prostate-specific antigen (PSA), patient age, Digital Rectal Exam (DRE) status, Leptin, IL-7, vascular endothelial growth factor, and Glypican-1. The model differentiated AgCaP from non-AgCaP with an area under the curve of 0.83 and was superior to PSA, %free PSA and PHI in all patient groups, regardless of PSA range. Applying the MiCheck test to all evaluable biopsy patients from the MiCheck-01 study demonstrated that up to 30% of biopsies could be avoided while delaying diagnosis of only 6.8% of GS ≥3+4 cancers, 5% of GS ≥4+3 cancers and no cancers of GS 8 or higher. CONCLUSIONS: The MiCheck test outperforms PSA, %free PSA and PHI tests in differentiating AgCaP vs. non-AgCaP patients. The MiCheck test could result in a significant number of biopsies being avoided with a low number of patients experiencing a delayed diagnosis.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia.

PURPOSE: Medical treatment for men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia is 5α-reductase inhibitor monotherapy or coadministration with an α-blocker. We assessed the effects of tadalafil 5 mg coadministered with finasteride 5 mg during 26 weeks on lower urinary tract symptoms and sexual symptoms. MATERIALS AND METHODS: In an international, randomized, double-blind, parallel study of men 45 years old or older who were 5α-reductase inhibitor naïve and had an I-PSS (International Prostate Symptom Score) of 13 or greater and prostate volume 30 ml or greater, 350 were treated with placebo/finasteride and 345 received tadalafil/finasteride for 26 weeks. Changes in lower urinary tract symptoms secondary to benign prostatic hyperplasia were assessed with the I-PSS, erectile dysfunction improvements were assessed with the IIEF-EF (International Index of Erectile Function-Erectile Function) in sexually active men and safety was assessed by evaluating adverse events. RESULTS: Least squares mean changes from baseline in I-PSS after 4, 12 and 26 weeks of tadalafil/finasteride coadministration were -4.0, -5.2 and -5.5, respectively. Corresponding values for placebo/finasteride coadministration were -2.3, -3.8 and -4.5 (p ≤ 0.022 at all visits favoring tadalafil/finasteride coadministration). I-PSS subscores (storage and voiding) and quality of life index were also numerically improved with tadalafil/finasteride coadministration. Least squares mean changes from baseline in IIEF-EF with tadalafil/finasteride coadministration were 3.7 after 4 weeks, and 4.7 after 12 and 26 weeks. Corresponding values for placebo/finasteride coadministration were -1.1, 0.6 and -0.0 (p <0.001 at all visits favoring tadalafil/finasteride coadministration). Tadalafil/finasteride coadministration was well tolerated and most adverse events were mild/moderate. CONCLUSIONS: The coadministration of tadalafil/finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. Tadalafil/finasteride coadministration also improves erectile function in men who have comorbid erectile dysfunction.