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BACKGROUND: Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought. METHODS: Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts. RESULTS: Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51). CONCLUSIONS: With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features. PLAIN LANGUAGE SUMMARY: Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.
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Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Docetaxel , Antagonistas de Androgênios , Perfilação da Expressão Gênica , Fenótipo , Biomarcadores Tumorais/genética , PrognósticoRESUMO
BACKGROUND: Characterization of markers of both immune suppression and activation may provide more prognostic information than assessment of single markers in localized prostate cancer. We therefore sought to determine the association between CD8 and PD-L1 expression in localized prostate tumors and biochemical recurrence (BCR) and metastasis-free survival (MFS). METHODS: Tissue microarrays were constructed on 109 men undergoing radical prostatectomy (RP) for localized prostate cancer at Dana-Farber Cancer Institute between 1991 and 2008. Fluorescence immunohistochemistry was used to evaluate the expression of six immune markers (CD3, CD4, CD8, PD-1, PD-L1, FOXP3). Quantitative multispectral imaging analysis was used to calculate the density of each marker, which was dichotomized by the median as "high" or "low." Cox proportional hazards regression models and Kaplan-Meier analyses were used to analyze associations between immune marker densities and time to BCR and MFS. RESULTS: Over a median follow-up of 8.1 years, 55 (51%) and 39 (36%) men developed BCR and metastases, respectively. Median time to BCR was shorter in men with low CD8 (hazard ratio [HR] = 2.27 [1.27-4.08]) and high PD-L1 expression (HR = 2.03 [1.17-3.53]). While neither low CD8 or high PD-L1 alone were independent predictors of BCR or MFS on multivariable analysis, men with low CD8 and/or high PD-L1 had a significantly shorter time to BCR (median 3.5 years vs. NR) and MFS (median 10.8 vs. 18.4 years) compared to those with high CD8 and low PD-L1 expression. The main limitation is the retrospective and singe-center nature of the study. CONCLUSION: The presence of higher CD8 and lower PD-L1 expression in prostatectomy specimens was associated a low risk of biochemical relapse and metastatic disease. These findings are hypothesis-generating and further study is needed.
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Antígeno B7-H1/biossíntese , Antígenos CD8/biossíntese , Neoplasias da Próstata/imunologia , Antígeno B7-H1/imunologia , Complexo CD3/biossíntese , Complexo CD3/imunologia , Antígenos CD8/imunologia , Estudos de Coortes , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/imunologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/imunologia , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/imunologia , Modelos de Riscos Proporcionais , Prostatectomia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Análise Serial de TecidosRESUMO
OBJECTIVES: To estimate the lifetime health and economic outcomes of selecting active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT) as initial management for low- or favorable-risk localized prostate cancer. METHODS: A discrete-event simulation model was developed using evidence from published randomized trials. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Costs were included from a public payer perspective in Australian dollars. Outcomes were discounted at 5% over a lifetime horizon. Probabilistic and scenario analyses quantified parameter and structural uncertainty. RESULTS: A total of 60% of patients in the AS arm eventually received radical treatment (surgery or radiotherapy) compared with 90% for RP and 91% for RT. Although AS resulted in fewer treatment-related complications, it led to increased clinical progression (AS 40.7%, RP 17.6%, RT 19.9%) and metastatic disease (AS 13.4%, RP 6.1%, RT 7.0%). QALYs were 10.88 for AS, 11.10 for RP, and 11.13 for RT. Total costs were A$17 912 for AS, A$15 609 for RP, and A$15 118 for RT. At a willingness to pay of A$20 000/QALY, RT had a 61.4% chance of being cost-effective compared to 38.5% for RP and 0.1% for AS. CONCLUSIONS: Although AS resulted in fewer and delayed treatment-related complications, it was not found to be a cost-effective strategy for favorable-risk localized prostate cancer over a lifetime horizon because of an increase in the number of patients developing metastatic disease. RT was the dominant strategy yielding higher QALYs at lower cost although differences compared with RP were small.
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Avaliação de Resultados em Cuidados de Saúde , Prostatectomia/métodos , Neoplasias da Próstata/radioterapia , Conduta Expectante , Idoso , Austrália , Humanos , Masculino , Anos de Vida Ajustados por Qualidade de Vida , Medição de RiscoRESUMO
BACKGROUND: The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings. METHODS: Two hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed. RESULTS: Higher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4-3.6, p = .001; binary >9.3: HR 1.7, 95% CI: 1.2-2.4, p = .007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6-3.3, p < .001; binary: HR 1.8, 95% CI: 1.3-2.5, p < .001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels >9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p = .007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99-1.9, p = .057). CONCLUSIONS: In the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.
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Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Interleucina-8/sangue , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: The successful development of effective cancer immunotherapy, in particular immune checkpoint inhibitors, has changed the treatment paradigm of many tumor types. In light of the limited efficacy of checkpoint inhibitors demonstrated in recent clinical trials in refractory prostate cancer, this review highlights important recent and ongoing studies that are shaping the pursuit of effective immunotherapy for prostate cancer. RECENT FINDINGS: We review two overarching themes with respect to recent studies of prostate cancer immunotherapy: evolving therapeutic strategies and novel biological findings, including the landscape of predictive biomarkers of immunotherapy response. SUMMARY: Novel and combinatorial immunotherapy strategies are being implemented across the clinical spectrum of prostate cancer. Greater understanding of complex tumor-immune interactions and the determinants of therapy response in prostate cancer is an area of intense investigation, and will inform both translational and clinical immuno-oncology research in the field.
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Imunoterapia/métodos , Neoplasias da Próstata/terapia , Humanos , Masculino , Oncologia/tendências , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologiaRESUMO
Greater personalization of cancer medicine continues to shape therapy development and patient selection accordingly. The treatment of prostate cancer has evolved considerably since the discovery of androgen deprivation therapy. The comprehensive profiling of the prostate cancer genome has mapped the targetable molecular landscape of the disease and identified opportunities for the implementation of novel and combination therapies. In this review, we provide an overview of the molecular biology of prostate cancer and tools developed to aid prognostication and prediction of therapy benefit. Modern treatment of advanced prostate cancer is reviewed as a paradigm of increasing precision-informed approach to patient care, and must be considered on a global scale with respect to the state of science and care delivery.
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Background: For patients with mCRPC, PSMA-targeted radioligand treatment has significantly improved the clinical outcome. A blood-based liquid biopsy assay for recognizing PSMA protein expression on circulating tumor cells may be beneficial for better informing therapeutic decision-making and identifying the patients most likely to benefit from PSMA-targeted radioligand therapy. Methods: Using high-throughput imaging and digital AI pathology algorithms, a four-color immunofluorescence assay has been developed to find PSMA protein expression on CTCs on a glass slide. Cell line cells (LNCaP/PC3s/22Rv1) spiked into healthy donor blood were used to study the precision, specificity, sensitivity, limit of detection, and overall accuracy of the assay. Clinical validation and low-pass whole-genome sequencing were performed in PSMA-PET-positive patients with high-risk mCRPC (N = 24) utilizing 3 mL of blood. Results: The PSMA CTC IF assay achieved analytical specificity, sensitivity, and overall accuracy above 99% with high precision. In the clinical validation, 76% (16/21) of the cases were PSMA positive with CTC heterogeneity, and 88% (21/24) of the patients contained at least one conventional CTC per milliliter of blood. Thirty-six low-pass-sequenced CTCs from 11 individuals with mCRPC frequently exhibited copy number increases in AR and MYC and losses in RB1, PTEN, TP53, and BRCA2 locus. Conclusions: The analytical validation utilizing Epic Sciences' liquid biopsy CTC platform demonstrated the potential to detect PSMA protein expression in CTCs from patients with mCRPC. This assay is positioned as an effective research tool to evaluate PSMA expression, heterogeneity, and therapeutic response in many ongoing clinical studies to target tumors that express PSMA.
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Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/terapia , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , ImunoterapiaRESUMO
The advent of more effective treatment combinations for metastatic hormone-sensitive prostate cancer (mHSPC) has been built on successes in therapy development for metastatic, castration-resistant prostate cancer (mCRPC). Both disease phases hold similar challenges and questions. Is there an optimal therapy sequence to maximize disease control and balance treatment burden? Are there clinical and biologically based subgroups that inform personalized and/or adaptive strategies? How can clinicians interpret data from clinical trials in the context of rapidly evolving technologies? Herein, we review the contemporary landscape of treatment for mHSPC, including disease subgroups informing both intensification and potential deintensification strategies. Furthermore, we provide current insights into the complex biology of mHSPC and discuss the potential clinical application of biomarkers to guide therapy selection and the development of novel personalized approaches.
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Medicina de Precisão , Neoplasias da Próstata , Masculino , Humanos , Tecnologia , HormôniosRESUMO
Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10-5) and identified clinically-relevant differences in absolute benefit, especially for localized cancers. In metastatic disease, classifiers of proliferation, PTEN or TP53 loss and treatment-persistent cells were prognostic. In localized disease, androgen receptor activity was protective whilst interferon signaling (that strongly associated with tumor lymphocyte infiltration) was detrimental. Post-Operative Radiation-Therapy Outcomes Score was prognostic in localized but not metastatic disease (interaction p=0.0001) suggesting the impact of tumor biology on clinical outcome is context-dependent on metastatic state. Transcriptome-wide testing has clinical utility for advanced prostate cancer and identified worse outcomes for localized cancers with tumor-promoting inflammation.
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BACKGROUND: The appropriate management of localized or metastatic hormone-sensitive prostate cancer (HSPC) patients harboring tumor BRCA mutations (tBRCAm) is not well-characterized. We sought to evaluate the prevalence and clinical outcomes of patients with tBRCAm and localized or de novo metastatic HSPC. METHODS: We performed a multicenter, international, retrospective cohort study of localized (cohort 1) and de novo metastatic (cohort 2) HSPC patients who underwent tumor BRCA1 and BRCA2 sequencing from 2013 to 2019. Primary endpoints included event-free survival (EFS) and metastases-free survival (MFS) for cohort 1, and time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for cohort 2. Kaplan-Meier method and Cox regression models estimated the association of endpoints with tBRCA status. RESULTS: Of 399 identified patients with localized and de novo metastatic HSPC who underwent tumor BRCA1 and BRCA2 sequencing, 3.1% (8/258) patients of cohort 1 and 10.6% (15/141) patients of cohort 2 harbored tBRCAm. The median follow-up was 33 and 36 months, respectively. In cohort 1, median EFS was 18.1 vs. 57 months (p = 0.28) and MFS was 37 vs. 153.4 months (p = 0.08) for patients with tBRCAm compared to patients with no tBRCAm. In cohort 2, the TTCRPC was 24 vs. 19 months (p = 0.65) and OS was 64 vs. 60 months (p = 0.95) in patients with and without tBRCAm, respectively. CONCLUSIONS: While tBRCAm seems to be associated with greater relapse risk in localized disease, tBRCAm did not influence the clinical outcomes of patients presenting with de novo metastatic HSPC treated with conventional therapies. tBRCAm may exert different prognostic effects across the clinical spectrum of prostate cancer.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Proteína BRCA1/genética , Proteína BRCA2/genética , Hormônios/uso terapêutico , Humanos , Masculino , Mutação , Recidiva Local de Neoplasia , Prevalência , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. METHODS: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. RESULTS: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov-Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). CONCLUSIONS: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476 , registered on December 22, 2005. EudraCT 2004-000193-31 , registered on October 4, 2004.
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Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Variações do Número de Cópias de DNA , Progressão da Doença , Humanos , Masculino , Estudos Prospectivos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
NF-κB activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB-driven resistance to androgen-deprivation therapy (ADT) in prostate cancer cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by using NF-κB inhibitors. However, low oral bioavailability and high toxicity of NF-κB inhibitors is a major challenge for clinical translation. Dimethylaminoparthenolide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies, including decrease of NF-κB in circulating leuchemic blasts. Here, we report that activation of NF-κB/p65 by castration in mouse and human prostate cancer models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCaP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT-sensitizing prostate cancer cells to castration were dependent on the ability of DMAPT to inhibit phosphorylated-p65 function. IMPLICATIONS: Our study shows that DMAPT, an oral NF-κB inhibitor in clinical development, inhibits phosphorylated-p65 upregulation of AR-V7 and delays prostate cancer castration resistance. This provides rationale for the development of DMAPT as a novel therapeutic strategy to increase durable response in patients receiving AR-targeted therapy.
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Antagonistas de Receptores de Andrógenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Sesquiterpenos/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos ICR , Camundongos SCID , NF-kappa B/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Sesquiterpenos/administração & dosagemRESUMO
BACKGROUND: It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs). OBJECTIVE: To assess the risk and onset of VTEs stratified by risk factors. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy. INTERVENTION: Patients with prophylactic anticoagulation were excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A regression analysis was performed to select risk factors for VTEs. The simulated number needed to treat (NNT) and the number needed to harm (NNH) with prophylactic anticoagulation were calculated based on the cumulative incidences retrieved from this study and hazard rates of recently published trials describing the efficacy of prophylactic anticoagulation to prevent VTEs and the risk of bleeding events. RESULTS AND LIMITATIONS: From 1120 patients, 121 (11%) had a VTE, which occurred prior to chemotherapy in 49 (4%) and on or after chemotherapy in 72 (6%). Six patients (<1%) had a bleeding event without anticoagulation. After backward regression, the one risk factor for a VTE during or after chemotherapy was the use of a venous access device. The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy would translate into an NNT of 45 (95% confidence interval [CI] 36-56) and an NNH of 186 (95% CI 87-506). Limitations are mainly related to the retrospective nature of the study. CONCLUSIONS: The mGCTs associated VTEs are most common before and during, but not after, chemotherapy. Avoiding venous access device and/or prophylactic anticoagulation with an acceptable risk-benefit profile may decrease VTE occurring on chemotherapy. PATIENT SUMMARY: We found that venous thromboembolic events (VTEs) occur rarely after chemotherapy. Based on experience of prophylactic anticoagulation in other cancers, we conclude that the risk of VTE in men undergoing chemotherapy for metastatic germ cell tumours can be decreased by thromboprophylaxis with a reasonable risk-benefit profile and by avoidance of venous access devices.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Tromboembolia Venosa , Trombose Venosa , Anticoagulantes/efeitos adversos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Testiculares/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Trombose Venosa/epidemiologia , Trombose Venosa/prevenção & controleRESUMO
Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8+ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.
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Receptor de Morte Celular Programada 1 , Neoplasias da Próstata , Linfócitos T CD8-Positivos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Humanos , Interferons/farmacologia , Masculino , Neoplasias da Próstata/tratamento farmacológico , RNA de Cadeia DuplaRESUMO
OBJECTIVE: Prostate cancer is one of the most common male cancers in the world and accounts for substantial morbidity, mortality, loss of disability-adjusted life-years, and financial burden to patients and to the community. Metastatic prostate cancer has been managed for over 70 years with androgen deprivation therapy, but further life-prolonging therapies were not available until 2004. Since then, drugs such as docetaxel, abiraterone, enzalutamide, cabazitaxel, radium-223 dichloride, and (not available in Australia) sipuleucel-T have all demonstrated efficacy in prolongation of survival in castrate-resistant prostate cancer, and improvement in cancer-related morbidity. DATA SOURCES: Peer-reviewed scientific publications, Australian Government agency reports, and expert opinion. CONCLUSION: More recently, several of these agents have been given earlier in the treatment course to the hormone-sensitive metastatic setting, with even greater benefits in survival. These treatments have come at a cost: a literal financial cost to the community, and often to the patients and their families; and financial costs to the community to supply the drugs to those who need them. They also carry non-financial costs, including side effects of treatment, exacerbation of other co-morbidities, metabolic and bone health challenges, and psychological and social stresses, including those associated with longer survival with metastatic cancer. IMPLICATIONS FOR NURSING PRACTICE: The role of the nurse in management of these issues has never been more important. Nurses are often uniquely placed to educate men with prostate cancer and their families, screen for and identify adverse effects of treatment, and provide education and support not otherwise available. Nurses are central to the streamline of care coordination within the multidisciplinary team and the holistic care journey for men and their partners through the health care system. This review discusses several of these aspects to inform practice.
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Enfermagem Oncológica/métodos , Neoplasias da Próstata/enfermagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Humanos , Masculino , Papel do Profissional de Enfermagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/psicologiaRESUMO
Fixed-tissue ChIP-seq for H3K27 acetylation (H3K27ac) profiling (FiTAc-seq) is an epigenetic method for profiling active enhancers and promoters in formalin-fixed, paraffin-embedded (FFPE) tissues. We previously developed a modified ChIP-seq protocol (FiT-seq) for chromatin profiling in FFPE. FiT-seq produces high-quality chromatin profiles particularly for methylated histone marks but is not optimized for H3K27ac profiling. FiTAc-seq is a modified protocol that replaces the proteinase K digestion applied in FiT-seq with extended heating at 65 °C in a higher concentration of detergent and a minimized sonication step, to produce robust genome-wide H3K27ac maps from clinical samples. FiTAc-seq generates high-quality enhancer landscapes and super-enhancer (SE) annotation in numerous archived FFPE samples from distinct tumor types. This approach will be of great interest for both basic and clinical researchers. The entire protocol from FFPE blocks to sequence-ready library can be accomplished within 4 d.
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Sequenciamento de Cromatina por Imunoprecipitação/métodos , Histonas/química , Histonas/metabolismo , Lisina/metabolismo , Inclusão em Parafina , Fixação de Tecidos , Acetilação , Animais , Fígado/citologia , CamundongosRESUMO
PURPOSE: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment. PATIENTS AND METHODS: Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses. RESULTS: Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; P = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes. CONCLUSION: Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/cirurgia , Orquiectomia , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life-threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population. METHODS: Data were collected from mGCT patients receiving first-line platinum-based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long-axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed. RESULTS: Data from 1135 patients were collected. Median age was 31 years (range 10-74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P < .001) and was associated with significantly higher risk of VTE in univariable analysis (22% vs 8%, OR 3.0, P < .001) and multivariable analysis (OR 1.8, P = .02). Other significant risk factors included, Khorana score ≥3 (OR 2.6, P = .008) and VAD use (OR 2.7, P < .001). CONCLUSIONS: Large RPLN and VAD use are independent risk factors for VTE in mGCT patients receiving chemotherapy. VAD use should be minimized in this population and thromboprophylaxis might be considered for large RPLN.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Metástase Linfática/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Retroperitoneais/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cateteres de Demora/efeitos adversos , Criança , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Retroperitoneais/mortalidade , Neoplasias Retroperitoneais/secundário , Espaço Retroperitoneal/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Dispositivos de Acesso Vascular/efeitos adversos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Adulto JovemRESUMO
Recent clinical trials have changed the treatment landscape for metastatic castration-sensitive prostate cancer. Ongoing and future studies using new therapeutic approaches hold the promise of further improving outcomes for patients with advanced prostate cancer.