Association of low PTEN expression by fluorescence immunohistochemistry (F-IHC) and lethal disease in men with surgically-treated prostate cancer (PrCa).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 15-15 ◽  
Author(s):  
Anis Hamid ◽  
Kathryn P. Gray ◽  
Ying Huang ◽  
Michaela Bowden ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multispectral Imaging ◽  
Cox Model ◽  
Tissue Microarrays ◽  
Pten Expression ◽  
Lower Quartile ◽  
Research Information ◽  
Pten Loss ◽  
Disease Outcomes ◽  
Definitive Therapy

15 Background: Loss of PTEN expression correlates with poorer clinical outcomes after definitive therapy for non-metastatic (M0) PrCa. While most studies have used biochemical-based end points, there is limited data regarding PTEN loss by IHC and risk of lethal disease after surgery. Methods: A retrospective cohort of patients who underwent radical prostatectomy (RP) was identified from the Dana-Farber Prostate Clinical Research Information Systems (CRIS) database. Formalin-fixed, paraffin-embedded RP specimens were used to construct tissue microarrays and F-IHC for PTEN was performed. Using multispectral imaging analysis, tumor-only PTEN expression was quantified. PTEN expression was analyzed continuously and dichotomously (low [ < lower quartile] vs other [≥lower quartile]). Kaplan-Meier method estimated the distribution of time from RP to metastatic disease and overall survival (OS). Cox model assessed association of PTEN status and the disease outcomes, with adjustment of age, Gleason score and pathological stage in multivariate analyses (MVA). Prognostic ability of PTEN was also explored using a logistic regression model. Results: The analysis cohort comprised 91 patients with either non-lethal (no metastatic or biochemical relapse) or lethal disease (metastasis post-RP). The median follow-up was 12.4 years. PTEN low was significantly associated with lethal disease as both a continuous (HR 1.82, 95% CI 1.35-2.44) and dichotomous (HR 2.94, 95% CI 1.52-5.56) variable. Significant association of PTEN-low expression and poorer OS was observed (cont: HR 2.22, 95% CI 1.54-3.23; low vs other: HR 4.00, 95% CI 1.89-8.33). MVA models yielded consistent results. A prognostic model assessing 10-year disease outcomes showed incremental prognostic improvement with PTEN status added to age/Gleason/stage (lethal disease: area under curve (AUC) 0.79 vs 0.84 [+PTEN status]; death: AUC 0.71 vs 0.76 [+PTEN status]). Conclusions: Low PTEN expression by F-IHC in primary prostate cancer is an independent prognostic biomarker of lethal disease and death after surgery. Quantitative F-IHC for PTEN is a viable diagnostic assay in this context.

scholarly journals P2X4 Purinergic Receptors as a Therapeutic Target in Aggressive Prostate Cancer

2021 ◽  
Author(s):  
Janielle P. Maynard ◽  
Jiayun Lu ◽  
Igor Vidal ◽  
Jessica Hicks ◽  
Luke Mummert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Purinergic Receptor ◽  
Treatment Options ◽  
Tumor Development ◽  
Intraepithelial Neoplasia ◽  
Tissue Microarrays ◽  
Migration And Invasion ◽  
Therapeutic Targeting ◽  
Pten Loss

Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. Herein, we report that the P2X4 purinergic receptor is overexpressed in PCa, associated with PCa metastasis, and a driver of tumor development in vivo. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer compared to benign tissue spots, in prostatic intraepithelial neoplasia, in cancer from White compared to Black men, and in PCa with ERG positivity or with PTEN loss. High P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with P2X4-specific agonist CTP increased transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. P2X4 antagonist 5-BDBD treatment resulted in a dose-dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP-C2, Myc-CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc-CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identifies P2X4 as a candidate for therapeutic targeting.

scholarly journals Circulating Tumor Cells as a Predictor of Treatment Response in Clinically Localized Prostate Cancer

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Simpa S. Salami ◽  
Udit Singhal ◽  
Daniel E. Spratt ◽  
Ganesh S. Palapattu ◽  
Brent K. Hollenbeck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Androgen Deprivation Therapy ◽  
Circulating Tumor Cell ◽  
Androgen Deprivation ◽  
Localized Prostate Cancer ◽  
Curative Intent ◽  
Pten Loss ◽  
Definitive Therapy

PURPOSE Using nonenrichment-based, potentially more sensitive Epic Sciences circulating tumor cell (CTC) platform, we sought to detect and characterize CTCs in untreated, high-risk localized prostate cancer and to evaluate their clinical implication. METHODS Between 2012 and 2015, blood samples were prospectively collected from patients with National Comprehensive Cancer Network high-risk localized prostate cancer undergoing either radiotherapy (XRT) plus androgen deprivation therapy or radical prostatectomy (RP) with curative intent. Samples were analyzed with the Epic Sciences platform with 4′,6-diamidino-2-phenylindole, CD45, cytokeratin (CK), and androgen receptor (AR) N-terminal staining. CTC counts were correlated with biochemical recurrence (BCR). RESULTS A diversity of CTC subtypes, including CK-positive, CK-negative, AR-positive, and CTC clusters, were observed in 73.3% (33 of 45) of patients with evaluable data. The median follow-up was 14.2 months (range, 0.5 to 43.7 months). BCR occurred more frequently in the RP group than XRT (15 of 26 v one of 19), with most patients in the XRT group continuing to receive androgen deprivation therapy. A higher proportion of metastatic events were observed in the RP group (five of 26 v one of 19). In the RP group, BCR and development of metastases were associated with a higher total number of CTCs, AR-positive CTCs, and CTC phenotypic heterogeneity. One patient who developed BCR and metastases quickly after RP had diverse phenotypical CTC subtypes, and single-cell genomic analyses of all detectable CTCs confirmed common prostate cancer copy number alterations and PTEN loss. CONCLUSION CTCs can be identified in most patients with high-risk localized prostate cancer before definitive therapy using the Epic Sciences platform. If confirmed in a larger cohort with longer follow-up, phenotypic and genomic characterization of CTCs pretherapy may provide an additional means of risk stratifying patients with newly diagnosed high-risk disease and potentially help identify patients who could require multimodal therapy.

scholarly journals Transcriptional landscape of PTEN loss in primary prostate cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eddie Luidy Imada ◽  
Diego Fernando Sanchez ◽  
Wikum Dinalankara ◽  
Thiago Vidotto ◽  
Ericka M. Ebot ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Meta Analysis ◽  
Pten Loss ◽  
Primary Prostate Cancer ◽  
Expression Atlas ◽  
Transcriptomic Signature ◽  
Transcriptional Changes ◽  
New Biomarkers ◽  
Adaptive Immune Systems ◽  
Transcriptional Landscape

Abstract Background PTEN is the most frequently lost tumor suppressor in primary prostate cancer (PCa) and its loss is associated with aggressive disease. However, the transcriptional changes associated with PTEN loss in PCa have not been described in detail. In this study, we highlight the transcriptional changes associated with PTEN loss in PCa. Methods Using a meta-analysis approach, we leveraged two large PCa cohorts with experimentally validated PTEN and ERG status by Immunohistochemistry (IHC), to derive a transcriptomic signature of PTEN loss, while also accounting for potential confounders due to ERG rearrangements. This signature was expanded to lncRNAs using the TCGA quantifications from the FC-R2 expression atlas. Results The signatures indicate a strong activation of both innate and adaptive immune systems upon PTEN loss, as well as an expected activation of cell-cycle genes. Moreover, we made use of our recently developed FC-R2 expression atlas to expand this signature to include many non-coding RNAs recently annotated by the FANTOM consortium. Highlighting potential novel lncRNAs associated with PTEN loss and PCa progression. Conclusion We created a PCa specific signature of the transcriptional landscape of PTEN loss that comprises both the coding and an extensive non-coding counterpart, highlighting potential new players in PCa progression. We also show that contrary to what is observed in other cancers, PTEN loss in PCa leads to increased activation of the immune system. These findings can help the development of new biomarkers and help guide therapy choices.

scholarly journals Multi-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study

2021 ◽  
Vol 9 (7) ◽  
pp. e002197
Author(s):  
Janis M Taube ◽  
Kristin Roman ◽  
Elizabeth L Engle ◽  
Chichung Wang ◽  
Carmen Ballesteros-Merino ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Multispectral Imaging ◽  
Immune Cell ◽  
Clinical Laboratory ◽  
Predictive Biomarkers ◽  
Spatial Arrangement ◽  
Tissue Microarrays ◽  
Fluorescent Detection ◽  
Nsclc Tissue ◽  
Tissue Sections

BackgroundEmerging data suggest predictive biomarkers based on the spatial arrangement of cells or coexpression patterns in tissue sections will play an important role in precision immuno-oncology. Multiplexed immunofluorescence (mIF) is ideally suited to such assessments. Standardization and validation of an end-to-end workflow that supports multisite trials and clinical laboratory processes are vital. Six institutions collaborated to: (1) optimize an automated six-plex assay focused on the PD-1/PD-L1 axis, (2) assess intersite and intrasite reproducibility of staining using a locked down image analysis algorithm to measure tumor cell and immune cell (IC) subset densities, %PD-L1 expression on tumor cells (TCs) and ICs, and PD-1/PD-L1 proximity assessments.MethodsA six-plex mIF panel (PD-L1, PD-1, CD8, CD68, FOXP3, and CK) was rigorously optimized as determined by quantitative equivalence to immunohistochemistry (IHC) chromogenic assays. Serial sections from tonsil and breast carcinoma and non-small cell lung cancer (NSCLC) tissue microarrays (TMAs), TSA-Opal fluorescent detection reagents, and antibodies were distributed to the six sites equipped with a Leica Bond Rx autostainer and a Vectra Polaris multispectral imaging platform. Tissue sections were stained and imaged at each site and delivered to a single site for analysis. Intersite and intrasite reproducibility were assessed by linear fits to plots of cell densities, including %PDL1 expression by TCs and ICs in the breast and NSCLC TMAs.ResultsComparison of the percent positive cells for each marker between mIF and IHC revealed that enhanced amplification in the mIF assay was required to detect low-level expression of PD-1, PD-L1, FoxP3 and CD68. Following optimization, an average equivalence of 90% was achieved between mIF and IHC across all six assay markers. Intersite and intrasite cell density assessments showed an average concordance of R2=0.75 (slope=0.92) and R2=0.88 (slope=0.93) for breast carcinoma, respectively, and an average concordance of R2=0.72 (slope=0.86) and R2=0.81 (slope=0.68) for NSCLC. Intersite concordance for %PD-L1+ICs had an average R2 value of 0.88 and slope of 0.92. Assessments of PD-1/PD-L1 proximity also showed strong concordance (R2=0.82; slope=0.75).ConclusionsAssay optimization yielded highly sensitive, reproducible mIF characterization of the PD-1/PD-L1 axis across multiple sites. High concordance was observed across sites for measures of density of specific IC subsets, measures of coexpression and proximity with single-cell resolution.

404 DEVELOPMENT OF MULTIPARAMETRIC PROGNOSTIC MODELS USING LARGE PROSTATE CANCER TISSUE MICROARRAYS

2011 ◽  
Vol 10 (2) ◽  
pp. 141
Author(s):  
S. Minner ◽  
M.C. Tsourlakis ◽  
J. Müller ◽  
L. Burkhardt ◽  
P. Tennstedt ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tissue Microarrays ◽  
Prognostic Models ◽  
Cancer Tissue ◽  
Prostate Cancer Tissue ◽  
Large Prostate

SPOP and CHD1 alterations in prostate cancer: Relationship with PTEN loss, tumor grade, perineural infiltration, and PSA recurrence

The Prostate ◽  
2021 ◽  
Author(s):  
Silvia Hernández‐Llodrà ◽  
Laura Segalés ◽  
Nuria Juanpere ◽  
Tech Marta Lorenzo ◽  
Marta Salido ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Grade ◽  
Pten Loss ◽  
Psa Recurrence
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