Novel Treatment Landscape For Metastatic Prostate Tumor

About 50% of men diagnosed with local prostate cancer will get metastatic cancer during their lifetime. Finding cancer early and treating it can lower that rate.Prostate cancer is a very heterogeneous disease, and contemporary management is focused on identification and treatment of the prognostically adverse high-risk tumors while minimizing overtreatment of indolent, low-risk tumors. In recent years, imaging has gained increasing importance in the detection, staging, posttreatment assessment, and detection of recurrence of prostate cancer. Several imaging modalities including conventional and functional methods are used in different clinical scenarios with their very own advantages and limitations. This continuing medical education article provides an overview of available imaging modalities currently in use for prostate cancer followed by a more specific section on the value of these different imaging modalities in distinct clinical scenarios, ranging from initial diagnosis to advanced, metastatic castration-resistant prostate cancer.

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A small percentage of men aren’t diagnosed with prostate cancer until it has become metastatic. Doctors can find out if it’s metastatic cancer when they take a small sample of the tissue and study the cells. Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone consisting of four main domains, the N-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain. AR plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress hormone-naïve prostate cancer, but prostate cancer changes AR and adapts to survive under castration levels of androgen. These mechanisms include AR point mutations, AR overexpression, changes of androgen biosynthesis, constitutively active AR splice variants without ligand binding, and changes of androgen cofactors. Studies of AR in CRPC revealed that AR was still active in CRPC, and it remains as a potential target to treat CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC is still incurable and can develop drug resistance. Understanding the mechanisms of this resistance can enable new-generation therapies for CRPC. Metastatic biopsy programmes combined with advances in genomic sequencing have provided new insights into the molecular landscape of castration-resistant prostate cancer (CRPC), identifying actionable targets, and emerging resistance mechanisms. The detection of DNA repair aberrations, such as mutation of BRCA2, could help select patients for poly(ADP-ribose) polymerase (PARP) inhibitor or platinum chemotherapy, and mismatch repair gene defects and microsatellite instability have been associated with responses to checkpoint inhibitor immunotherapy. Poor prognostic features, such as the presence of RB1 deletion, might help guide future therapeutic strategies. Our understanding of the molecular features of CRPC is now being translated into the clinic in the form of increased molecular testing for use of these agents and for clinical trial eligibility. Genomic testing offers opportunities for improving patient selection for systemic therapies and, ultimately, patient outcomes. However, challenges for precision oncology in advanced prostate cancer still remain, including the contribution of tumour heterogeneity, the timing and potential cooperation of multiple driver gene aberrations, and diverse resistant mechanisms. Defining the optimal use of molecular biomarkers in the clinic, including tissue-based and liquid biopsies, is a rapidly evolving field. Several promising new AR-targeted therapies have been developed. Prostate cancer has become the most common form of non-cutaneous (internal) malignancy in men, accounting for 26% of all new male visceral cancer cases in the UK. The aetiology and pathogenesis of prostate cancer are not understood, but given the age-adjusted geographical variations in prostate cancer incidence quoted in epidemiological studies, there is increasing interest in nutrition as a relevant factor. In particular, foods rich in phytochemicals have been proposed to reduce the risk of prostate cancer. Epidemiological studies have reported evidence that plant-based foods including cruciferous vegetables, garlic, tomatoes, pomegranate and green tea are associated with a significant reduction in the progression of prostate cancer. Apalutamide is a new Food and Drug Administration-approved androgen agonist binding to the ligand-binding domain, and clinical trials of other new AR-targeted agents binding to the ligand-binding domain or N-terminal domain are underway.

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The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis. Radiolabelled small molecules for imaging prostate cancer have rapidly emerged over the last few years with gallium-68-labelled prostate-specific-membrane-antigen-11 (68Ga-PSMA11), the most widely used. However, the current evidence-based guidelines for management of prostate cancer were established using computed tomography (CT), magnetic resonance imaging (MRI) and bone scan, despite their limitations. Prostate-specific-membrane antigen (PSMA) positron-emission tomography (PET)/CT, however, has higher sensitivity and specificity and can lead to both upstaging and downstaging and subsequent changes in management of prostate cancer. The literature for PSMA PET/CT is mostly in the setting of biochemical recurrence and primary staging of intermediate-to-high-risk prostate cancer. Preliminary studies also suggest that there may be a role in nonmetastatic castrate-resistant prostate cancer (nmCRPC) and possibly response to therapy. Despite high sensitivity and specificity, PSMA PET/CT as a single modality for staging advanced prostate cancer is suboptimal, given the low PSMA expression in this subgroup and the complementary role of fluorodeoxyglucose (FDG) PET/CT is required. This is also true in early-stage prostate adenocarcinoma with neuroendocrine differentiation or small-/large-cell neuroendocrine tumours of the prostate. Lack of a globally accepted standardized reporting system for PSMA PET/CT is a current limitation. This is essential to pave the way to incorporating this invaluable molecular imaging modality in clinical trials to assess its impact on outcome, particularly when upstaging or downstaging conventionally imaged disease.

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