The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common ...feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
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•GR induction is a common feature of enzalutamide-resistant prostate cancer•GR expression and activity promote resistance to enzalutamide•GR binds and regulates a subset of AR targets in a enzalutamide-insensitive manner•AR inhibition induces high levels of GR in primed prostate cells
Prostate cancer cells that have become resistant to androgen receptor (AR) antagonists escape the AR blockade by turning on expression of the closely related glucocorticoid receptor, which functionally substitutes for AR to drive growth, thus identifying GR as a potential therapeutic target.
Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to ...inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.
To present the results from the APCCC 2019.
Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.
The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.
Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.
These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.
The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019, 10 important areas of controversy in advanced prostate cancer management were identified and discussed, and experts voted on 123 predefined consensus questions. The full report of the results is summarised here.
In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low ...level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics.
To present the report of APCCC 2017.
Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; “oligometastatic” prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions.
The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process.
Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data.
The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them.
The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.
At the Advanced Prostate Cancer Consensus Conference, 10 important areas of controversy in advanced prostate cancer management were identified, discussed, and the experts voted on 150 predefined consensus questions. The full report of the results is summarised here.
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here we identify induction of glucocorticoid receptor (GR) expression as a common ...feature of drug resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a novel mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
Kidney cancer. Clinical practice guidelines Motzer, Robert J; Carducci, Michael A; Fishman, Mayer ...
Journal of the National Comprehensive Cancer Network
3, Številka:
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Journal Article
We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance.
An individual participant ...data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internal-external validation procedure using the AUC curve.
Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internal-external validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively.
Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance.