Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets.

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression.

PURPOSE: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features. EXPERIMENTAL DESIGN: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically. RESULTS: BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes. CONCLUSIONS: BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.

Emerging Subtypes and New Treatments for Castration-Resistant Prostate Cancer.

Genomic characterization of metastatic castration-resistant prostate cancer (mCRPC) has been remodeling the treatment landscape of this disease in the past decade. The emergence of molecularly defined subsets of mCRPC is altering the treatment paradigm from therapeutics with nonspecific activity across the spectrum, including androgen receptor (AR)-directed treatments, docetaxel, and cabazitaxel, to targeted approaches directed at molecular subsets of disease. The meaningful benefit of PARP inhibitors in mCRPC carrying mutations in DNA repair genes demonstrated in a phase III trial epitomizes this transition in the treatment paradigm of mCRPC and brings new challenges related to how to sequence and integrate the targeted therapies on top of the treatments with broad activity in all mCRPC. To enable and sustain the advance of precision oncology in the management of mCRPC, genomic characterization is required, including somatic and germline testing, for all patients with the ultimate goal of longitudinal molecular profiling guiding treatment decisions and sequential treatments of this lethal disease. This article reviews the emerging molecular subtypes of mCRPC that are driving the evolution of mCRPC treatment.

Bibliometric and Comparative Analysis of Castration Resistant and Refractory, Hormone Resistant and Refractory Prostate Cancer Publications.

INTRODUCTION: Prostate cancer is one of the most common cancer among men in the world. Radical prostatectomy is the gold standard treatment for localized prostate cancer but advanced diseases are treated with hormonal therapy. Unfortunately, this treatment is not curative and approximately after 2 years, castration resistant prostate cancer occurs. In this study we aimed to investigate the terminology of castration resistant and refractory, hormone resistant and refractory articles on Web of Science database. MATERIALS AND METHODS: We searched the articles in the title section such as castration resistant prostate cancer, castration refractory prostate cancer, hormone resistant prostate cancer and hormone refractory prostate cancer between 1975 and 2018. Categories, publication years, document types, authors, countries, funding agencies and citation reports were recorded in 4 groups. RESULTS: There were 6733 articles in the system. Most of the articles (72.16%) were published as using castration resistant title. The United States of America and Italy were in the top 5 countries in 4 titles. Oncology and urology nephrology categories consisted more than 80% of the articles. Of these articles, only 1745 (26%) articles had funding agency. DISCUSSION: Different terminology can be used in some diseases. One of these diseases is castration resistant prostate cancer which is referred to different terms such as castration refractory, hormone resistant and refractory. In this study we searched the literature and discussed the results. CONCLUSION: Castration resistant prostate cancer is a serious health problem for clinicians and patients. If international associations, journals and authors use the same terminology, the articles can be published without different titles in the literature.

The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact.

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12-/- and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12-/- and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. Our analyses revealed five mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: (i) AR-high tumors (ARPC), (ii) AR-low tumors (ARLPC), (iii) amphicrine tumors composed of cells co-expressing AR and NE genes (AMPC), (iv) double-negative tumors (i.e. AR-/NE-; DNPC) and (v) tumors with small cell or NE gene expression without AR activity (SCNPC). RE1-silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the five mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.

Going towards a precise definition of the therapeutic management of de-novo metastatic castration sensitive prostate cancer patients: How prognostic classification impact treatment decisions.

De-novo metastatic castration sensitive prostate cancer (mCSPC) is a subgroup of prostate cancer associated with poor prognosis. Recently, the treatment of mCSPC has been enriched by new life-prolonging options, including the combination of docetaxel or abiraterone acetate with androgen deprivation therapy (ADT). Of note, the advantage of chemohormonal therapy was more relevant in the subgroup of high-volume disease compared to low-volume, while the survival prolongation of abiraterone was observed only in high-risk patients. Choosing the most appropriate therapy is one of the most debated issues. This review describes the latest news on de-novo mCSPC to better outline patients' management. At the ESMO 2018 Congress two novel studies focused on this setting have been presented, trying to define the role of radiotherapy to the primary tumour and the efficacy of abiraterone acetate in the subset of low-risk patients. We have analysed these results in light of the evidence already available.

A molecular portrait of epithelial-mesenchymal plasticity in prostate cancer associated with clinical outcome.

The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states via the epithelial-mesenchymal transition (EMT) program can regulate metastatic processes, cancer progression, and treatment resistance. Transcriptional investigations using reversible models of EMT, revealed the mesenchymal-to-epithelial reverting transition (MErT) to be enriched in clinical samples of metastatic castrate resistant prostate cancer (mCRPC). From this enrichment, a metastasis-derived gene signature was identified that predicted more rapid cancer relapse and reduced survival across multiple human carcinoma types. Additionally, the transcriptional profile of MErT is not a simple mirror image of EMT as tumour cells retain a transcriptional "memory" following a reversible EMT. This memory was also enriched in mCRPC samples. Cumulatively, our studies reveal the transcriptional profile of epithelial-mesenchymal plasticity and highlight the unique transcriptional properties of MErT. Furthermore, our findings provide evidence to support the association of epithelial plasticity with poor clinical outcomes in multiple human carcinoma types.

[Aggressive variants of castration resistant prostate cancer (CRPC): neuroendocrine prostate cancer.] / Variantes agresivas de cáncer de próstata resistente a la castracion (CPRC): cáncer de próstata neuroendocrino.

Castration resistant prostate cancer (CRPC) is characterized by an important molecular, pathological and clinical heterogeneity. Although most of them present androgen receptor (AR) signal dependence, there are independent phenotypes. Neuroendocrine prostate cancer (NEPC) is a rare histologic subtype with adverse prognosis due to late diagnosis, heterogeneous clinical features and lack of effective systemic treatments. Platinum based chemotherapy is the standard treatment, presenting short limited responses. There are pure forms or mixed with adenocarcinoma component. De novo diagnosis is unusual, being more frequent in advanced stages of prostate cancer, as a consequence of the inhibition of androgen receptor performed by various treatments. Thus, it could represent an aggressive evolution from carcinoma through a NEEpithelial transdifferentiation. Development of preclinical studies has permitted characterization of molecular and genomic alterations associated with this evolution and they may help to develop new therapeutic targets. Over the last years, there have been important advances in identification and characterization of clinical and pathological CRPC variants. NEPC is one of the most aggressive subtypes. A better knowledge of the disease biology is necessary to develop new treatments and biomarkers that help to manage this aggressive variant of PC.

Variantes agresivas de cáncer de próstata resistente a la castración (cprc): cáncer de próstata neuroendocrino / Recommendations for follow up in castration resistant prostate cancer

El cáncer de próstata resistente a la castración (CPRC) se caracteriza por una importante heterogeneidad molecular, patológica y clínica. Aunque la mayoría presentan dependencia a la señal del receptor androgénico (RA), existen fenotipos independientes a ésta. El cáncer de próstata neuroendocrino (CPNE) es un subtipo histológico poco frecuente y de pronóstico adverso debido al diagnóstico tardío, características clínicas heterogéneas y a la falta de tratamientos sistémicos efectivos. El tratamiento estándar es la quimioterapia (QT) basada en platino, presentando respuestas de escasa duración. Existen formas puras o mixtas con un componente de adenocarcinoma. Es raro su diagnóstico de novo, siendo más frecuente su aparición en estados avanzados del cáncer de próstata (CP), como consecuencia de la inhibición del receptor androgénico (RA) realizada por diversos tratamientos. Así, podría representar una evolución agresiva desde un adenocarcinoma (CPAD) a través de un mecanismo de transdiferenciación epitelio-NE. El desarrollo de estudios preclínicos han permitido la determinación de alteraciones moleculares y genómicas asociadas a esta evolución y que pueden ayudar al desarrollo de nuevas dianas terapéuticas. En los últimos años se han producido importantes avances en la identificación y caracterización de variantes clínicas y patológicas del CPRC. El CPNE es uno de los subtipos más agresivos. Un mayor conocimiento de la biología de la enfermedad es necesario para desarrollar nuevos tratamientos y biomarcadores que ayuden al manejo de esta variante agresiva del CP

Castration resistant prostate cancer (CRPC) is characterized by an important molecular, pathological and clinical heterogeneity. Although most of them present androgen receptor (AR) signal dependence, there are independent phenotypes. Neuroendocrine prostate cancer (NEPC) is a rare histologic subtype with adverse prognosis due to late diagnosis, heterogeneous clinical features and lack of effective systemic treatments. Platinum based chemotherapy is the standard treatment, presenting short limited responses. There are pure forms or mixed with adenocarcinoma component. De novo diagnosis is unusual, being more frequent in advanced stages of prostate cancer, as a consequence of the inhibition of androgen receptor performed by various treatments. Thus, it could represent an aggressive evolution from carcinoma through a NEEpithelial transdifferentiation. Development of preclinical studies has permitted characterization of molecular and genomic alterations associated with this evolution and they may help to develop new therapeutic targets. Over the last years, there have been important advances in identification and characterization of clinical and pathological CRPC variants. NEPC is one of the most aggressive subtypes. A better knowledge of the disease biology is necessary to develop new treatments and biomarkers that help to manage this aggressive variant of PC

Molecular Subtypes of Prostate Cancer.

PURPOSE OF REVIEW: This review will examine the taxonomy of PCa subclasses across disease states, explore the relationship among specific alterations, and highlight current clinical relevance. RECENT FINDINGS: Prostate cancer (PCa) is driven by multiple genomic alterations, with distinct patterns and clinical implications. Alterations occurring early in the timeline of the disease define core subtypes of localized, treatment-naive PCa. With time, an increase in number and severity of genomic alterations adds molecular complexity and is associated with progression to metastasis. These later events are not random and are influenced by the underlying subclasses. All the subclasses of localized disease initially respond to androgen deprivation therapy (ADT), but with progression to castrate-resistant PCa (CRPC), mechanisms of resistance against ADT shift the molecular landscape. In CRPC, resistance mechanisms largely define the biology and sub-classification of these cancers, while clinical relevance and opportunities for precision therapy are still being defined.

Emerging Variants of Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (CRPC) is associated with substantial clinical, pathologic, and molecular heterogeneity. Most tumors remain driven by androgen receptor (AR) signaling, which has clinical implications for patient selection for AR-directed approaches. However, histologic and clinical resistance phenotypes can emerge after AR inhibition, in which the tumors become less dependent on the AR. In this review, we discuss prostate cancer variants including neuroendocrine (NEPC) and aggressive variant (AVPC) prostate cancers and their clinical implications. Improvements in the understanding of the biologic mechanisms and molecular features underlying prostate cancer variants may help prognostication and facilitate the development of novel therapeutic approaches for subclasses of patient with CRPC.

High-risk prostate cancer-classification and therapy.

Approximately 15% of patients with prostate cancer are diagnosed with high-risk disease. However, the current definitions of high-risk prostate cancer include a heterogeneous group of patients with a range of prognoses. Some have the potential to progress to a lethal phenotype that can be fatal, while others can be cured with treatment of the primary tumour alone. The optimal management of this patient subgroup is evolving. A refined classification scheme is needed to enable the early and accurate identification of high-risk disease so that more-effective treatment paradigms can be developed. We discuss several principles established from clinical trials, and highlight other questions that remain unanswered. This Review critically evaluates the existing literature focused on defining the high-risk population, the management of patients with high-risk prostate cancer, and future directions to optimize care.

External validation of risk classification in patients with docetaxel-treated castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) patients have poor prognoses, and docetaxel (DTX) is among the few treatment options. An accurate risk classification to identify CRPC patient groups for which DTX would be effective is urgently warranted. The Armstrong risk classification (ARC), which classifies CRPC patients into 3 groups, is superior; however, its usefulness remains unclear, and further external validation is required before clinical use. This study aimed to examine the clinical significance of the ARC through external validation in DTX-treated Japanese CRPC patients. METHODS: CRPC patients who received 2 or more DTX cycles were selected for this study. Patients were classified into good-, intermediate-, and poor-risk groups according to the ARC. Prostate-specific antigen (PSA) responses and overall survival (OS) were calculated and compared between the risk groups. A multivariate analysis was performed to clarify the relationship between the ARC and major patient characteristics. RESULTS: Seventy-eight CRPC patients met the inclusion criteria. Median PSA levels at DTX initiation was 20 ng/mL. Good-, intermediate-, and poor-risk groups comprised 51 (65%), 17 (22%), and 10 (13%) patients, respectively. PSA response rates ≥ 30% and ≥ 50% were 33%, 41%, and 30%, and 18%, 41%, and 20% in the good-, intermediate-, and poor-risk groups, respectivcixely, with no significant differences (p = 0.133 and 0.797, respectively). The median OS in the good-, intermediate-, and poor-risk groups were statistically significant (p < 0.001) at 30.1, 14.2, and 5.7 months, respectively. A multivariate analysis revealed that the ARC and PSA doubling time were independent prognostic factors. CONCLUSIONS: Most of CRPC patients were classified into good-risk group according to the ARC and the ARC could predict prognosis in DTX-treated CRPC patients. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000011969.