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BACKGROUND: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide. METHODS: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort. RESULTS: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035). CONCLUSIONS: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity.
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Antineoplásicos , Negro ou Afro-Americano , DNA Tumoral Circulante , Neoplasias de Próstata Resistentes à Castração , Brancos , Humanos , Masculino , Antineoplásicos/uso terapêutico , Negro ou Afro-Americano/genética , DNA Tumoral Circulante/genética , Mutação/genética , Nitrilas , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/etnologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/secundário , Estudos Retrospectivos , Resultado do Tratamento , Brancos/genéticaRESUMO
BACKGROUND: Bipolar androgen therapy (BAT) is a novel therapy known to be effective in a subset of men with metastatic castrate resistant prostate cancer (mCRPC). A better understanding of responders and nonresponders to BAT would be useful to clinicians considering BAT therapy for patients. Herein we analyze clinical and genetic factors in responders/nonresponders to better refine our understanding regarding which patients benefit from this innovative therapy. METHODS: mCRPC patients were assessed for response or no response to BAT. Patients with PSA declines of greater than 50% from baseline after 2 or more doses of testosterone were considered to be responders. Whereas, nonresponders had no PSA decline after 2 doses of testosterone and subsequently manifest a PSA increase of >50%. Differences between these two groups of patients were analyzed using clinical and laboratory parameters. All patients underwent genomic testing using circulating tumor DNA (ctDNA) and germline testing pre-BAT. RESULTS: Twenty five patients were nonresponders and 16 were responders. Baseline characteristics between nonresponders and responders varied. Responders were more likely to have had a radical prostatectomy as definitive therapy and were more likely to have been treated with an androgen receptor (AR) antagonist (enzalutamide or apalutamide) immediately before BAT (compared to abiraterone). Duration of prior enzalutamide therapy was longer in responders. Nonresponders were more likely to have bone-only metastases and responders were more likely to have nodal metastases. Assays detected ctDNA AR amplifications more often in responding patients. Responders trended toward having the presence of more TP53 mutations at baseline. CONCLUSIONS: BAT responders are distinct from nonresponders in several ways however each of these distinctions are imperfect. Patterns of metastatic disease, prior therapies, duration of prior therapies, and genomics each contribute to an understanding of patients that will or will not respond. Additional studies are needed to refine the parameters that clinicians can utilize before choosing among the numerous treatment alternatives available for CRPC patients.
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Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Androgênios , Feniltioidantoína/uso terapêutico , Nitrilas/uso terapêutico , Testosterona , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antígeno Prostático Específico/uso terapêutico , Receptores Androgênicos/genéticaRESUMO
BACKGROUND: Black men are at higher risk for prostate cancer death. Previous studies showed a benefit of different therapies, including immune-based therapy, for Black men with metastatic prostate cancer. We sought to explore the efficacy of the PD-L1 inhibitor avelumab in Black men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after abiraterone or enzalutamide. METHODS: This pilot phase II study enrolled self-identified Black patients who developed mCRPC on next-generation hormonal therapies (NHTs) abiraterone acetate or enzalutamide (NCT03770455). Enrolled patients received avelumab 10mg/kg IV every 2 weeks while remaining on the same NHTs. The primary endpoint of our study wasâ ≥â 50% reduction in prostate specific antigen (PSA) atâ ≥8 weeks. RESULTS: A total of eight patients were enrolled. The median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). The median time to initiate avelumab was 8 days (3-14). With a median follow-up of 196 days, no patients achieved the primary endpoint. The median time to PSA progression was 35 days (95 CI%, 0-94.8) and the median time to radiographic and/or clinical progression was 44 days (95 CI%, 0-118.5). The study was closed prematurely due to safety concerns related to the rapid clinical progression observed in the patients enrolled on study. CONCLUSION: In conclusion, the addition of avelumab to NHT did not demonstrate clinical activity in Black men with new mCRPC. The unexpected short interval between PSA and radiographic and/or clinical progression observed in this study has potential clinical implications.ClinicalTrials.gov Identifier: NCT03770455 (IND number 139559).
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Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Nitrilas/uso terapêutico , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. METHODS: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. RESULTS: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). CONCLUSIONS: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.
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Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Neoplasias Ósseas/genética , Neoplasias Ósseas/radioterapia , Humanos , Masculino , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Advanced prostate cancer (aPC) in Black men was reported to present with aggressive features and to be associated with poor prognosis. Herein, we compared the cell-free DNA (cfDNA) genomic landscape of aPC in Black vs White men. Patients (pts) with aPC from 6 academic institutions and available cfDNA comprehensive genomic profiling (CGP) were included. Association between mutated genes and race was evaluated using Barnard's test and a Probabilistic Graphical Model (PGM) machine learning approach. Analysis included 743 aPC pts (217 Black, 526 White) with available cfDNA CGP. The frequency of alterations in the androgen receptor gene was significantly higher in Black vs White men (55.3% vs 35% respectively, P < .001). Additionally, alterations in EGFR, MYC, FGFR1, and CTNNB1 were present at higher frequencies in Black men. PGM analysis and Barnard's test were concordant. Findings from the largest cohort of Black men with aPC undergoing cfDNA CGP may guide further drug development in these men.
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Ácidos Nucleicos Livres , Neoplasias da Próstata , Ácidos Nucleicos Livres/genética , Receptores ErbB , Genômica , Humanos , Masculino , Neoplasias da Próstata/genética , Receptores Androgênicos/genéticaRESUMO
BACKGROUND: The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. METHODS: A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. RESULTS: A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). CONCLUSION: In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Hormônios/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In multicellular organisms, cells are organized in a 3-dimensional framework and this is essential for organogenesis and tissue morphogenesis. Systems to recapitulate 3D cell growth are therefore vital for understanding development and cancer biology. Cells organized in 3D environments can evolve certain phenotypic traits valuable to physiologically relevant models that cannot be accessed in 2D culture. Cellular spheroids constitute an important aspect of in vitro tumor biology and they are usually prepared using the hanging drop method. Here a 3D printed approach is demonstrated to fabricate bespoke hanging drop devices for the culture of tumor cells. The design attributes of the hanging drop device take into account the need for high-throughput, high efficacy in spheroid formation, and automation. Specifically, in this study, custom-fit, modularized hanging drop devices comprising of inserts (Q-serts) were designed and fabricated using fused filament deposition (FFD). The utility of the Q-serts in the engineering of unicellular and multicellular spheroids-synthetic tumor microenvironment mimics (STEMs)-was established using human (cancer) cells. The culture of spheroids was automated using a pipetting robot and bioprinted using a custom bioink based on carboxylated agarose to simulate a tumor microenvironment (TME). The spheroids were characterized using light microscopy and histology. They showed good morphological and structural integrity and had high viability throughout the entire workflow. The systems and workflow presented here represent a user-focused 3D printing-driven spheroid culture platform which can be reliably reproduced in any research environment and scaled to- and on-demand. The standardization of spheroid preparation, handling, and culture should eliminate user-dependent variables, and have a positive impact on translational research to enable direct comparison of scientific findings.
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Neoplasias , Esferoides Celulares , Humanos , Neoplasias/genética , Impressão Tridimensional , Microambiente TumoralRESUMO
BACKGROUND: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history (FH) records are incomplete in the major published studies from prostate cancer patients. METHODS: Prospective family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes. Comprehensive first degree FH were obtained in all PCa of patients and analysis of prevalent FH was assessed at the time of sample collection. RESULTS: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. One or more first degree relatives (FDR) with any cancer was not predictive for germline PV/LPVs for men with PCa (p = .96). Separate analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast or ovarian cancer was predictive for PV/LPVs (p = .028, p = .015 respectively). Patients with a FDR with breast cancer had 1.8 increased risk of PV/LPVs, and patients with a FDR with ovarian cancer had 2.9 increased risk of PV/LPV. CONCLUSION: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. Notably having FDRs with PCa does not predict for PV/LPVs. These data emphasize the contribution of FH in a data set with complete ascertainment of FH.
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Mutação em Linhagem Germinativa , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Próstata/patologia , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men. CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.
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Proteína BRCA2/genética , Negro ou Afro-Americano/genética , Mutação em Linhagem Germinativa , Metástase Neoplásica/genética , Neoplasias da Próstata/genética , População Branca/genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Neoplasias da Próstata/patologiaRESUMO
An increasing number of people are infected with antibiotic-resistant bacteria each year, sometimes with fatal consequences. In this manuscript, we report a novel urea-functionalized crown ether that can bind to the bacterial lipid phosphatidylethanolamine (PE), facilitate PE flip-flop and displays antibacterial activity against the Gram-positive bacterium Bacillus cereus with a minimum inhibitory concentration comparable to that of the known PE-targeting lantibiotic duramycin.
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FosfatidiletanolaminasRESUMO
BACKGROUND: The predictive and prognostic role of BRAF alterations has been evaluated in colorectal cancer (CRC); however, BRAF alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of BRAF alterations among patients with non-CRC GI malignancies. METHODS: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function BRAF alterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA). RESULTS: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. BRAF GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) (p < 0.001). Non-CRC GI malignancies with the highest prevalence of BRAF GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among BRAF GOF alterations, class II (28% vs. 6.8%, p < 0.001) and class III (23% vs. 14%, p < 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of BRAF amplifications (3.1% vs. 0.3%, p < 0.001) and BRAF fusions (12% vs. 2.2%, p < 0.001) were higher in non-CRC GI malignancies compared to CRC. CONCLUSIONS: Non-CRC GI malignancies demonstrate a distinct BRAF alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of BRAF fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with BRAF alterations, especially BRAF fusions.
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PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. EXPERIMENTAL DESIGN: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA. RESULTS: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing. CONCLUSIONS: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.
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BACKGROUND: Prostate cancer (PC) rarely metastasizes to the central nervous system (CNS). In this retrospective single-institution study at a tertiary cancer center, we aimed to evaluate the clinical and genetic characteristics of advanced PC patients with CNS metastases. PATIENTS AND METHODS: Between January 2010 and March 2020, 12 out of 579 patients with extracranial metastatic PC were identified to have CNS metastases based on imaging, including six patients with brain metastases (BMs), five patients with dural metastases, and one unknown. These patients were followed up through March 2022. Clinical data were compared to the overall cohort of patients evaluated at our cancer center during that decade. Genetics information was also analyzed for the patients with available data via cell-free DNA (cfDNA) blood samples. RESULTS: Median time from development of extracranial metastatic disease to development of CNS metastases was 5.5 years (95% CI, 1.8-7.0). Median overall survival (mOS) from diagnosis of CNS metastases was 6.1 months (95% CI, 5.8-8.2). Notably, there was no significant difference in mOS after development of extracranial metastases in patients with CNS metastases (6.4 years; 95% CI, 4.6-7.9) compared to the patients without known CNS metastases (5.2 years; 95% CI, 4.6-5.7) (P = .91). For the cohort with CNS metastases, nine patients had germline testing and seven patients had somatic testing via cfDNA. CONCLUSION: PC patients with CNS metastases did not often die from a neurological cause. With advancing therapies, the overall prognosis of metastatic PC continues to improve, and CNS metastases will become more common.
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Neoplasias do Sistema Nervoso Central , Neoplasias da Próstata , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Humanos , Masculino , Neoplasias do Sistema Nervoso Central/secundário , Estudos Retrospectivos , Centros de Atenção Terciária , Neoplasias Encefálicas/secundário , Ácidos Nucleicos Livres , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Taxa de SobrevidaRESUMO
PURPOSE: Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker demonstrating improved assessment of treatment response in patients receiving immune checkpoint inhibitors (ICIs). Here, we performed a pilot study to support the role of ctDNA for longitudinal treatment response monitoring in patients with advanced genitourinary (GU) malignancies receiving ICIs. MATERIALS AND METHODS: Patients with histologically confirmed advanced GU malignancies were prospectively enrolled. All eligible patients received ICI treatment for at least 12 weeks, followed by serial collection of blood samples every 6-8 weeks and conventional scans approximately every 12 weeks until disease progression. ctDNA analysis was performed using Signatera, a tumor-informed multiplex-polymerase chain reaction next-generation sequencing assay. Overall, the objective response rate (ORR) was reported and its association with ctDNA status was evaluated. Concordance rate between ctDNA dynamics and conventional imaging was also assessed. RESULTS: ctDNA analysis was performed on 98 banked plasma samples from 20 patients (15 renal, four urothelial, and one prostate). The median follow-up from the time of initiation of ICI to progressive disease (PD) or data cutoff was 67.7 weeks (range, 19.6-169.6). The ORR was 70% (14/20). Eight patients ultimately developed PD. The overall concordance between ctDNA dynamics and radiographic response was observed in 83% (15/18) of patients. Among the three patients with discordant results, two developed CNS metastases and one progressed with extracranial systemic disease while ctDNA remained undetectable. CONCLUSION: In this pilot study, longitudinal ctDNA analysis for monitoring response to ICI in patients with advanced GU tumors was feasible. Larger prospective studies are warranted to validate the utility of ctDNA as an ICI response monitoring tool in patients with advanced GU malignancies.
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DNA Tumoral Circulante , Neoplasias , Neoplasias Urogenitais , Masculino , Humanos , DNA Tumoral Circulante/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Projetos Piloto , Neoplasias Urogenitais/tratamento farmacológico , Neoplasias Urogenitais/genéticaRESUMO
Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor (AR)-targeted agents is often lethal. Unfortunately, biomarkers for this deadly disease remain under investigation, and underpinning mechanisms are ill-understood. Here, we applied deep sequencing to â¼100 mCRPC patients prior to the initiation of first-line AR-targeted therapy, which detected AR /enhancer alterations in over a third of patients, which correlated with lethality. To delve into the mechanism underlying why these patients with cell-free AR /enhancer alterations developed more lethal prostate cancer, we next performed genome-wide cell-free DNA epigenomics. Strikingly, we found that binding sites for transcription factors associated with developmental stemness were nucleosomally more accessible. These results were corroborated using cell-free DNA methylation data, as well as tumor RNA sequencing from a held-out cohort of mCRPC patients. Thus, we validated the importance of AR /enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.
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Introduction: The treatment landscape of metastatic renal cell carcinoma has advanced significantly with the approval of combination regimens containing an immune checkpoint inhibitor (ICI) for patients with treatment-naïve disease. Little information is available regarding the activity of single-agent ICIs for patients with previously untreated mRCC not enrolled in clinical trials. Methods: This retrospective, multicenter cohort included consecutive treatment-naïve mRCC patients from six institutions in the United States who received ≥1 dose of an ICI outside a clinical trial, between June 2017 and October 2019. Descriptive statistics were used to analyze outcomes including objective best response rate (ORR), progression-free survival (PFS), and tolerability. Results: The final analysis included 27 patients, 70% men, median age 64 years (range 42-92), 67% Caucasian, and 33% with ECOG 2 or 3 at baseline. Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC. All patients had evidence of metastatic disease involving the lungs (59%), lymph node (41%), CNS (19%), liver (11%), adrenal gland (11%), and bone (11%). The median time on ICI was 3.1 (0.1-26.8) months, and the median PFS was 6.3 (95% CI, 0-18.6) months. Among the 21 patients with an evaluable response, the best ORR was 33%, including two complete responses and five partial responses. The ORR was 29% (n = 1 complete response, n = 5 partial response) in clear cell and 5% (n = 1 complete response) in non-clear cell RCC. Adverse events (AEs) of any cause were reported in 37% and included fatigue (11%), dermatitis (11%), diarrhea (7%), and shortness of breath (7%). Significant AEs (30%) included shortness of breath (7%), acute kidney injury (4%), dermatitis (4%), Clostridium difficile infection (4%), cerebrovascular accident (4%), and fatigue (7%). Three patients discontinued therapy due to grade 4 AEs. Conclusions: In this multi-institutional case series, single-agent ICI demonstrated objective responses and was well tolerated in a heterogeneous treatment-naïve mRCC cohort. ICI monotherapy is not the standard of care for patients with mRCC, and further investigation is necessary to explore predictive biomarkers for optimal treatment selection in this setting.
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To report a multi-institutional case series of patients with advanced microsatellite instability high (MSI-H) prostate adenocarcinoma identified with clinical cell-free DNA (cfDNA) next-generation sequencing (NGS) testing and treated with immune checkpoint inhibitors. Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months. Four patients (44%) achieved PSA50 after a median of 4 (3-12) weeks after treatment initiation including three patients with >99% PSA decline. Among the patients evaluable for radiographic response (n=5), the response rate was 60% with one complete response and two partial responses. Best response was observed after a median of 3.3 (1.4-7.6) months. At time of cut-off, four patients were still on pembrolizumab while four patients discontinued therapy due to progressive disease and one due to COVID-19 infection. Half of the patients with PSA50 had both MSI-H and pathogenic alterations in BRCA1 and BRCA2 in their G360 assays. The use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H is feasible in clinical practice and may overcome some of the obstacles associated with prostate cancer tumor tissue testing. The robust activity of pembrolizumab in selected patients supports the generalized testing for MSI-H.