A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy

James McKiernan, Michael J. Donovan, Eric Margolis, Alan Wayne Partin, H Ballentine Carter, Gordon Brown, Philipp Torkler, Mikkel Noerholm, Johan Skog, Neal Shore, Gerry Andriole, Ian Thompson, Peter Carroll

Research output: Contribution to journalArticle

Abstract

Background: Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption. Objective: Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. Design, setting, and participants: A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2–10 ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. Outcome measurements and statistical analysis: Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. Results and limitations: In a total of 503 patients, with median age of 64 yr, median PSA 5.4 ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n = 519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. Conclusions: EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. Patient summary: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2–10 ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data. ExoDx Prostate (IntelliScore) is a urine-based test that relies solely on a three-gene signature to predict high-grade prostate cancer at initial biopsy for men with prostate-specific antigen 2–10 ng/ml. The test has been prospectively validated on over 1000 men from two multisite trials.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2018

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Exosomes
Prostate-Specific Antigen
Prostatic Neoplasms
Urine
Biopsy
Gene Expression
Prostate
Area Under Curve

Keywords

  • Exosomes
  • Extended validation study
  • High grade prostate cancer
  • Initial biopsy
  • Prostate cancer
  • Risk assessment tools

ASJC Scopus subject areas

  • Urology

Cite this

A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy. / McKiernan, James; Donovan, Michael J.; Margolis, Eric; Partin, Alan Wayne; Carter, H Ballentine; Brown, Gordon; Torkler, Philipp; Noerholm, Mikkel; Skog, Johan; Shore, Neal; Andriole, Gerry; Thompson, Ian; Carroll, Peter.

In: European Urology, 01.01.2018.

Research output: Contribution to journalArticle

McKiernan, James ; Donovan, Michael J. ; Margolis, Eric ; Partin, Alan Wayne ; Carter, H Ballentine ; Brown, Gordon ; Torkler, Philipp ; Noerholm, Mikkel ; Skog, Johan ; Shore, Neal ; Andriole, Gerry ; Thompson, Ian ; Carroll, Peter. / A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy. In: European Urology. 2018.
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title = "A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy",
abstract = "Background: Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption. Objective: Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. Design, setting, and participants: A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2–10 ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. Outcome measurements and statistical analysis: Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. Results and limitations: In a total of 503 patients, with median age of 64 yr, median PSA 5.4 ng/ml, 14{\%} African American, 70{\%} Caucasian, 53{\%} positive biopsy rate (22{\%} GG1, 17{\%} GG2, and 15{\%} ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n = 519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26{\%} of unnecessary prostate biopsies and 20{\%} of total biopsies, with negative predictive value (NPV) 89{\%} and missing 7{\%} of ≥GG2 PCa. Alternative cut-point 20 would avoid 40{\%} of unnecessary biopsies and 31{\%} of total biopsies, with NPV 89{\%} and missing 11{\%} of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. Conclusions: EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. Patient summary: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2–10 ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data. ExoDx Prostate (IntelliScore) is a urine-based test that relies solely on a three-gene signature to predict high-grade prostate cancer at initial biopsy for men with prostate-specific antigen 2–10 ng/ml. The test has been prospectively validated on over 1000 men from two multisite trials.",
keywords = "Exosomes, Extended validation study, High grade prostate cancer, Initial biopsy, Prostate cancer, Risk assessment tools",
author = "James McKiernan and Donovan, {Michael J.} and Eric Margolis and Partin, {Alan Wayne} and Carter, {H Ballentine} and Gordon Brown and Philipp Torkler and Mikkel Noerholm and Johan Skog and Neal Shore and Gerry Andriole and Ian Thompson and Peter Carroll",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.eururo.2018.08.019",
language = "English (US)",
journal = "European Urology",
issn = "0302-2838",
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TY - JOUR

T1 - A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy

AU - McKiernan, James

AU - Donovan, Michael J.

AU - Margolis, Eric

AU - Partin, Alan Wayne

AU - Carter, H Ballentine

AU - Brown, Gordon

AU - Torkler, Philipp

AU - Noerholm, Mikkel

AU - Skog, Johan

AU - Shore, Neal

AU - Andriole, Gerry

AU - Thompson, Ian

AU - Carroll, Peter

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption. Objective: Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. Design, setting, and participants: A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2–10 ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. Outcome measurements and statistical analysis: Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. Results and limitations: In a total of 503 patients, with median age of 64 yr, median PSA 5.4 ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n = 519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. Conclusions: EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. Patient summary: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2–10 ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data. ExoDx Prostate (IntelliScore) is a urine-based test that relies solely on a three-gene signature to predict high-grade prostate cancer at initial biopsy for men with prostate-specific antigen 2–10 ng/ml. The test has been prospectively validated on over 1000 men from two multisite trials.

AB - Background: Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption. Objective: Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. Design, setting, and participants: A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2–10 ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. Outcome measurements and statistical analysis: Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. Results and limitations: In a total of 503 patients, with median age of 64 yr, median PSA 5.4 ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n = 519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. Conclusions: EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. Patient summary: It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2–10 ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data. ExoDx Prostate (IntelliScore) is a urine-based test that relies solely on a three-gene signature to predict high-grade prostate cancer at initial biopsy for men with prostate-specific antigen 2–10 ng/ml. The test has been prospectively validated on over 1000 men from two multisite trials.

KW - Exosomes

KW - Extended validation study

KW - High grade prostate cancer

KW - Initial biopsy

KW - Prostate cancer

KW - Risk assessment tools

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