Editorial

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Open AccessEditorial

Prostate Cancer: Pathophysiology, Pathology and Therapy

by Vasiliki Tzelepi

Cancers 2023, 15(1), 281; https://doi.org/10.3390/cancers15010281 - 31 Dec 2022

Cited by 1 | Viewed by 4134

Prostate cancer (PCa) is a major health care challenge in the developed world, being the most common type of cancer in men in the USA [...] Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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13 pages, 854 KiB

Open AccessArticle

Interactions of SNPs in Folate Metabolism Related Genes on Prostate Cancer Aggressiveness in European Americans and African Americans

by Hui-Yi Lin, Susan E. Steck, Indrani Sarkar, Elizabeth T. H. Fontham, Alan Diekman, Lora J. Rogers, Calvin T. Ratliff, Jeannette T. Bensen, James L. Mohler and L. Joseph Su

Cancers 2023, 15(6), 1699; https://doi.org/10.3390/cancers15061699 - 10 Mar 2023

Viewed by 1685

Abstract

Background: Studies showed that folate and related single nucleotide polymorphisms (SNPs) could predict prostate cancer (PCa) risk. However, little is known about the interactions of folate-related SNPs associated with PCa aggressiveness. The study’s objective is to evaluate SNP–SNP interactions among the DHFR 19-bp [...] Read more.

Background: Studies showed that folate and related single nucleotide polymorphisms (SNPs) could predict prostate cancer (PCa) risk. However, little is known about the interactions of folate-related SNPs associated with PCa aggressiveness. The study’s objective is to evaluate SNP–SNP interactions among the DHFR 19-bp polymorphism and 10 SNPs in folate metabolism and the one-carbon metabolism pathway associated with PCa aggressiveness. Methods: We evaluated 1294 PCa patients, including 690 European Americans (EAs) and 604 African Americans (AAs). Both individual SNP effects and pairwise SNP–SNP interactions were analyzed. Results: None of the 11 individual polymorphisms were significant for EAs and AAs. Three SNP–SNP interaction pairs can predict PCa aggressiveness with a medium to large effect size. For the EA PCa patients, the interaction between rs1801133 (MTHFR) and rs2236225 (MTHFD1), and rs1801131 (MTHFR) and rs7587117 (SLC4A5) were significantly associated with aggressive PCa. For the AA PCa patients, the interaction of DHFR-19bp polymorphism and rs4652 (LGALS3) was significantly associated with aggressive PCa. Conclusions: These SNP–SNP interactions in the folate metabolism-related genes have a larger impact than SNP individual effects on tumor aggressiveness for EA and AA PCa patients. These findings can provide valuable information for potential biological mechanisms of PCa aggressiveness. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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39 pages, 8167 KiB

Open AccessEditor’s ChoiceArticle

Integrating Pharmacogenomics Data-Driven Computational Drug Prediction with Single-Cell RNAseq to Demonstrate the Efficacy of a NAMPT Inhibitor against Aggressive, Taxane-Resistant, and Stem-like Cells in Lethal Prostate Cancer

by Suman Mazumder, Taraswi Mitra Ghosh, Ujjal K. Mukherjee, Sayak Chakravarti, Farshad Amiri, Razan S. Waliagha, Farnaz Hemmati, Panagiotis Mistriotis, Salsabil Ahmed, Isra Elhussin, Ahmad-Bin Salam, Windy Dean-Colomb, Clayton Yates, Robert D. Arnold and Amit K. Mitra

Cancers 2022, 14(23), 6009; https://doi.org/10.3390/cancers14236009 - 06 Dec 2022

Cited by 2 | Viewed by 3346

Abstract

Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) [...] Read more.

Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) is nearly universal. Further, the presence of cancer stem-like cells (EMT/epithelial-to-mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/lethal/advanced variants of PCa (AVPC). In this study, we introduced a pharmacogenomics data-driven optimization-regularization-based computational prediction algorithm (“secDrugs”) to predict novel drugs against lethal PCa. Integrating secDrug with single-cell RNA-sequencing/scRNAseq as a ‘Double-Hit’ drug screening tool, we demonstrated that single-cells representing drug-resistant and stem-cell-like cells showed high expression of the NAMPT pathway genes, indicating potential efficacy of the secDrug FK866 which targets NAMPT. Next, using several cell-based assays, we showed substantial impact of FK866 on clinically advanced PCa as a single agent and in combination with taxanes or AR-inhibitors. Bulk-RNAseq and scRNAseq revealed that, in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes, HES1 and CD44. Further, we combined a microfluidic chip-based cell migration assay with a traditional cell migration/‘scratch’ assay and demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using PCa patient datasets, we showed that FK866 is potentially capable of reversing the expression of several genes associated with biochemical recurrence, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept candidate for drug repurposing, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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14 pages, 2050 KiB

Open AccessArticle

Genotype-to-Phenotype Associations in the Aggressive Variant Prostate Cancer Molecular Profile (AVPC-m) Components

by Rama Soundararajan, Paul Viscuse, Patrick Pilie, Jingjing Liu, Souzana Logotheti, Caddie Laberiano Fernández, Daniele Lorenzini, Anh Hoang, Wei Lu, Luisa Maren Solis Soto, Ignacio I. Wistuba, Mingchu Xu, Xingzhi Song, Peter D. A. Shepherd, Nora M. Navone, Rebecca S. S. Tidwell, Guillermina Lozano, Christopher Logothetis, Jianhua Zhang, James P. Long, Marcos R. Estecio, Vasiliki Tzelepi and Ana M. Aparicio Show full author list Hide full author list

Cancers 2022, 14(13), 3233; https://doi.org/10.3390/cancers14133233 - 30 Jun 2022

Cited by 6 | Viewed by 2330

Abstract

The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen indifference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective [...] Read more.

The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen indifference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective clinical trials, we investigated the status of the AVPC-m components in 28 patient tumor-derived xenografts (PDXs) developed at MDACC. We subjected single formalin-fixed, paraffin-embedded (FFPE) blocks from each PDX to immunohistochemistry (IHC), targeted next-generation genomic sequencing (NGS) and Clariom-S Affymetrix human microarray expression profiling. Standard validated IHC assays and a 10% labeling index cutoff resulted in high reproducibility across three separate laboratories and three independent readers for all tumor suppressors, as well as strong correlations with loss-of-function transcriptional scores (LOF-TS). Adding intensity assessment to labeling indices strengthened the association between IHC results and LOF-TS for TP53 and RB1, but not for PTEN. For TP53, genomic alterations determined by NGS had slightly higher agreement scores with LOF-TS than aberrant IHC, while for RB1 and PTEN, NGS and IHC determinations resulted in similar agreement scores with LOF-TS. Nonetheless, our results indicate that the AVPC-m components can be assessed reproducibly by IHC using various widely available standardized assays. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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10 pages, 643 KiB

Open AccessArticle

mpMRI-US Fusion-Guided Targeted Cryotherapy in Patients with Primary Localized Prostate Cancer: A Prospective Analysis of Oncological and Functional Outcomes

by Esaú Fernández-Pascual, Celeste Manfredi, Cristina Martín, Claudio Martínez-Ballesteros, Carlos Balmori, Enrique Lledó-García, Luis Miguel Quintana, Raphael Curvo, Joaquín Carballido-Rodríguez, Fernando J. Bianco, Jr. and Juan Ignacio Martínez-Salamanca

Cancers 2022, 14(12), 2988; https://doi.org/10.3390/cancers14122988 - 17 Jun 2022

Cited by 6 | Viewed by 1641

Abstract

Targeted therapy (TT) for prostate cancer (PCa) aims to ablate the malignant lesion with an adequate margin of safety in order to obtain similar oncological outcomes, but with less toxicity than radical treatments. The main aim of this study was to evaluate the [...] Read more.

Targeted therapy (TT) for prostate cancer (PCa) aims to ablate the malignant lesion with an adequate margin of safety in order to obtain similar oncological outcomes, but with less toxicity than radical treatments. The main aim of this study was to evaluate the recurrence rate (RR) in patients with primary localized PCa undergoing mpMRI/US fusion targeted cryotherapy (FTC). A secondary objective was to evaluate prostate-specific antigen (PSA) as a predictor of recurrences. We designed a prospective single-center single-cohort study. Patients with primary localized PCa, mono or multifocal lesions, PSA ≤ 15 ng/mL, and a Gleason score (GS) ≤ 4 + 3 undergoing FTC were enrolled. RR was chosen as the primary outcome. Recurrence was defined as the presence of clinically significant prostate cancer in the treated areas. PSA values measured at different times were tested as predictors of recurrence. Continuous variables were assessed with the Bayesian t-test and categorical assessments with the chix-squared test. Univariate and logistic regression assessment were used for predictions. A total of 75 cases were included in the study. Ten subjects developed a recurrence (RR: 15.2%), while fifty-six (84.8%) patients showed a recurrence-free status. A %PSA drop of 31.5% during the first 12 months after treatment predicted a recurrence with a sensitivity of 53.8% and a specificity of 79.2%. A PSA drop of 55.3% 12 months after treatment predicted a recurrence with a sensitivity of 91.7% and a specificity of 51.9%. FTC for primary localized PCa seems to be associated with a low but not negligible percentage of recurrences. Serum PSA levels may have a role indicating RR. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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13 pages, 2057 KiB

Open AccessArticle

Contemporary Grading of Prostate Cancer: The Impact of Grading Criteria and the Significance of the Amount of Intraductal Carcinoma

by Vasiliki Tzelepi, Ioanna Maria Grypari, Souzana Logotheti, Stavros Kontogiannis, Panagiotis Kallidonis, Maria Melachrinou and Vasiliki Zolota

Cancers 2021, 13(21), 5454; https://doi.org/10.3390/cancers13215454 - 29 Oct 2021

Cited by 5 | Viewed by 2040

Abstract

(1) Background: Prognostic grade group (PGG) is an important prognostic parameter in prostate cancer that guides therapeutic decisions. The cribriform pattern and intraductal carcinoma (IDC) are two histological patterns, that have additional prognostic significance. However, discrepancies exist regarding the handling of IDC according [...] Read more.

(1) Background: Prognostic grade group (PGG) is an important prognostic parameter in prostate cancer that guides therapeutic decisions. The cribriform pattern and intraductal carcinoma (IDC) are two histological patterns, that have additional prognostic significance. However, discrepancies exist regarding the handling of IDC according to the guidelines published by two international genitourinary pathology societies. Furthermore, whether, in addition to its presence, the amount of IDC is also of importance has not been studied before. Lastly, the handling of tertiary patterns has also been a matter of debate in the literature. (2) Methods: A total of 129 prostatectomy cases were retrieved and a detailed histopathologic analysis was performed. (3) Results: Two cases (1.6%) upgraded their PGG, when IDC was incorporated in the grading system. The presence and the amount of IDC, as well as the presence of cribriform carcinoma were associated with adverse pathologic characteristics. Interestingly, in six cases (4.7%) there was a difference in PGG when using the different guidelines regarding the handling of tertiary patterns. In total, 6.2% of the cases would be assigned a different grade depending on the guidelines followed. (4) Conclusions: These findings highlight a potential area of confusion among pathologists and clinicians and underscore the need for a consensus grading system. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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12 pages, 1453 KiB

Open AccessArticle

Significant Inter- and Intralaboratory Variation in Gleason Grading of Prostate Cancer: A Nationwide Study of 35,258 Patients in The Netherlands

by Rachel N. Flach, Peter-Paul M. Willemse, Britt B. M. Suelmann, Ivette A. G. Deckers, Trudy N. Jonges, Carmen van Dooijeweert, Paul J. van Diest and Richard P. Meijer

Cancers 2021, 13(21), 5378; https://doi.org/10.3390/cancers13215378 - 27 Oct 2021

Cited by 12 | Viewed by 2190

Abstract

Purpose: Our aim was to analyze grading variation between pathology laboratories and between pathologists within individual laboratories using nationwide real-life data. Methods: We retrieved synoptic (n = 13,397) and narrative (n = 29,377) needle biopsy reports from the Dutch Pathology Registry [...] Read more.

Purpose: Our aim was to analyze grading variation between pathology laboratories and between pathologists within individual laboratories using nationwide real-life data. Methods: We retrieved synoptic (n = 13,397) and narrative (n = 29,377) needle biopsy reports from the Dutch Pathology Registry and prostate-specific antigen values from The Netherlands Cancer Registration for prostate cancer patients diagnosed between January 2017 and December 2019. We determined laboratory-specific proportions per histologic grade and unadjusted odds ratios (ORs) for International Society of Urological Pathologists Grades 1 vs. 2–5 for 40 laboratories due to treatment implications for higher grades. Pathologist-specific proportions were determined for 21 laboratories that consented to this part of analysis. The synoptic reports of 21 laboratories were used for analysis of case-mix correction for PSA, age, year of diagnosis, number of biopsies and positive cores. Results: A total of 38,321 reports of 35,258 patients were included. Grade 1 ranged between 19.7% and 44.3% per laboratory (national mean = 34.1%). Out of 40 laboratories, 22 (55%) reported a significantly deviant OR, ranging from 0.48 (95% confidence interval (CI) 0.39–0.59) to 1.54 (CI 1.22–1.93). Case-mix correction was performed for 10,294 reports, altering the status of 3/21 (14%) laboratories, but increasing the observed variation (20.8% vs. 17.7%). Within 15/21 (71%) of laboratories, significant inter-pathologist variation existed. Conclusion: Substantial variation in prostate cancer grading was observed between and within Dutch pathology laboratories. Case-mix correction did not explain the variation. Better standardization of prostate cancer grading is warranted to optimize and harmonize treatment. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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18 pages, 2006 KiB

Open AccessArticle

Ten Year Results of Extensive Nodal Radiotherapy and Moderately Hypofractionated Simultaneous Integrated Boost in Unfavorable Intermediate-, High-, and Very High-Risk Prostate Cancer

by Nadia Gisella Di Muzio, Chiara Lucrezia Deantoni, Chiara Brombin, Claudio Fiorino, Cesare Cozzarini, Flavia Zerbetto, Paola Mangili, Roberta Tummineri, Italo Dell’Oca, Sara Broggi, Marcella Pasetti, Anna Chiara, Paola Maria Vittoria Rancoita, Antonella Del Vecchio, Mariaclelia Stefania Di Serio and Andrei Fodor

Cancers 2021, 13(19), 4970; https://doi.org/10.3390/cancers13194970 - 03 Oct 2021

Cited by 8 | Viewed by 3027

Abstract

Aims: To report 10-year outcomes of WPRT and HD moderately hypofractionated SIB to the prostate in UIR, HR, and VHR PCa. Methods: From 11/2005 to 12/2015, 224 UIR, HR, and VHR PCa patients underwent WPRT at 51.8 Gy/28 fractions and SIB at 74.2 [...] Read more.

Aims: To report 10-year outcomes of WPRT and HD moderately hypofractionated SIB to the prostate in UIR, HR, and VHR PCa. Methods: From 11/2005 to 12/2015, 224 UIR, HR, and VHR PCa patients underwent WPRT at 51.8 Gy/28 fractions and SIB at 74.2 Gy (EQD2 88 Gy) to the prostate. Androgen deprivation therapy (ADT) was prescribed in up to 86.2% of patients. Results: Median follow-up was 96.3 months (IQR: 71–124.7). Median age was 75 years (IQR: 71.3–78.1). At last follow up, G3 GI–GU toxicity was 3.1% and 8%, respectively. Ten-year biochemical relapse-free survival (bRFS) was 79.8% (95% CI: 72.3–88.1%), disease-free survival (DFS) 87.8% (95% CI: 81.7–94.3%), overall survival (OS) 65.7% (95% CI: 58.2–74.1%), and prostate cancer-specific survival (PCSS) 94.9% (95% CI: 91.0–99.0%). Only two patients presented local relapse. At univariate analysis, VHR vs. UIR was found to be a significant risk factor for biochemical relapse (HR: 2.8, 95% CI: 1.17–6.67, p = 0.021). After model selection, only Gleason Score ≥ 8 emerged as a significant factor for biochemical relapse (HR = 2.3, 95% CI: 1.12–4.9, p = 0.023). Previous TURP (HR = 3.5, 95% CI: 1.62–7.54, p = 0.001) and acute toxicity ≥ G2 (HR = 3.1, 95% CI = 1.45–6.52, p = 0.003) were significant risk factors for GU toxicity ≥ G3. Hypertension was a significant factor for GI toxicity ≥ G3 (HR = 3.63, 95% CI: 1.06–12.46, p = 0.041). ADT (HR = 0.31, 95% CI: 0.12–0.8, p = 0.015) and iPsa (HR = 0.37, 95% CI: 0.16–0.83, p = 0.0164) played a protective role. Conclusions: WPRT and HD SIB to the prostate combined with long-term ADT, in HR PCa, determine good outcomes with acceptable toxicity. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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16 pages, 4038 KiB

Open AccessArticle

Biologically Targeted Radiation Therapy: Incorporating Patient-Specific Hypoxia Data Derived from Quantitative Magnetic Resonance Imaging

by Emily J. Her, Annette Haworth, Yu Sun, Scott Williams, Hayley M. Reynolds, Angel Kennedy and Martin A. Ebert

Cancers 2021, 13(19), 4897; https://doi.org/10.3390/cancers13194897 - 29 Sep 2021

Cited by 9 | Viewed by 2392

Abstract

Purpose: Hypoxia has been linked to radioresistance. Strategies to safely dose escalate dominant intraprostatic lesions have shown promising results, but further dose escalation to overcome the effects of hypoxia require a novel approach to constrain the dose in normal tissue.to safe levels. In [...] Read more.

Purpose: Hypoxia has been linked to radioresistance. Strategies to safely dose escalate dominant intraprostatic lesions have shown promising results, but further dose escalation to overcome the effects of hypoxia require a novel approach to constrain the dose in normal tissue.to safe levels. In this study, we demonstrate a biologically targeted radiotherapy (BiRT) approach that can utilise multiparametric magnetic resonance imaging (mpMRI) to target hypoxia for favourable treatment outcomes. Methods: mpMRI-derived tumour biology maps, developed via a radiogenomics study, were used to generate individualised, hypoxia-targeting prostate IMRT plans using an ultra- hypofractionation schedule. The spatial distribution of mpMRI textural features associated with hypoxia-related genetic profiles was used as a surrogate of tumour hypoxia. The effectiveness of the proposed approach was assessed by quantifying the potential benefit of a general focal boost approach on tumour control probability, and also by comparing the dose to organs at risk (OARs) with hypoxia-guided focal dose escalation (DE) plans generated for five patients. Results: Applying an appropriately guided focal boost can greatly mitigate the impact of hypoxia. Statistically significant reductions in rectal and bladder dose were observed for hypoxia-targeting, biologically optimised plans compared to isoeffective focal DE plans. Conclusion: Results of this study suggest the use of mpMRI for voxel-level targeting of hypoxia, along with biological optimisation, can provide a mechanism for guiding focal DE that is considerably more efficient than application of a general, dose-based optimisation, focal boost. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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22 pages, 10231 KiB

Open AccessArticle

Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

by Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Eri Banno, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuko Sakai, Kazuhiro Yoshikawa, Kazuto Nishio and Hirotsugu Uemura

Cancers 2021, 13(16), 3975; https://doi.org/10.3390/cancers13163975 - 06 Aug 2021

Cited by 4 | Viewed by 2311

Abstract

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of [...] Read more.

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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15 pages, 1305 KiB

Open AccessArticle

High Tumor Burden Predicts Poor Response to Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients

by Yu-Ting Hsieh, Bing-Juin Chiang, Chia-Chang Wu, Chun-Hou Liao, Chia-Da Lin and Chung-Hsin Chen

Cancers 2021, 13(16), 3966; https://doi.org/10.3390/cancers13163966 - 05 Aug 2021

Cited by 4 | Viewed by 2406

Abstract

To assess the predictive value of tumor burden on the biochemical response, and radiological response in Taiwanese metastatic castration-resistant prostate cancer (mCRPC) patients receiving enzalutamide. The mCRPC patients treated with enzalutamide were recruited from three hospitals. High tumor burden (HTB) was classified as [...] Read more.

To assess the predictive value of tumor burden on the biochemical response, and radiological response in Taiwanese metastatic castration-resistant prostate cancer (mCRPC) patients receiving enzalutamide. The mCRPC patients treated with enzalutamide were recruited from three hospitals. High tumor burden (HTB) was classified as metastases at either appendicular bone or visceral organ. Good prostate-specific antigen (PSA) response was defined as PSA reduction of 80%. In this cohort, there were 104 (54.2%) HTB patients and 88 (45.8%) with low tumor burden (LTB). Compared to LTB patients, fewer HTB patients had good PSA response (odds ratio: 0.43, range: 0.22–0.87, p = 0.019) and fewer radiological response (complete and partial remission) (odds ratio: 0.78, range: 0.36–1.68, p = 0.52) to enzalutamide. The disease control rate which also contained stable disease, was still lower in HTB (76.0%) than LTB group (92.9%, OR: 0.24, range: 0.07–0.77, p = 0.016) in the multivariable model. In addition, HTB patients had significantly shorter progression–free survival duration than did LTB patients (median: 8.3 vs. 21.6 months, log-rank test p = 0.003) in the univariable analysis. The tumor burden before the use of enzalutamide was associated with treatment outcomes. HTB reduced PSA response rate, radiological response rate and progression-free survival duration. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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12 pages, 3598 KiB

Open AccessArticle

ELOVL5-Mediated Long Chain Fatty Acid Elongation Contributes to Enzalutamide Resistance of Prostate Cancer

by Huan Xu, Sangsang Li, Yi Sun, Lingfan Xu, Xin Hong, Zhong Wang and Hailiang Hu

Cancers 2021, 13(16), 3957; https://doi.org/10.3390/cancers13163957 - 05 Aug 2021

Cited by 8 | Viewed by 2768

Abstract

Prostate cancer (PCa) exhibits an elevated level of de novo lipogenesis that provides both energy and basic metabolites for its malignant development. Long-chain polyunsaturated fatty acids (PUFAs) are elongated and desaturated from palmitate but their effects on PCa progression remain largely unknown. Here, [...] Read more.

Prostate cancer (PCa) exhibits an elevated level of de novo lipogenesis that provides both energy and basic metabolites for its malignant development. Long-chain polyunsaturated fatty acids (PUFAs) are elongated and desaturated from palmitate but their effects on PCa progression remain largely unknown. Here, we showed that PUFAs were significantly upregulated by androgen deprivation therapy (ADT) and elevated in neuroendocrine (NE)-like PCa cells. The key enzyme of PUFA elongation, ELOVL5, was overexpressed in NE-like PCa cells as well. Furthermore, we demonstrated that knocking down ELOVL5 in enzalutamide resistant NE-like PCa cells diminished the neuroendocrine phenotypes and enzalutamide resistance, while overexpressing ELOVL5 augmented the enzalutamide resistance of PCa cells in vitro and in vivo. Mechanistically, ELOVL5-mediated PUFA elongation enhanced the lipid raft-associated AKT-mTOR signaling activation and therefore contributes to the enzalutamide resistance. These findings suggest that ELOLV5-mediated PUFA elongation may be a potential novel target for the treatment of enzalutamide resistant NE-like PCa. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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13 pages, 1164 KiB

Open AccessArticle

Association between Androgen Deprivation Therapy and Risk of Dementia in Men with Prostate Cancer

by Jui-Ming Liu, Chin-Yao Shen, Wallis C. Y. Lau, Shih-Chieh Shao, Kenneth K. C. Man, Ren-Jun Hsu, Chun-Te Wu and Edward Chia-Cheng Lai

Cancers 2021, 13(15), 3861; https://doi.org/10.3390/cancers13153861 - 31 Jul 2021

Cited by 6 | Viewed by 2611

Abstract

The risk of dementia after androgen deprivation therapy (ADT) in patients with advanced prostate cancer (PCa) remains controversial. This study aimed to evaluate the association between ADT and the incidence of dementia in patients with PCa. We identified patients newly diagnosed with PCa [...] Read more.

The risk of dementia after androgen deprivation therapy (ADT) in patients with advanced prostate cancer (PCa) remains controversial. This study aimed to evaluate the association between ADT and the incidence of dementia in patients with PCa. We identified patients newly diagnosed with PCa in the National Health Insurance Database of Taiwan from 1 January 2002 to 30 June 2016 and in The Health Improvement Network of the United Kingdom (UK) from 1 January 1998 to 31 March 2018. We classified patients with PCa into ADT and ADT-naïve groups. Propensity score (PS) methods were used to minimize the differences in characteristics between the groups. We performed a Cox proportional hazard model to obtain the adjusted hazard ratio (HR) to compare the incidence of dementia between the groups. Our ADT group comprised 8743 and 73,816 patients in Taiwan and the UK, respectively, which were matched 1:1 to ADT-naïve patients by PS. The incidence rates of dementia in the ADT group were 2.74 versus 3.03 per 1000 person-years in the ADT naïve groups in Taiwan, and 2.81 versus 2.79 per 1000 person-years in the UK. There was no statistical difference between ADT and ADT-naïve groups (adjusted HR: 1.12; 95% confidence interval (CI): 0.87–1.43 in Taiwan and adjusted HR: 1.02; 95% CI: 0.85–1.23 in the UK). We found no association between the incidence of dementia and ADT in patients with advanced PCa in either database. Further studies are warranted to evaluate other possible triggers of incident dementia in patients receiving ADT for advanced PCa. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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13 pages, 3572 KiB

Open AccessArticle

Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

by Fuqiang Ban, Eric Leblanc, Ayse Derya Cavga, Chia-Chi Flora Huang, Mark R. Flory, Fan Zhang, Matthew E. K. Chang, Hélène Morin, Nada Lallous, Kriti Singh, Martin E. Gleave, Hisham Mohammed, Paul S. Rennie, Nathan A. Lack and Artem Cherkasov

Cancers 2021, 13(14), 3488; https://doi.org/10.3390/cancers13143488 - 12 Jul 2021

Cited by 16 | Viewed by 4313

Abstract

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., [...] Read more.

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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Graphical abstract

12 pages, 8621 KiB

Open AccessCommunication

Prostate Cancer in 2021: Novelties in Prognostic and Therapeutic Biomarker Evaluation

by Alessia Cimadamore, Roberta Mazzucchelli, Antonio Lopez-Beltran, Francesco Massari, Matteo Santoni, Marina Scarpelli, Liang Cheng and Rodolfo Montironi

Cancers 2021, 13(14), 3471; https://doi.org/10.3390/cancers13143471 - 11 Jul 2021

Cited by 11 | Viewed by 3443

Abstract

The 2021 novelties in prognostic and therapeutic tissue markers in patients with prostate cancer (PCa) can be subdivided into two major groups. The first group is related to prognostic markers based on morphological and immunohistochemical evaluations. The novelties in this group can then [...] Read more.

The 2021 novelties in prognostic and therapeutic tissue markers in patients with prostate cancer (PCa) can be subdivided into two major groups. The first group is related to prognostic markers based on morphological and immunohistochemical evaluations. The novelties in this group can then be subdivided into two subgroups, one involving morphologic evaluation only, i.e., PCa grading, and the other involving both morphologic and immunohistochemical evaluations, i.e., aggressive variant PCa (AVPCa). Grading concerns androgen-dependent PCa, while AVPCa represents a late phase in its natural history, when it becomes androgen-independent. The novelties of the other major group are related to molecular markers predicting significant disease or response to therapy. This group mainly includes novelties in the molecular evaluation of PCa in tissue material and liquid biopsies. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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11 pages, 1489 KiB

Open AccessArticle

Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients

by Nada Lallous, Oliver Snow, Christophe Sanchez, Ana Karla Parra Nuñez, Bei Sun, Ahmed Hussain, Joseph Lee, Helene Morin, Eric Leblanc, Martin E. Gleave and Artem Cherkasov

Cancers 2021, 13(12), 2939; https://doi.org/10.3390/cancers13122939 - 11 Jun 2021

Cited by 14 | Viewed by 4194

Abstract

Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of [...] Read more.

Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of 24 AR mutations, identified in men with castration-resistant PCa, to five AR antagonists. In the current work, we evaluated 44 additional PCa-associated AR mutants, reported in the literature, and thus expanded the study of the effect of darolutamide to a total of 68 AR mutants. Unlike other AR antagonists, we demonstrate that darolutamide exhibits consistent efficiency against all characterized gain-of-function mutations in a full-length AR. Additionally, the response of the AR mutants to clinically used bicalutamide and enzalutamide, as well as to major endogenous steroids (DHT, estradiol, progesterone and hydrocortisone), was also investigated. As genomic profiling of PCa patients becomes increasingly feasible, the developed “AR functional encyclopedia” could provide decision-makers with a tool to guide the treatment choice for PCa patients based on their AR mutation status. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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13 pages, 3664 KiB

Open AccessFeature PaperArticle

Pain Progression at Initiation of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Post Hoc Analysis of the PROSELICA Study

by Nicolas Delanoy, Debbie Robbrecht, Mario Eisenberger, Oliver Sartor, Ronald de Wit, Florence Mercier, Christine Geffriaud-Ricouard, Johann de Bono and Stéphane Oudard

Cancers 2021, 13(6), 1284; https://doi.org/10.3390/cancers13061284 - 13 Mar 2021

Cited by 6 | Viewed by 2698

Abstract

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m² (CABA20) was non-inferior to cabazitaxel 25 mg/m² (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected [...] Read more.

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m² (CABA20) was non-inferior to cabazitaxel 25 mg/m² (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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17 pages, 3544 KiB

Open AccessArticle

MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1

by Luis Álvarez-Carrión, Irene Gutiérrez-Rojas, María Rosario Rodríguez-Ramos, Juan A. Ardura and Verónica Alonso

Cancers 2021, 13(3), 436; https://doi.org/10.3390/cancers13030436 - 24 Jan 2021

Cited by 2 | Viewed by 2105

Abstract

Advanced prostate cancer preferential metastasis to bone is associated with osteomimicry. MINDIN is a secreted matrix protein upregulated in prostate tumors that overexpresses bone-related genes during prostate cancer progression. Na+/H+ exchanger regulatory factor (NHERF-1) is a scaffold protein that has been involved both [...] Read more.

Advanced prostate cancer preferential metastasis to bone is associated with osteomimicry. MINDIN is a secreted matrix protein upregulated in prostate tumors that overexpresses bone-related genes during prostate cancer progression. Na+/H+ exchanger regulatory factor (NHERF-1) is a scaffold protein that has been involved both in tumor regulation and osteogenesis. We hypothesize that NHERF-1 modulation is a mechanism used by MINDIN to promote prostate cancer progression. We analyzed the expression of NHERF-1 and MINDIN in human prostate samples and in a premetastatic prostate cancer mouse model, based on the implantation of prostate adenocarcinoma TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) cells in immunocompetent C57BL/6 mice. The relationship between NHERF-1 and MINDIN and their effects on cell proliferation, migration, survival and osteomimicry were evaluated. Upregulation of MINDIN and downregulation of NHERF-1 expression were observed both in human prostate cancer samples and in the TRAMP-C1 model. MINDIN silencing restored NHERF-1 expression to control levels in the mouse model. Stimulation with MINDIN reduced NHERF-1 expression and triggered its mobilization from the plasma membrane to the cytoplasm in TRAMP-C1 cells. MINDIN-dependent downregulation of NHERF-1 promoted tumor cell migration and proliferation without affecting osteomimicry and adhesion. We propose that MINDIN downregulates NHERF-1 expression leading to promotion of processes involved in prostate cancer progression. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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12 pages, 2355 KiB

Open AccessArticle

The Predictive Role of Prostate-Specific Antigen Changes Following Transurethral Resection of the Prostate for Patients with Localized Prostate Cancer

by Chun-Te Wu, Yun-Ching Huang, Wen-Cheng Chen and Miao-Fen Chen

Cancers 2021, 13(1), 74; https://doi.org/10.3390/cancers13010074 - 29 Dec 2020

Cited by 3 | Viewed by 2126

Abstract

Regarding localized prostate cancer (PC), questions remain regarding which patients are appropriate candidates for conservative management. Some localized PC was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. It is known that TURP usually affects [...] Read more.

Regarding localized prostate cancer (PC), questions remain regarding which patients are appropriate candidates for conservative management. Some localized PC was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. It is known that TURP usually affects the level of prostate-specific antigen (PSA). In the present study, we examined whether changes in PSA levels after TURP possess a predictive value for localized PC. We retrospectively reviewed the clinical data of 846 early-stage PC patients who underwent TURP for urinary symptoms upon diagnosis at our hospital. Of 846 patients, 687 had tumor involvement in TURP specimens, and 362 had post-TURP PSA assessment. Our data revealed that, in addition to low GS and PSA levels at diagnosis, ≤5% tumor involvement in TURP specimens, greater PSA reduction (≥68%) following TURP, and post-TURP PSA ≤ 4 were significantly associated with better progression-free survival (PFS). Survival analysis revealed that the addition of prostate-directed local therapy significantly improved PFS in intermediate- and high-risk groups, but not in the low-risk group. Moreover, in the intermediate-risk group, local therapy improved PFS only for patients who were associated with post-TURP PSA > 4 ng/mL or <68% PSA reduction following TURP. We also found that local therapy had no obvious improvement in PFS for those with post-TURP ≤ 4 ng/mL regardless of pre-TURP PSA. In conclusion, conservative management is considered for patients at low or intermediate risk who have greater PSA reduction following TURP and low post-TURP PSA. Therefore, the levels of PSA following TURP might be helpful for risk stratification and the selection of patients for conservative management. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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Review

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18 pages, 2854 KiB

Open AccessEditor’s ChoiceReview

Liver Microenvironment Response to Prostate Cancer Metastasis and Hormonal Therapy

by Alison K. Buxton, Salma Abbasova, Charlotte L. Bevan and Damien A. Leach

Cancers 2022, 14(24), 6189; https://doi.org/10.3390/cancers14246189 - 15 Dec 2022

Cited by 5 | Viewed by 3127

Abstract

Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as [...] Read more.

Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as anti-androgens which block androgen synthesis or directly target the androgen receptor. The incidence of liver metastases is reportedly increasing, with a potential correlation with use of anti-androgen therapies. A key player in prostate cancer progression and therapeutic response is the microenvironment of the tumor(s). This is a dynamic and adaptive collection of cells and proteins, which impart signals and stimuli that can alter biological processes within prostate cancer cells. Investigation in the prostate primary site has demonstrated that cells of the microenvironment are also responsive to hormones and hormonal therapies. In this review, we collate information about what happens when cancer moves to the liver: the types of prostate cancer cells that metastasize there, the response of resident mesenchymal cells of the liver, and how the interactions between the cancer cells and the microenvironment may be altered by hormonal therapy. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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18 pages, 3986 KiB

Open AccessReview

Cribriform Patterned Lesions in the Prostate Gland with Emphasis on Differential Diagnosis and Clinical Significance

by Maria Destouni, Andreas C. Lazaris and Vasiliki Tzelepi

Cancers 2022, 14(13), 3041; https://doi.org/10.3390/cancers14133041 - 21 Jun 2022

Cited by 7 | Viewed by 4723

Abstract

Cribriform glandular formations are characterized by a continuous proliferation of cells with intermingled lumina and can constitute a major or minor part of physiologic (normal central zone glands), benign (clear cell cribriform hyperplasia and basal cell hyperplasia), premalignant (high-grade prostatic intraepithelial neoplasia), borderline [...] Read more.

Cribriform glandular formations are characterized by a continuous proliferation of cells with intermingled lumina and can constitute a major or minor part of physiologic (normal central zone glands), benign (clear cell cribriform hyperplasia and basal cell hyperplasia), premalignant (high-grade prostatic intraepithelial neoplasia), borderline (atypical intraductal cribriform proliferation) or clearly malignant (intraductal, acinar, ductal and basal cell carcinoma) lesions. Each displays a different clinical course and variability in clinical management and prognosis. The aim of this review is to summarize the current knowledge regarding the morphological features, differential diagnosis, molecular profile and clinical significance of the cribriform-patterned entities of the prostate gland. Areas of controversy regarding their management, i.e., the grading of Intaductal Carcinoma, will also be discussed. Understanding the distinct nature of each cribriform lesion leads to the correct diagnosis and ensures accuracy in clinical decision-making, prognosis prediction and personalized risk stratification of patients. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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11 pages, 897 KiB

Open AccessReview

The Continuum of Metastatic Prostate Cancer: Interpreting PSMA PET Findings in Recurrent Prostate Cancer

by Adam M. Kase, Winston Tan, John A. Copland III, Hancheng Cai, Ephraim E. Parent and Ravi A. Madan

Cancers 2022, 14(6), 1361; https://doi.org/10.3390/cancers14061361 - 08 Mar 2022

Cited by 5 | Viewed by 3176

Abstract

Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, [...] Read more.

Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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29 pages, 1376 KiB

Open AccessReview

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

by Sofia Papanikolaou, Aikaterini Vourda, Spyros Syggelos and Kostis Gyftopoulos

Cancers 2021, 13(11), 2795; https://doi.org/10.3390/cancers13112795 - 04 Jun 2021

Cited by 23 | Viewed by 4488

Abstract

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that [...] Read more.

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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Other

Jump to: Editorial, Research, Review

15 pages, 1141 KiB

Open AccessSystematic Review

Salvage Radical Prostatectomy after Primary Focal Ablative Therapy: A Systematic Review and Meta-Analysis

by Fernando Blank, Meredith Meyer, Hannah Wang, Hasan Abbas, Shima Tayebi, Wei-Wen Hsu and Abhinav Sidana

Cancers 2023, 15(10), 2727; https://doi.org/10.3390/cancers15102727 - 12 May 2023

Cited by 1 | Viewed by 1356

Abstract

Context: Focal therapy (FT) has been gaining popularity as a treatment option for localized intermediate-risk prostate cancer (PCa) due to the associated lower morbidity compared to whole-gland treatment. However, there is an increased risk of local cancer recurrence requiring subsequent treatment in a [...] Read more.

Context: Focal therapy (FT) has been gaining popularity as a treatment option for localized intermediate-risk prostate cancer (PCa) due to the associated lower morbidity compared to whole-gland treatment. However, there is an increased risk of local cancer recurrence requiring subsequent treatment in a small proportion of patients. Objective: To conduct a systematic review and meta-analysis to better describe and analyze patient postoperative, oncologic, and functional outcomes for those who underwent salvage radical prostatectomy (sRP) to manage their primary FT failure. Evidence acquisition: A systematic review was completed using three databases (PubMed, Embase, and CINAHL) from October to December 2021 to identify data on outcomes in patients who received sRP for cancer recurrence after prior focal treatment. Evidence synthesis: 12 articles (482 patients) were included. Median time to sRP was 24 months. Median follow-up time was 27 months. A meta-analysis revealed a postoperative complication rate of 15% (95% CI: 0.09, 0.24), with 4.6% meeting criteria for a major complication Clavien (CG) grade ≥3. Severe GU toxicity was seen in 3.6% of the patients, and no patients had severe GI toxicity. Positive surgical margins (PSM) were found in 27% (95% CI: 0.19, 0.37). Biochemical recurrence (BCR) after sRP occurred in 23% (95% CI: 0.17, 0.30), indicating a BCR-free probability of 77% at 2 years. Continence (pad-free) and potency (ability to have penetrative sex) were maintained in 67% (95% CI: 0.53, 0.78) and 37% (95% CI: 0.18, 0.62) at 12 months, respectively. Conclusion: Our evidence shows acceptable complication rates and oncologic outcomes; however, with suboptimal functional outcomes for patients undergoing sRP for recurrent PCa after prior FT. Inferior outcomes were observed for salvage treatment compared to primary radical prostatectomy (pRP). More high-quality studies are needed to better characterize outcomes after this sequence of PCa treatments. Patient summary: We looked at treatment outcomes and toxicity for men treated with sRP for prior FT failure. We conclude that these patients will have significant detriment to genitourinary function, with outcomes being worse than those for pRP patients. Full article

(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)

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