A Urine-Based Exosomal Gene Expression Test Stratifies Risk of High-Grade Prostate Cancer in Men with Prior Negative Prostate Biopsy Undergoing Repeat Biopsy

Abstract BACKGROUND: Initial prostate biopsy often fails to identify prostate cancer resulting in patient anxiety, especially when clinical features such as prostate specific antigen (PSA) remain elevated, leading to the need for repeat biopsies. Prostate biomarker tests, such as the ExoDx™ Prostate(IntelliScore), or EPI test, have been shown to provide individualized risk assessment of clinically significant prostate cancer at initial biopsy; however, the performance in the repeat biopsy setting is not well established. Methods: As part of a previous prospective clinical validation study evaluating the performance of the EPI test, we collected first-catch, non-DRE urine samples across 22 sites from men with at least one prior negative biopsy scheduled to undergo a repeat prostate biopsy to rule out prostate cancer. All men were 50 years or older with a PSA 2-10ng/mL. Exosomal mRNA was extracted and expression of three genomic markers, PCA3, ERG and SPDEF was measured. The resulting EPI score was correlated with biopsy results. Results: 229 men with a prior negative biopsy underwent repeat biopsies. ExoDx Prostate demonstrated good performance ruling out high-grade (Grade group 2, GG2, or higher) prostate cancer (HGPCa) using the previously validated 15.6 cut point in the initial biopsy setting. The EPI test yielded an NPV of 92% independent of other clinical features and would have avoided 26% of unnecessary biopsies while missing only five patients with HGPCa (2.1%). Furthermore, the EPI test provided additional information at a cut-point of 20 and 29.6 with an NPV of 94%, potentially delaying 35% and 61% of unnecessary biopsies, respectively. AUC curves and Net Health Benefit Analyses demonstrated superior performance of ExoDx Prostate over PSA and clinical only risk calculators, i.e. ERSPC.Conclusions: The EPI test provided good performance using the 15.6 cut-point for ruling out HGPCa / GG2 or higher in men undergoing a repeat prostate biopsy with a PSA of 2-10ng/ml. Furthermore, the test utilizes gene expression data independent of clinical features to predict the likelihood of HGPCa / GG2 on a subsequent needle biopsy.

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A Urine-Based Exosomal Gene Expression Test Stratifies Risk of High-Grade Prostate Cancer in Men with Prior Negative Prostate Biopsy Undergoing Repeat Biopsy

10.21203/rs.3.rs-26752/v3 ◽

2020 ◽

Author(s):

James McKiernan ◽

Mikkel Noerholm ◽

Vasisht Tadigotla ◽

Sonia Kumar ◽

Phillipp Torkler ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Clinical Features ◽

Prostate Biopsy ◽

Repeat Biopsy ◽

Superior Performance ◽

High Grade ◽

Cut Point ◽

Negative Biopsy ◽

Initial Biopsy

Abstract BACKGROUND: Initial prostate biopsy often fails to identify prostate cancer resulting in patient anxiety, especially when clinical features such as prostate specific antigen (PSA) remain elevated, leading to the need for repeat biopsies. Prostate biomarker tests, such as the ExoDx™ Prostate(IntelliScore), or EPI test, have been shown to provide individualized risk assessment of clinically significant prostate cancer at initial biopsy; however, the performance in the repeat biopsy setting is not well established. Methods: As part of a previous prospective clinical validation study evaluating the performance of the EPI test, we collected first-catch, non-DRE urine samples across 22 sites from men with at least one prior negative biopsy scheduled to undergo a repeat prostate biopsy to rule out prostate cancer. All men were 50 years or older with a PSA 2-10ng/mL. Exosomal mRNA was extracted and expression of three genomic markers, PCA3, ERG and SPDEF was measured. The resulting EPI score was correlated with biopsy results. Results: 229 men with a prior negative biopsy underwent repeat biopsies. ExoDx Prostate demonstrated good performance ruling out high-grade (Grade group 2, GG2, or higher) prostate cancer (HGPCa) using the previously validated 15.6 cut point in the initial biopsy setting. The EPI test yielded an NPV of 92% independent of other clinical features and would have avoided 26% of unnecessary biopsies while missing only five patients with HGPCa (2.1%). Furthermore, the EPI test provided additional information at a cut-point of 20 and 29.6 with an NPV of 94%, potentially delaying 35% and 61% of unnecessary biopsies, respectively. AUC curves and Net Health Benefit Analyses demonstrated superior performance of ExoDx Prostate over PSA and clinical only risk calculators, i.e. ERSPC.Conclusions: The EPI test provided good performance using the 15.6 cut-point for ruling out HGPCa / GG2 or higher in men undergoing a repeat prostate biopsy with a PSA of 2-10ng/ml. Furthermore, the test utilizes gene expression data independent of clinical features to predict the likelihood of HGPCa / GG2 on a subsequent needle biopsy.

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Can Urinary PCA3 Supplement PSA in the Early Detection of Prostate Cancer?

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.8505 ◽

2014 ◽

Vol 32 (36) ◽

pp. 4066-4072 ◽

Cited By ~ 141

Author(s):

John T. Wei ◽

Ziding Feng ◽

Alan W. Partin ◽

Elissa Brown ◽

Ian Thompson ◽

...

Keyword(s):

Prostate Cancer ◽

Early Detection ◽

Prostate Biopsy ◽

Predictive Value ◽

Specific Antigen ◽

Digital Rectal Examination ◽

Repeat Biopsy ◽

Individual Risk ◽

High Grade ◽

Initial Biopsy

Purpose Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA. Patients and Methods In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20). Results For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer. Conclusion These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.

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A urine-based Exosomal gene expression test stratifies risk of high-grade prostate Cancer in men with prior negative prostate biopsy undergoing repeat biopsy

BMC Urology ◽

10.1186/s12894-020-00712-4 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

James McKiernan ◽

Mikkel Noerholm ◽

Vasisht Tadigotla ◽

Sonia Kumar ◽

Phillipp Torkler ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Prostate Biopsy ◽

Repeat Biopsy ◽

High Grade ◽

Negative Prostate Biopsy

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Extended analysis of a validated urine-exosome signature to predict high grade prostate cancer on initial biopsy: Performance across multiple sub-groups.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.42 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 42-42 ◽

Cited By ~ 1

Author(s):

Michael Donovan ◽

Stefan Bentink ◽

Mikkel Noerholm ◽

Vince O'Neill ◽

Johan Skog

Keyword(s):

Prostate Cancer ◽

Family History ◽

African Americans ◽

Gene Expression Signature ◽

High Grade ◽

Cut Point ◽

Negative Biopsy ◽

Initial Biopsy ◽

Intended Use ◽

Biopsy Rate

42 Background: We recently completed a prospective observational clinical trial of a first-catch urine exosome gene expression signature (ExoIntelliScore Prostate) to predict high-grade prostate cancer, HGPCA (>/=GS7) on initial biopsy. The assay accurately predicted HGPCA with an NPV>90% for an intended use popuation: men >/= 50 years with an equivocal PSA of 2-10 ng/mL presenting for their first biopsy. Given the current high prostate biopsy rate and potential impact of race, we sought to further understand performance of the assay by constructing sub-cohorts from the validation study. Methods: Utilizing the ExoIntelliScore Prostate result and clinical data from the 519 patient intended use clinical validation cohort (IU), we constructed several subgroups including: i. prior negative (A, n=149), ii. combined prior negative + initial biopsy (B, n=668) and African Americans, AA (C, n=87). Area under the curve (AUC), NPV, PPV, sensitivity and specificity with validated cut-point assess performance. Results: There was demographic comparability between the initial intended use (IU) and various subgroups, i.e., prior negative (A), combined prior negative and initial biopsy (B) and African Americans (C) with some exceptions observed (bold) for AA patients; family history (IU, 23%; A: 27%, B: 24%, C: 30%; positive biopsy rate (IU, 48%; A: 34%, B: 45%, C:52%; and >/= GS7 (IU, 28%; A: 13%, B: 27%; C: 34%). The AUC range for ExoIntelliscore Prostate + standard of care (i.e., age, race, PSA and family history) between IU and A, B subgroups was 0.72-0.74; AUC for AA was 0.62, except for prior negative biopsy AA patients, AUC 0.80; supporting importance of prior negative biopsy. Of note, applying the ExoIntelliscore Prostate cut-point, A, B yielded an NPV of 91%; including NPV of 89% for AA (initial biopsy) and NPV of 91% for AA with initial + prior negative biopsy. Conclusions: The ExoIntelliScore Prostate performed equally well in men with or without a prior negative biopsy with comparable results also seen for African Americans. Additional confirmatory studies with more patients is necessary to confirm initial observations.

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Performance of a clinically validated urine exosome gene expression test to predict high grade prostate cancer in men with a prior negative biopsy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.119 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 119-119 ◽

Cited By ~ 1

Author(s):

Michael Joseph Donovan ◽

Phillipp Torkler ◽

Mikkel Noerholm ◽

Johan Skog ◽

James M McKiernan

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Family History ◽

Positive Family History ◽

Low Grade ◽

High Grade ◽

Patient Anxiety ◽

Cut Points ◽

Negative Biopsy ◽

Initial Biopsy

119 Background: The over-diagnosis of low grade, indolent prostate cancer (PCa) initiates significant patient anxiety regarding treatment options and health risk. To address this clinical need, we developed and subsequently validated a noninvasive, easy to administer, supportive diagnostic test (ExoDx Prostate(IntelliScore), EPI) to guide the initial prostate biopsy decision process for men with PSA 2-10ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GS 7 PCa) from low-grade (GS 6) and benign disease, thereby potentially reducing the number of unnecessary biopsies. As many men have had prior negative/ benign biopsies, we sought to understand the performance of EPI in this selected population. Methods: Utilizing men with prior negative biopsies from two clinical trials we evaluated performance of the EPI test with respect to subsequent biopsy outcomes. We used the previously validated and alternative EPI cut-points of 15.6 and 20, respectively, to assess performance with AUC, sensitivity, and NPV. Results: A total of N = 286 patients with a prior negative biopsy; mean age 65 years, mean PSA 6.2 ng/mL, 22% positive family history, 15% African American; 32% positive biopsy rate: 20% GS6 (ISUP1) and 12% > / = GS7 PCa (ISUP≥2). AUC 0.68 vs. AUC 0.59 for standard of care (i.e. PSA, age, race, family history) and AUC 0.51 for PSA alone. By comparison the EPI initial biopsy AUC was 0.71. Using the previously validated EPI cut-points of 15.6 (or alternative 20) yielded NPVs of 92% and 95%, and number of avoided biopsies of 23% and 32%, respectively, and sensitivity of 85.7% for both cut-points. Notably, EPI in the initial biopsy setting had a sensitivity of 92 vs. 87% and an NPV of 91 vs. 90%, for the 15.6 and 20 cut-points, respectively. Conclusions: The EPI test is a noninvasive, first-catch, non-DRE gene expression array that accurately discriminates low-grade and benign biopsy outcomes from high-grade prostate cancer. The test performs well in both the initial and prior negative biopsy patients and has the potential to reduce the overall number of unnecessary biopsies in both settings.

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Atypical Small Acinar Proliferation: Repeat Biopsy and Detection of High Grade Prostate Cancer

Prostate Cancer ◽

10.1155/2015/810159 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Andrew Leone ◽

Katherine Rotker ◽

Christi Butler ◽

Anthony Mega ◽

Jianhong Li ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Prostate Biopsy ◽

Repeat Biopsy ◽

Gleason Grade ◽

High Grade ◽

Atypical Small Acinar Proliferation ◽

Prostate Biopsies ◽

Significant Difference ◽

Initial Biopsy

Purpose. Atypical small acinar proliferation (ASAP) is diagnosed in 1-2% of prostate biopsies. 30–40% of patients with ASAP may be diagnosed with prostate cancer (PCa) on repeat biopsy. Our objective was to examine the association between ASAP and subsequent diagnosis of intermediate/high risk PCa.Materials and Methods. Ninety-six patients who underwent prostate biopsy from 2000 to 2013 and were diagnosed with ASAP were identified. Clinicopathologic features were analyzed. Comparison was made between those with subsequent PCa on repeat biopsy and those with benign repeat pathology.Results. 56/96 (58%) patients had a repeat biopsy. 22/56 (39%) were subsequently diagnosed with PCa. There was no significant difference in patients’ characteristics. Presence of HGPIN on initial biopsy was associated with a benign repeat biopsy (68% versus 23%). 17/22 (77%) had Gleason grade (GG) 3+3 disease and only 5/22 (23%) had GG 3+4 disease.Conclusions. 22/56 patients (39%) of patients who underwent a subsequent prostate biopsy following a diagnosis of ASAP were found to have PCa. 77% of these men were diagnosed with GG 3+3 PCa. Only 23% were found to have intermediate risk PCa and no high risk PCa was identified. Immediate repeat prostate biopsy in patients diagnosed with ASAP may be safely delayed. A multi-institutional cohort is being analyzed.

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