BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.

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Novel therapies are changing treatment paradigms in metastatic prostate cancer

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00978-z ◽

2020 ◽

Vol 13 (1) ◽

Cited By ~ 1

Author(s):

Eric Powers ◽

Georgia Sofia Karachaliou ◽

Chester Kao ◽

Michael R. Harrison ◽

Christopher J. Hoimes ◽

...

Keyword(s):

Prostate Cancer ◽

Treatment Options ◽

Parp Inhibitors ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Systemic Treatments ◽

Terminal Diagnosis ◽

Specific Membrane ◽

Repair Genes

Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.

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Genetic biomarkers to guide poly(ADP‐ribose) polymerase inhibitor precision treatment of prostate cancer

Pharmacogenomics ◽

10.2217/pgs-2020-0019 ◽

2020 ◽

Vol 21 (15) ◽

pp. 1101-1115

Author(s):

Reka Varnai ◽

Csilla Sipeky

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Parp Inhibitors ◽

Castration Resistant Prostate Cancer ◽

Repair Gene ◽

Castration Resistant ◽

Damage Repair ◽

Precision Therapy ◽

Polymerase Inhibitor ◽

Near Future

Precision therapy for a subgroup of genetically defined metastatic castration-resistant prostate cancer patients may become a reality in the near future. DNA damage repair gene mutated prostate cancer might be vulnerable to treatment with PARP inhibitors (PARPi). PARPi clinical trials for prostate cancer investigate both germline and somatic genomic alterations of 43 genes for the applicability as genomic biomarker of PARPi sensitivity. Clinical trials with preliminary results show that BRCA2 and BRCA1, but also ATM, additionally BRIP1, FANCA, CDK12 and PALB2 may affect clinical end points, and may be potential candidates for genome-guided patient selection in PARPi treatment of prostate cancer.

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Targeting Inflammatory Signaling in Prostate Cancer Castration Resistance

Journal of Clinical Medicine ◽

10.3390/jcm10215000 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5000

Author(s):

Shangwei Zhong ◽

Changhao Huang ◽

Zhikang Chen ◽

Zihua Chen ◽

Jun-Li Luo

Keyword(s):

Prostate Cancer ◽

Early Stage ◽

Evolutionary Process ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Inflammatory Signaling ◽

Primary Tumors ◽

Castration Resistant ◽

Primary Prostate Cancer

Although castration-resistant prostate cancer (CRPC) as a whole, by its name, refers to the tumors that relapse and/or regrow independently of androgen after androgen deprivation therapy (ADT), untreated tumor, even in early-stage primary prostate cancer (PCa), contains androgen-independent (AI) PCa cells. The transformation of androgen-dependent (AD) PCa to AI PCa under ADT is a forced evolutionary process, in which the small group of AI PCa cells that exist in primary tumors has the unique opportunity to proliferate and expand selectively and dominantly, while some AD PCa cells that have escaped from ADT-induced death acquire the capability to survive in an androgen-depleted environment. The adaptation and reprogramming of both PCa cells and the tumor microenvironment (TME) under ADT make PCa much stronger than primary tumors so that, currently, there are no effective therapeutic methods available for the treatment of CRPC. Many mechanisms have been found to be related to the emergence and maintenance of PCa castration resistance; in this review, we focus on the role of inflammatory signaling in both PCa cells and the TME for the emergence and maintenance of CRPC and summarize the recent advances of therapeutic strategies that target inflammatory signaling for the treatment of CRPC.

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The role of microbiota in driving castration-resistant prostate cancer

10.26226/morressier.5f69edb69b74b699bf38c5cf ◽

2020 ◽

Author(s):

Arianna Calcinotto

Keyword(s):

Prostate Cancer ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

Current Cancer Drug Targets ◽

10.2174/1568009617666171122145852 ◽

2018 ◽

Vol 18 (9) ◽

pp. 869-876

Author(s):

Samanta Salvi ◽

Vincenza Conteduca ◽

Cristian Lolli ◽

Sara Testoni ◽

Valentina Casadio ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Clinical Trial Design ◽

Complete Information ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Anti Cancer ◽

Hormone Sensitive ◽

Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

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Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092066 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2066 ◽

Cited By ~ 12

Author(s):

Namrata Khurana ◽

Suresh C. Sikka

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Critical Role ◽

Castration Resistant Prostate Cancer ◽

Form Complex ◽

Androgen Receptor Signaling ◽

Castration Resistant ◽

Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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