Integrative molecular profiling challenges robustness of prognostic signature scores in multifocal prostate cancer.

96 Background: Tissue based biomarkers are increasingly utilized in men diagnosed with low grade prostate cancer (PCa) to guide definitive management vs. active surveillance. PCa is uniquely multifocal, suggesting ideal prognostic biomarkers should be robust to both undersampling of a high grade component of a mixed-grade tumor focus, as well as unsampled multifocal high grade tumor foci. Methods: To assess the robustness of prognostic biomarkers to multifocality, we designed a comprehensive multiplexed targeted RNA sequencing assay (mxRNAseq) capable of assessing multiple classes of transcriptional alterations and deriving available prognostic signature scores (e.g. Prolaris CCP and OncotypeDX GPS). We applied this assay to a retrospective cohort of 176 FFPE tissue samples representing the range of PCa progression. Single candidate biomarkers and derived prognostic signatures were analyzed in multifocal cases with only low-grade disease as well as those with extreme grade differences across tumor foci. Results: Our mxRNAseq assay robustly detected known coding gene/lncRNA expression, gene fusions, splice variants, and expressed somatic and germline mutations. Supervised clustering of target gene expression confirmed expected transcriptional module deregulation and derived prognostic signatures across PCa progression. Prognostic biomarkers (including derived signatures) showed no significant expression differences between low grade foci from prostates with and without high grade disease foci and were uniformly higher in high vs. low grade foci from the same case. In four cases of extreme multifocality (Gleason score 6 vs. ≥ 8 foci), prognostic signatures were significantly lower in low vs. high grade foci. In a clinical prostatectomy cohort of 1,418 men with diagnostic biopsy Gleason score 3+3 = 6 or 3+4 = 7, 21 (1.5%) had Gleason score ≥ 4+4 = 8, suggesting the initial biopsy missed or undersampled the most clinically relevant focus. Conclusions: Using a novel comprehensive mxRNAseq assay, our results challenge the robustness of prognostic biomarkers between multifocal low and high grade PCa foci, critically important in the context of un/under-sampled aggressive tumor foci.

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Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures

Cancers ◽

10.3390/cancers12030537 ◽

2020 ◽

Vol 12 (3) ◽

pp. 537 ◽

Cited By ~ 1

Author(s):

Renuka Sriram ◽

Mark Van Criekinge ◽

Justin DeLos Santos ◽

Fayyaz Ahamed ◽

Hecong Qin ◽

...

Keyword(s):

Prostate Cancer ◽

Magnetic Resonance ◽

Gleason Score ◽

Prostate Tissue ◽

Resonance Spectroscopy ◽

Low Grade ◽

High Grade ◽

Metabolic Alterations ◽

Ldh Activity ◽

Benign Prostate

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR.

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3D Mueller matrix mapping of layered distributions of depolarisation degree for analysis of prostate adenoma and carcinoma diffuse tissues

Scientific Reports ◽

10.1038/s41598-021-83986-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Volodymyr A. Ushenko ◽

Benjamin T. Hogan ◽

Alexander Dubolazov ◽

Gennadii Piavchenko ◽

Sergey L. Kuznetsov ◽

...

Keyword(s):

Gleason Score ◽

Mueller Matrix ◽

Low Grade ◽

High Grade ◽

Tissue Samples ◽

Prostate Tumour ◽

Carcinoma Tissue ◽

Matrix Mapping ◽

Prostate Adenoma ◽

Malignant Prostate

AbstractProstate cancer is the second most common cancer globally in men, and in some countries is now the most diagnosed form of cancer. It is necessary to differentiate between benign and malignant prostate conditions to give accurate diagnoses. We aim to demonstrate the use of a 3D Mueller matrix method to allow quick and easy clinical differentiation between prostate adenoma and carcinoma tissues with different grades and Gleason scores. Histological sections of benign and malignant prostate tumours, obtained by radical prostatectomy, were investigated. We map the degree of depolarisation in the different prostate tumour tissues using a Mueller matrix polarimeter set-up, based on the superposition of a reference laser beam with the interference pattern of the sample in the image plane. The depolarisation distributions can be directly related to the morphology of the biological tissues. The dependences of the magnitude of the 1st to 4th order statistical moments of the depolarisation distribution are determined, which characterise the distributions of the depolarisation values. To determine the diagnostic potential of the method three groups of histological sections of prostate tumour biopsies were formed. The first group contained 36 adenoma tissue samples, while the second contained 36 carcinoma tissue samples of a high grade (grade 4: poorly differentiated—4 + 4 Gleason score), and the third group contained 36 carcinoma tissue samples of a low grade (grade 1: moderately differentiated—3 + 3 Gleason score). Using the calculated values of the statistical moments, tumour tissues are categorised as either adenoma or carcinoma. A high level (> 90%) accuracy of differentiation between adenoma and carcinoma samples was achieved for each group. Differentiation between the high-grade and low-grade carcinoma samples was achieved with an accuracy of 87.5%. The results demonstrate that Mueller matrix mapping of the depolarisation distribution of prostate tumour tissues can accurately differentiate between adenoma and carcinoma, and between different grades of carcinoma. This represents a first step towards the implementation of 3D Mueller matrix mapping for clinical analysis and diagnosis of prostate tumours.

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The genomic relationship among matched prostate cancer foci.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5028 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5028-5028

Author(s):

David James VanderWeele ◽

Christopher D. Brown ◽

Robert L. Grossman ◽

Jerome B. Taxy ◽

Walter Michael Stadler ◽

...

Keyword(s):

Prostate Cancer ◽

Lymph Node ◽

Gleason Score ◽

Somatic Mutations ◽

Local Therapy ◽

Low Grade ◽

High Grade ◽

Genomic Relationship ◽

High Confidence ◽

Cancer Management

5028 Background: Cancer management is influenced by how one views progression and how one calculates the risk of metastases and death. For prostate cancer, this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. Despite recommendations supporting active surveillance for Gleason 6 prostate cancer, the vast majority of American patients receive aggressive local therapy, in part based on a presumption that low grade cancer progresses to high grade, lethal disease. Methods: To assess the genomic relationship between low and high grade disease, laser capture microdissection was used to isolate concurrent cancer foci from prostates with multifocal disease, and somatic mutations were identified using exome sequencing. The relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects, and a lymph node metastasis was examined for two of those subjects. Results: We obtained an average of 41-fold median coverage of the exome, with an average high confidence mutation rate of 0.8/Mb. Seventy of 79 (0.886) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 15 of 80 (0.188) high confidence somatic mutations in the high grade focus were private. Seven of the 80 (0.088) were shared with low grade foci, and 65 (0.813) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations is consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.

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Comparing magnetic resonance imaging/ultrasound-fusion biopsy and systemic 12-core transrectal ultrasound biopsy for whole gland pathology.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.84 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 84-84

Author(s):

Daniel Su ◽

Arvin George ◽

Minhaj Siddiqui ◽

Soroush Rais-Bahrami ◽

Lambros Stamatakis ◽

...

Keyword(s):

Prostate Cancer ◽

Gleason Score ◽

Prostate Biopsy ◽

Core Biopsy ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Low Grade ◽

High Grade ◽

Fusion Biopsy ◽

Clinically Significant

84 Background: Historically, pathologic findings from standard 12-core prostate biopsies are upgraded in 25 to 33% of patients after radical prostatectomy (RP). MRI/US fusion prostate biopsy has been shown to upgrade prostate cancer compared to standard 12-core biopsy in 32% of patients. MRI/US fusion biopsy may offer a more accurate representation of whole gland pathology. We evaluate the rate of pathologic upgrade in standard 12-core biopsy and MRI/US fusion biopsy when compared with whole gland pathology from RP. Methods: Patients who underwent random prostate biopsy, fusion biopsy and subsequently RP for prostate cancer from 2012 to 2013 were included. Pathology was reviewed by a single pathologist. The cohort was divided into clinically significant high-grade (Gleason score 4+3 or higher) and clinically insignificant low-grade (Gleason score 3+4 or lower) sub cohorts. Pathological upgrade was defined as any increase in Gleason sum or primary Gleason score. McNemar’s test was used to compare the proportion of patients who were upgraded from random biopsy to RP versus the proportion that were upgraded from fusion biopsy to RP. Results: Sixty eight patients underwent 12-core and fusion prostate biopsy then subsequently RP. Mean prostate-specific antigen was 9.2ng/ml. There are total of 43 patients with clinically insignificant low-grade and 25 patients with clinically significant high-grade. Fusion biopsy upgraded 19 patients (28%) compared to 12-core biopsy, eight of these patients had negative 12-core biopsy. Pathology on the RP specimen upgraded 18 of the 12-core results (26%) compare to only eight fusion biopsy results (11%). (p =0.0095) 14 patients (20%) who had clinically insignificant low-grade disease on 12-core biopsy were upgraded to clinically significant high-grade on RP. Only two patients (3%) with clinically insignificant low-grade from fusion biopsy were upgraded on RP. (p< 0.0005) Conclusions: Prostate cancer detected on MRI/US fusion prostate biopsy has significantly lower rates of pathologic upgrade than standard 12-core biopsy when both were compared to prostatectomy specimens. MRI/US fusion biopsy may represent whole gland pathology more accurately compared to 12-core biopsy.

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Clinical use of the SelectMDx urinary-biomarker test with or without mpMRI in prostate cancer diagnosis: a prospective, multicenter study in biopsy-naïve men

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-021-00367-8 ◽

2021 ◽

Author(s):

Rianne J. Hendriks ◽

Marloes M. G. van der Leest ◽

Bas Israël ◽

Gerjon Hannink ◽

Anglita YantiSetiasti ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Stratification ◽

Specific Antigen ◽

Low Grade ◽

Diagnostic Study ◽

High Grade ◽

Net Benefit ◽

Conditional Strategy ◽

Detection Rates ◽

Guided Biopsy

Abstract Background Risk stratification in men with suspicion of prostate cancer (PCa) requires reliable diagnostic tests, not only to identify high-grade PCa, also to minimize the overdetection of low-grade PCa, and reduction of “unnecessary” prostate MRIs and biopsies. This study aimed to evaluate the SelectMDx test to detect high-grade PCa in biopsy-naïve men. Subsequently, to assess combinations of SelectMDx test and multi-parametric (mp) MRI and its potential impact on patient selection for prostate biopsy. Methods This prospective multicenter diagnostic study included 599 biopsy-naïve patients with prostate-specific antigen level ≥3 ng/ml. All patients underwent a SelectMDx test and mpMRI before systematic transrectal ultrasound-guided biopsy (TRUSGB). Patients with a suspicious mpMRI also had an in-bore MR-guided biopsy (MRGB). Histopathologic outcome of TRUSGB and MRGB was used as reference standard. High-grade PCa was defined as ISUP Grade Group (GG) ≥ 2. The primary outcome was the detection rates of low- and high-grade PCa and number of biopsies avoided in four strategies, i.e., (1) SelectMDx test-only, (2) mpMRI-only, (3) SelectMDx test followed by mpMRI when SelectMDx test was positive (conditional strategy), and (4) SelectMDx test and mpMRI in all (joint strategy). A positive SelectMDx test outcome was a risk score of ≥−2.8. Decision curve analysis (DCA) was performed to assess clinical utility. Results Prevalence of high-grade PCa was 31% (183/599). Thirty-eight percent (227/599) of patients had negative SelectMDx test in whom biopsy could be avoided. Low-grade PCa was not detected in 35% (48/138) with missing 10% (18/183) high-grade PCa. Yet, mpMRI-only could avoid 49% of biopsies, not detecting 4.9% (9/183) of high-grade PCa. The conditional strategy reduces the number of mpMRIs by 38% (227/599), avoiding biopsy in 60% (357/599) and missing 13% (24/183) high-grade PCa. Low-grade PCa was not detected in 58% (80/138). DCA showed the highest net benefit for the mpMRI-only strategy, followed by the conditional strategy at-risk thresholds >10%. Conclusions SelectMDx test as a risk stratification tool for biopsy-naïve men avoids unnecessary biopsies in 38%, minimizes low-grade PCa detection, and misses only 10% high-grade PCa. Yet, using mpMRI in all patients had the highest net benefit, avoiding biopsy in 49% and missing 4.9% of high-risk PCa. However, if mpMRI availability is limited or expensive, using mpMRI-only in SelectMDx test positive patients is a good alternative strategy.

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Effect of Statins on the Risk of Different Stages of Prostate Cancer: A Meta-Analysis

Urologia Internationalis ◽

10.1159/000518164 ◽

2021 ◽

pp. 1-9

Author(s):

Yun Li ◽

Xuan Cheng ◽

Jia-lian Zhu ◽

Wen-wen Luo ◽

Huai-rong Xiang ◽

...

Keyword(s):

Prostate Cancer ◽

Lower Risk ◽

Advanced Prostate Cancer ◽

Meta Analysis ◽

Cochrane Library ◽

Low Grade ◽

High Grade ◽

The Cochrane Library ◽

The Relationship ◽

Comprehensive Literature Search

Introduction: The aim of this article was to investigate the relationship between statins and the risk of different stages or grades of prostate cancer. Methods: A comprehensive literature search was performed for articles published until December 18, 2020, on the PubMed, Embase, and the Cochrane Library databases. The pooled relative risk (RR) and 95% confidence interval (CI) were then analyzed using the STATA.16.0 software. Results: A total of 588,055 patients from 14 studies were included in the analysis. We found that the use of statins expressed a significant correlation with a lower risk of advanced prostate cancer (RR = 0.81, 95% CI: 0.73–0.91; RR = 0.86, 95% CI: 0.75–0.99, respectively). However, no evidence suggested that the use of statins was beneficial for the prevention of localized prostate cancer incidence. Similarly, the pooled results also revealed no association between the use of statins and the risk of high-grade and low-grade prostate cancer. Conclusion: It has been found that the use of statins is associated with a lower risk of advanced prostate cancer but was not related to the risk of localized, low-grade, or high-grade prostate cancer.

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The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

10.1101/832360 ◽

2019 ◽

Author(s):

Siyuan Cheng ◽

Nestor Prieto-Dominguez ◽

Shu Yang ◽

Zachary M. Connelly ◽

Samantha StPierre ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Hippo Pathway ◽

Luciferase Reporter ◽

Low Grade ◽

Beta Catenin ◽

High Grade ◽

Protein Levels ◽

Neuroendocrine Prostate Cancer ◽

Functional Involvement

ABSTRACTBACKGROUNDAfter long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.METHODSImmunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.RESULTSYAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.CONCLUSIONSThe expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.

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Differential Expression of Matrix Metalloproteinase-2 Expression in Disseminated Tumor Cells and Micrometastasis in Bone Marrow of Patients with Nonmetastatic and Metastatic Prostate Cancer: Theoretical Considerations and Clinical Implications—An Immunocytochemical Study

Bone Marrow Research ◽

10.1155/2012/259351 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Nigel P. Murray ◽

Eduardo Reyes ◽

Pablo Tapia ◽

Leonardo Badínez ◽

Nelson Orellana

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Matrix Metalloproteinase ◽

Tumor Cells ◽

Gleason Score ◽

Stromal Cells ◽

Disseminated Tumor Cells ◽

Matrix Metalloproteinase 2 ◽

Low Grade ◽

Immunocytochemical Study

Matrix metalloproteinase-2 (MMP-2) is important in the dissemination and invasion of tumor cells and activates angiogenesis. We present an immunocytochemical study of MMP-2 expression in circulating prostate cells (CPCs), disseminated tumor cells (DTCs), and micrometastasis (mM) in bone marrow of men with prostate cancer. Methods and Patients. Tumor cells were identified with anti-PSA immunocytochemistry. Positive samples underwent processing with anti-MMP-2, its expression was compared with Gleason score, concordance of expression, and metastatic and nonmetastatic disease. Results. 215 men participated, CPCs were detected in 62.7%, DTCs in 62.2%, and mM in 71.4% in nonmetastatic cancer; in metastatic cancer all had CPCs, DTCs, and mM detected. All CPCs and DTCs expressed MMP-2; in mM MMP-2 expression was positively associated with increasing Gleason score. MMP-2 expression in CPCs and DTCs showed concordance. In low grade tumors, mM and surrounding stromal cells were MMP-2 negative, with variable expression in high grade tumors; in metastatic disease, both mM and stromal cells were MMP-2 positive. Conclusions. CPCs and DTCs are different from mM, with inhibition of MMP-2 expression in mM of low grade tumors. With disease progression, MMP-2 expression increases in both mM and surrounding stromal cells, with implications for the use of bisphosphonates or MMP-2 inhibitors.

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Overdiagnosis and Overtreatment of Prostate Cancer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.98 ◽

2012 ◽

pp. e35-e39 ◽

Cited By ~ 4

Author(s):

Ian M. Thompson

Keyword(s):

Prostate Cancer ◽

Active Surveillance ◽

Specific Antigen ◽

The United States ◽

Assessment Tools ◽

Low Grade ◽

High Grade ◽

Surveillance Strategy ◽

Psa Testing ◽

Prostate Cancer Prevention

Overview: Prostate cancer is a ubiquitous disease, affecting as many as two-thirds of men in their 60s. Through widespread prostate-specific antigen (PSA) testing, increasing rates of prostate biopsy, and increased sampling of the prostate, a larger fraction of low-grade, low-volume tumors have been detected, consistent with tumors often found at autopsy. These tumors have historically been treated in a manner similar to that used for higher-grade tumors but, more recently, it has become evident that with a plan of active surveillance that reserves treatment for only those patients whose tumors show evidence of progression, very high disease-specific survival can be achieved. Unfortunately, the frequency of recommendation of an active surveillance strategy in the United States is low. An alternative strategy to improve prostate cancer detection is through selected biopsy of those men who are at greater risk of harboring high-grade, potentially lethal cancer. This strategy is currently possible through the use of risk assessment tools such as the Prostate Cancer Prevention Trial Risk Calculator ( www.prostate.cancer.risk.calculator.com ) as well as others. These tools can predict with considerable accuracy a man's risk of low-grade and high-grade cancer, allowing informed decision making for the patient with a goal of detection of high-risk disease. Ultimately, other biomarkers including PCA3, TMPRSS2:ERG, and [-2]proPSA will likely aid in discriminating these two types of cancer before biopsy.

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