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      Association between a 17-gene genomic prostate score and multi-parametric prostate MRI in men with low and intermediate risk prostate cancer (PCa)

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          Abstract

          Background

          We aimed to directly compare results from multi-parametric prostate MRI (mpMRI) and a biopsy-based 17-gene RT-PCR assay providing a Genomic Prostate Score (GPS) among individuals who were candidates for active surveillance with low and intermediate risk prostate cancer (PCa).

          Patients and methods

          We evaluated the association between GPS results (scale 0–100) and endorectal mpMRI findings in men with clinically localized PCa. MR studies were reviewed to a five-tier scale of increasing suspicion of malignancy. Mean apparent diffusion coefficient (ADC) was calculated from a single dominant lesion. Mean rank of the GPS (0–100) among MRI strata was compared with the Kruskal-Wallis test and Dunn's multiple comparison test. Spearman's correlation was performed to examine the association between mean ADC and scaled GPS.

          Results

          Of 186 patients who received GPS testing, 100 were identified who received mpMRI. Mean GPS results differed between mpMRI categories (p = 0.001); however a broad range was observed in all mpMRI categories. Among men with biopsy Gleason pattern 3+3, mean GPS results were not significantly different among MRI groups (p = 0.179), but GPS differences were seen among MRI categories for patients with pattern 3+4 (p = 0.010). Mean ADC was weakly associated with GPS (σ = -0.151). Stromal response (p = 0.015) and cellular organization (p = 0.045) gene group scores differed significantly by MRI findings, but no differences were seen among androgen signaling or proliferation genes.

          Conclusions

          Although a statistically significant association was observed between GPS results and MRI scores, a wide range of GPS values were observed across imaging categories suggesting that mpMRI and genomic profiling may offer non- overlapping clinical insights.

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          Most cited references19

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          Time trends and local variation in primary treatment of localized prostate cancer.

          PURPOSE In the absence of high-level evidence or clinical guidelines supporting any given active treatment approach over another for localized prostate cancer, clinician and patient preferences may lead to substantial variation in treatment use. METHODS Data were analyzed from 36 clinical sites that contributed data to the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Distribution of primary treatment use was measured over time. Prostate cancer risk was assessed using the D'Amico risk groups and the Cancer of the Prostate Risk Assessment (CAPRA) score. Descriptive analyses were performed, and a hierarchical model was constructed that controlled for year of diagnosis, cancer risk variables, and other patient factors to estimate the proportion of variation in primary treatment selection explicable by practice site. Results Among 11,892 men analyzed, 6.8% elected surveillance, 49.9% prostatectomy, 11.6% external-beam radiation, 13.3% brachytherapy, 4.0% cryoablation, and 14.4% androgen deprivation monotherapy. Prostate cancer risk drives treatment selection, but the data suggest both overtreatment of low-risk disease and undertreatment of high-risk disease. The former trend appears to be improving over time, while the latter is worsening. Treatment varies with age, comorbidity, and socioeconomic status. However, treatment patterns vary markedly across clinical sites, and this variation is not explained by case-mix variability or known patient factors. Practice site explains a proportion of this variation ranging from 13% for androgen deprivation monotherapy to 74% for cryoablation. CONCLUSION Substantial variation exists in management of localized prostate cancer that is not explained by measurable factors. A critical need exists for high-quality comparative effectiveness research in localized prostate cancer to help guide treatment decision making.
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            A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling.

            Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease. To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology. Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies-a discovery prostatectomy study (n=441), a biopsy study (n=167), and a prospectively designed, independent clinical validation study (n=395)-testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS). The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility. Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p<0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1.3-3.0; p=0.003) at surgical pathology. GPS predicted high-grade and/or high-stage disease after controlling for established clinical factors (p<0.005) such as an OR of 2.1 (95% CI, 1.4-3.2) when adjusting for Cancer of the Prostate Risk Assessment score. A limitation of the validation study was the inclusion of men with low-volume intermediate-risk PCa (Gleason score 3+4), for whom some providers would not consider AS. Genes representing multiple biological pathways discriminate PCa aggressiveness in biopsy tissue despite tumor heterogeneity, multifocality, and limited sampling at time of biopsy. The biopsy-based 17-gene GPS improves prediction of the presence or absence of adverse pathology and may help men with PCa make more informed decisions between AS and immediate treatment. Prostate cancer (PCa) is often present in multiple locations within the prostate and has variable characteristics. We identified genes with expression associated with aggressive PCa to develop a biopsy-based, multigene signature, the Genomic Prostate Score (GPS). GPS was validated for its ability to predict men who have high-grade or high-stage PCa at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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              The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy.

              Multivariate prognostic instruments aim to predict risk of recurrence among patients with localized prostate cancer. We devised a novel risk assessment tool which would be a strong predictor of outcome across various levels of risk, and which could be easily applied and intuitively understood. We studied 1,439 men diagnosed between 1992 and 2001 who had undergone radical prostatectomy and were followed in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, a longitudinal, community based disease registry of patients with prostate cancer. Disease recurrence was defined as prostate specific antigen (PSA) 0.2 ng/ml or greater on 2 consecutive occasions following prostatectomy or a second cancer treatment more than 6 months after surgery. The University of California, San Francisco-Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score was developed using preoperative PSA, Gleason score, clinical T stage, biopsy results and age. The index was developed and validated using Cox proportional hazards and life table analyses. A total of 210 patients (15%) had recurrence, 145 by PSA criteria and 65 by second treatment. Based on the results of the Cox analysis, points were assigned based on PSA (0 to 4 points), Gleason score (0 to 3), T stage (0 to 1), age (0 to 1) and percent of biopsy positive cores (0 to 1). The UCSF-CAPRA score range is 0 to 10, with roughly double the risk of recurrence for each 2-point increase in score. Recurrence-free survival at 5 years ranged from 85% for a UCSF-CAPRA score of 0 to 1 (95% CI 73%-92%) to 8% for a score of 7 to 10 (95% CI 0%-28%). The concordance index for the UCSF-CAPRA score was 0.66. The UCSF-CAPRA score is a straightforward yet powerful preoperative risk assessment tool. It must be externally validated in future studies.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Supervision
                Role: Formal analysisRole: MethodologyRole: Software
                Role: MethodologyRole: Resources
                Role: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 October 2017
                2017
                : 12
                : 10
                : e0185535
                Affiliations
                [1 ] Departments of Urology, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [2 ] Department of Urology, University of California San Francisco, San Francisco, California, United States of America
                [3 ] Department of Radiology, University of California San Francisco, San Francisco, California, United States of America
                [4 ] Genomic Health Inc., Redwood City, California, United States of America
                [5 ] Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
                King's College London, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: HJL and PGF: Employment at Genomic Health Inc. MRC and PRC: Departmental research support, Genomic Health Inc. This does not alter our adherence to the PLOS ONE policies on sharing data and materials.

                [¤]

                Current address: Department of Urology, Yale University School of Medicine, New Haven, Connecticut, United States of America

                Article
                PONE-D-16-36825
                10.1371/journal.pone.0185535
                5634556
                29016610
                124b40d0-0dcd-4e20-aa49-f6b09388f5bc

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 13 September 2016
                : 14 September 2017
                Page count
                Figures: 4, Tables: 2, Pages: 13
                Funding
                The authors H. Jeffrey Lawrence, MD (HJL) and Phillip Febbo, MD (PF) are full-time employees of Genomic Health Inc, Redwood City, CA. PF and HJL reviewed the manuscript prior to submission. Genomic Health Inc. did not play a role in the study design, data collection, analysis, decision to publish, and only provided financial support in the form of the authors’ salaries. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
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                Genitourinary Tract Tumors
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                Custom metadata
                De-identified data are available from the UCSF Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data for this study. For further information please contact niloufar.ameli@ 123456ucsf.edu .

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