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

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 119-119 ◽  
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.

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

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 42-42 ◽  
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.

Performance of a validated urine exosome gene expression assay to predict high-grade prostate cancer utilizing the International Society of Urological Pathology (ISUP) 2014 grading system.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 49-49 ◽  
Author(s):  
Michael Donovan ◽  
Phillipp Torkler ◽  
Johan Skog ◽  
Mikkel Noerholm ◽  
Peter Carroll
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
International Society ◽  
Grading System ◽  
Low Grade ◽  
High Grade ◽  
Cut Points ◽  
Combined Training ◽  
Gleason Grading ◽  
Gene Expression Assay

49 Background: Overdetection and overtreatment of indolent prostate cancer (PCa) remains a significant health issue requiring noninvasive assays to guide the prostate biopsy decision process. We demonstrated that a urine exosome gene expression assay (ExoDx P rostate ( I ntelliScore) (EPI) discriminates GS 7 PCa from GS 6 and benign disease, potentially reducing the number of unnecessary biopsies. The International Society of Urological Pathology (ISUP) proposed a prognostic PCa grading system to accurately reflect the biology of PCa; ISUP separates GS 7 PCa into group 2 (GS 3+4) and group 3 (GS 4+3). We sought to evaluate the performance of the EPI test according to the newly proposed ISUP system. Methods: The 519 patient validation cohort was re-annotated using ISUP and assessed benign (B) +/- ISUP 1 and B+ISUP 1+2 (GS 3+3, GS 3+4) from ISUP 3-5 (GS >= 4+3). We used validated / adjusted cut-points to assess performance with the AUC, sensitivity, specificity and NPV. In addition, we investigated the association of the EPI score with the benign biopsies (BB) and ISUP groups in the combined training and test cohort (n=774). Results: Applying the adjusted cut point (EPI 20) on the 519 ISUP cohort discriminated benign biopsies (BB) + ISUP 1 from >/=ISUP 2, 37% of biopsies avoided, NPV of 90%, equivalent to Gleason grading. Utilizing either the validated (15.6) or adjusted cut points on BB+ISUP 1+ 2 vs. >/=ISUP 3 (dominant pattern 4), 26% vs 37% biopsies avoided, with an improved NPV 98%. In the combined training / test cohort, higher EPI scores were significantly associated with ISUP categories. In this analysis EPI in BB vs. all ISUP groups (p<0.0001); BB+ISUP 1 vs. >/= ISUP2 (p<0.0001) and BB+ISUP 1+2 vs. >/=ISUP3 (p<0.0001); supporting accurate discrimination in high grade PCa. Conclusions: The EPI test is a noninvasive, first-catch non-DRE gene expression assay that accurately discriminates low-grade from high-grade PCa in both ISUP as well as Gleason score based grading systems. The test has the potential to reduce the number of unnecessary biopsies and performs equally well in contemporary approaches to PCa stratification.

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

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.

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

2020 ◽  
Author(s):  
James McKiernan ◽  
Mikkel Noerholm ◽  
Vasisht Tadigotla ◽  
Sonia Kumar ◽  
Phillipp Torkler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Features ◽  
Prostate Biopsy ◽  
Specific Antigen ◽  
Repeat Biopsy ◽  
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 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. 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.

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

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.

A gene expression signature to predict high-grade prostate cancer response to oxaliplatin.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 150-150
Author(s):  
Philippe Pourquier ◽  
Stephane Puyo ◽  
Pierre Richaud ◽  
Jacques Robert ◽  
Nadine Houede
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Trials ◽  
Cell Lines ◽  
Gene Expression Signature ◽  
Chemotherapeutic Agents ◽  
Low Grade ◽  
Gleason Grade ◽  
High Grade ◽  
Expression Signature

150 Background: Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade prostate cancers are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low. Moreover, none of these trials took into account the tumor grade. Methods: We used an in silico approach to screen for drug candidates that could be used as an alternative to taxanes, based on a 86 genes signature which could distinguish between low-grade and high-grade tumors. We extracted from the NCI60 panel databases the expression profiles of the 86 genes across 60 human tumor cell lines and the corresponding in vitro cytotoxicity data of 152 drugs and looked for correlation between their expression level and cell sensitivity to each of these drugs. Results: Among the 86 genes, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the 60 cell lines was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. This signature was validated at the functional level since repression of each of these genes conferred a significant change in the sensitivity of PCa cell lines to oxaliplatin but not cisplatin. Conclusions: Our results provide a proof of concept that gene expression signature specific from high grade PCa could be used for the identification of alternative therapies to taxanes. They could also be used to select patients for further clinical trials and as predictive markers of response to these drugs, which represents a further step forward towards personalized therapy of PCa.

Evolving Recommendations on Prostate Cancer Screening

2016 ◽  
pp. e80-e87
Author(s):  
Otis W. Brawley ◽  
Ian M. Thompson ◽  
Henrik Grönberg
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
New Technologies ◽  
Prostate Cancer Screening ◽  
Large Population ◽  
Specific Antigen ◽  
Population Based ◽  
Low Grade ◽  
Diagnostic Study ◽  
High Grade

Results of a number of studies demonstrate that the serum prostate-specific antigen (PSA) in and of itself is an inadequate screening test. Today, one of the most pressing questions in prostate cancer medicine is how can screening be honed to identify those who have life-threatening disease and need aggressive treatment. A number of efforts are underway. One such effort is the assessment of men in the landmark Prostate Cancer Prevention Trial that has led to a prostate cancer risk calculator (PCPTRC), which is available online. PCPTRC version 2.0 predicts the probability of the diagnosis of no cancer, low-grade cancer, or high-grade cancer when variables such as PSA, age, race, family history, and physical findings are input. Modern biomarker development promises to provide tests with fewer false positives and improved ability to find high-grade cancers. Stockholm III (STHLM3) is a prospective, population-based, paired, screen-positive, prostate cancer diagnostic study assessing a combination of plasma protein biomarkers along with age, family history, previous biopsy, and prostate examination for prediction of prostate cancer. Multiparametric MRI incorporates anatomic and functional imaging to better characterize and predict future behavior of tumors within the prostate. After diagnosis of cancer, several genomic tests promise to better distinguish the cancers that need treatment versus those that need observation. Although the new technologies are promising, there is an urgent need for evaluation of these new tests in high-quality, large population-based studies. Until these technologies are proven, most professional organizations have evolved to a recommendation of informed or shared decision making in which there is a discussion between the doctor and patient.

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