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The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients.
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OBJECTIVES: Castration resistant prostate cancer (CRPC) is an heterogeneous disease the molecular basis of which we are starting to know in depth. Currently, there are various pathways and targets under study, and probably many others to be characterized. In this paper, we review the most recent knowledge concerning the molecular biology of CRPC with a special focus on the therapeutic application of this knowledge. METHODS: We performed a bibliographic review using PUBMED as the search engine, including the following terms: “Castration resistant prostate cancer”, “genomics”, “molecular biology”, “AR”, “WNT”, “mTOR”, “PTEN”, cell-cycle”, “DNA damage repair gene” and “chromatin modifier genes”. RESULTS: CRPC has a high load of genetic alterations, probably derived from therapeutic pressure. The most frequent alterations involve the androgen receptor (RA) [60-70%] and the PI3K- AKT-mTOR [40-60%], even though other relevant pathways alterations have been identified such as those relative to cellular cycle [25%], DNA lesion repair genes [20%] and other pathway like WNT-βcatenin [15-22%]. The knowledge of these pathways is helping as a base for development of new therapeutic targets with promising results and multiple ongoing studies. CONCLUSIONS: Over the last decade, the progress in the knowledge of the molecular bases of CRPC has been very relevant. Even though AR alterations are the most frequent and best characterized, anomalies in other pathways have been also identified as important in the biology of CRPC and derived a notable therapeutic development.
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OBJECTIVES: Prostate cancer is the mostfrequent neoplasia diagnosed in males. Treatmentof metastatic prostate cancer is based on androgendeprivation therapy (ADT) up to its change to thecastration resistance state. Recently, new molecules havebeen developed that significantly increase survival andquality of life of these patients. Abiraterone acetate incombination with prednisone is the first oral hormone therapy that contributed to this change in the approachof the disease.METHODS: Systematic bibliographic review aboutabiraterone in the treatment of metastatic castrationresistant prostate cancer (CPRC), with data on efficacy,safety and quality of life.RESULTS: Treatment with abiraterone and prednisone hasdemonstrated a significant increase in overall survival(OS 34.7 vs 30.3 months) and radiologic progressionfree survival (RPFS 16.5 months vs 8.3 months) incomparison to placebo and prednisone in patientswith metastatic castration resistant prostate cancer(mCPRC). It also demonstrated an increase in OS andRPFS compared to placebo plus prednisone in mCPRCpatients after at least one cytotoxic chemotherapybased treatment (OS 15.8 vs 11.2 months; RPFS 5.6vs 3.6 months). Side effects related to abirateronetherapy are mainly related with mineral corticoid excess(Hypertension, hypokalemia, fluid retention) and, to alesser extent, transaminase alterations or cardiovasculareffects. Perceived quality of life results show a benefit inthe abiraterone treatment group.CONCLUSIONS: Abiraterone acetate is a newhormonal treatment for metastatic castration resistantprostate cancer both before and after chemotherapy.The results of the available studies demonstrate asignificant improvement in terms of efficacy, with atolerability profile generally acceptable, predictableand manageable, and an improvement in patient´sperceived quality of life.
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Androgen deprivation therapy is part of the initial treatment of patients with metastatic prostate cancer. Nevertheless, after an initial response and despite maintaining an effective testosterone suppression, the tumor is able to continue growing. Enzalutamide is an oral second generation pure antiandrogen that acts at various levels in the signal activation cascade of the androgen receptor and has demonstrated being effective in this phase of the disease. In the clinical trials completed, it has demonstrated benefits in overall patient survival in patients with the diagnosis of metastatic castration resistant prostate cancer. Recent studies have also demonstrated benefits in progression free survival in patients with non-metastatic castration resistant prostate cancer.Enzalutamide has an excellent toxicity profile, but we have to avoid it in patients with history of seizure episodes, mainly if they are under anti-epileptic drug therapy. Enzalutamide is rapidly metabolized by the liver, mainly through the CYP2C8 and to a lesser extent by CYP3A4/5 so that its metabolism may be altered when cytochrome isoenzyme inductor or inhibitor drugs are given concomitantly. Moreover, enzalutamide may require dose adjustment for other drugs since it is a potent inductor of CYP3A4 and a moderate inductor of CYP2C9 y el CYP2C19. Even though treatment with enzalutamide has significantly altered the natural history of the disease, in most cases it will progress by development of resistance mechanisms, among which we may emphasize androgen receptor mutations, overexpression, amplification and variants, as well as the intracrine production of androgens.Enzalutamide must be considered as first line therapy in patients with castration resistant prostate cancer.
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Prostate cancer is the second mortalitycause among males with cancer. Patients withmetastatic castration resistant prostate cancer (mCRPC)essentially die due to tumor progression in a castrationresistance situation.Docetaxel based chemotherapy was the first therapeuticstrategy that demonstrated a survival increase, inaddition to pain decrease, increase in tumor responsesand quality of life benefit, and it currently continuesbeing useful after the incorporation of new therapies forthe treatment of mCRPC. Cabazitaxel, a taxane withefficacy in docetaxel resistant tumors, was the seconddrug demonstrating increased survival in this scenario,and it is an additional alternative option effective inselected patients. Patients with aggressive variantsand those with DNA repair genes alterations maybenefit from platin-based therapies. In the absence ofvalidated biomarkers, we should base our decisions onclinical and patient`s preferences criteria.It is important to design a comprehensive therapeuticplan at an early stage including the treatments withdemonstrated efficacy on survival. For this, it is essentiala comprehensive and multidisciplinary evaluation ofthe patient at the start of therapy and during tumorevolution. This evaluation must be done with anadequate information process and shared decisiontogether with the patient.
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We review the role of immunotherapy in castration resistant prostate cancer. Two immunotherapeutic strategies have been applied, isolated or in combination, either with each other or with other agents with demonstrated efficacy in this scenario that would play a role as immunomodulators: vaccines or monoclonal antibodies aimed to block immune response checkpoint inhibitors. Although CRPC presents, a priori, characteristics suggesting that immunotherapy may play a relevant role as a therapeutic strategy, its clinical application has demonstrated a limited and heterogeneous activity, in terms of proportion of responders and response intensity. Generally, the objective response rate is very low, although, in patients who have response it is possible to detect a clear, long-lasting benefit. Only the autologous vaccine Sipuleucel T has demonstrated an overall survival increase in patients with good prognosis criteria. In these treatments, it is characteristic that no progression free survival increase is visible due to its action mechanism. PSA evolution may not be considered a surrogate variable of radiological response or clinical benefit in this environment either. It is necessary to identify what patient`s or tumor´s characteristics are able to maximize the response. An important limitation is the absence of response predictive biomarkers that serve for patient preselection. As a general rule, the best responses with isolated immunotherapeutic treatments have been observed in patients with low tumor load, which may suggest that their optimal application could be in earlier phases of the disease (high risk localized, biochemical failure, etc) Combination strategy, without doubt the one with best future, is based on additional treatments increasing cell lysis with the subsequent antigen exposure and/ or producing an immunomodulatory effect that can surmount tumor induced immunologic tolerance. The results obtained suggest that immunotherapy may be more effective in combined therapy with other active therapies (abiraterone, enzalutamide, Radium 223, docetaxel) in a fight to achieve disease chronification.
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OBJECTIVE: To analyze the available evidence on Radium 223 therapy, an alfa particle emitter with specific action on bone metastases, studied on patients with castration resistant prostate cancer.EVIDENCE ACQUISITION:We review the pivotal study ALSYMPCA, that served to get the drug approval for this phase of the disease, and the new data obtained from its use. We also performed a search of ongoing studies with Radium 223 alone or in combination with other molecules.EVIDENCE SINTHESIS: According to the ALSYMPCA study, Radium 223 significantly prolongs the overall survival of patients with castration resistant prostate cancer and bone metastases; approximately 3.6 months in comparison with patients who received placebo, which turns into a median life expectancy of 14.9 months, and a 36-month survival of 46%, associated with a 30% reduction in death risk. Overall survival results were consistent both in patients who receive Docetaxel previously and those who did not.RESULTS: for secondary variables support the positive effect of Radium 223 therapy on symptomatic skeletal events (for example, the use of external beam radiotherapy to alleviate pain) and bone markers, confirming its efficacy in bone metastases.CONCLUSIONS: Radium 223 is the first treatment directed to bone that has demonstrated significant improvement on overall survival. It also prolonged the time to the first skeletal event and the median time to PSA increase significantly. All this in addition to its manageable adverse effects, lower than those appeared in the placebo arm of the pivotal study ALSYMPCA.
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Prostate cancer is a health problem inmany Countries worldwide. Understanding the essentialfunction of androgens in the prostate physiology led tothe development of hormonal blockade as a therapeuticoption in advanced disease, with limited responsewith time and development of resistance. In this stage,where castration resistant prostate cancer (CRPC) isdefined, it is associated with poor prognosis becausesurvival varies between 18 and 24 months. Even withcastration levels, tumors are dependent on the functionalandrogen receptor (AR). In this paper, we analyzepretreatment clinical parameters such as prognostic orprogression-predictive biomarkers, castration resistancemechanisms, the development of new technologies forthe use of the so called liquid biopsies from biological ayufluidsand the identification of circulating tumor cells asCRPC response and progression biomarkers. Currentlyongoing clinical trials are partially oriented to the searchof new prognostic and predictive biomarkers, that willenable to open up precision medicine and so to improveoncological patient´s quality of life with it.
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Prostate Cancer is the second most frequent malignant neoplasm in males in the world. At the end of the disease, when the tumor becomes resistant to castration, we have a wide range of treatment possibilities aimed at the Androgenic Receptor, androgens synthesis, the skeleton, chemotherapy, and even new molecular targets that are still under investigation. Today, the best sequence of treatment for each patient has not been established yet.OBJECTIVE: The objective of this work is to review the current scene of treatment in castrate resistant prostate cancer, as well as the latest developments and strategies to choose the best sequence in each patient.MATERIAL AND METHODS: A literature review was performed through Medline Database (Pubmed) using as key words: “Castrate Resistant Prostate Cancer”, “Sequencing”, “Biomarkers”, “Systemic Therapy”. We also reviewed ASCO GU 2017 abstracts.RESULTS: Since Docetaxel was approved in 2004, which increased overall survival by about 2 months in patients with Metastatic Castration Resistant Prostate Cancer, in recent years a large number of therapies have been approved, demonstrating an increase in overall survival after several phase III clinical trials: Cabacitaxel, Abiraterone, Enzalutamide, Sipuleucel-T, Denosumab, Radium 223. And more recently, some investigations about new targeted therapies directed to the androgen receptor, with greater affinity than enzalutamide, or more accurate inhibitors of CYP 17 enzyme than abiraterone, as well as, agents as monoclonal antibodies (anti PD1), vaccines, poly adenosine diphosphate-ribose polymerase inhibitors, are coming to the light. In the future, these outcomes could tune up the treatment sequencing, through the study of predictive biomarkers that will indicate the right target of each therapy.CONCLUSIONS: In the near future, outcomes of different clinical trials that are studying new molecules, will allow us to apply the sequencing of different therapies based on biomarkers present in blood (circulating tumor cells) or in specimen biopsies, achieving an increase in overall survival and improving quality of life of patients in the advanced stage of the disease, however the best choice of sequence is unknown at this moment.
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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 NE- Epithelial 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.
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OBJECTIVES: There is no broad consensus about what diagnostic tests use for CRPC follow up as well as their frequency. Our objective is to review and analyze the most important CRPC follow up patterns described in the literature to date. METHODS: We performed a critical analysis of the recommendations for follow up most universally employed (PCWG3, RADAR, St Gallen consensus, NCCN guidelines, EAU guidelines) RESULTS: CT scan and bone scan are the routine recommended diagnostic tests, in front of other techniques such as PET/CT or MRI, that may improve the diagnostic efficacy but they have the problem of availability and lack of internal validity for follow up. CONCLUSIONS: Follow up is different for non metastatic and metastatic CRPC. For nm CRPC, it is recommended to perform monitoring that includes PSA and imaging tests, without consensus about periodicity. For mCRPC, it is recommendable to do follow up with periodic PSA and imaging tests, since it is possible to have radiological progression without PSA progression.
