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Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
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Quinases Ciclina-Dependentes/metabolismo , Neoplasias da Próstata/patologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Reparo do DNA , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos , Masculino , Mutação de Sentido Incorreto , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS AND FINDINGS: We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. CONCLUSIONS: utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.
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Biomarcadores Tumorais/análise , Cistectomia/estatística & dados numéricos , DNA de Neoplasias/análise , Neoplasia Residual/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Urina/química , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Missouri , Invasividade Neoplásica/patologia , Neoplasia Residual/etiologia , Intervalo Livre de Progressão , Neoplasias da Bexiga Urinária/etiologiaRESUMO
[This corrects the article DOI: 10.1371/journal.pmed.1003732.].
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BACKGROUND: DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. METHODS: A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. RESULTS: The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. CONCLUSIONS: Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.
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Neoplasias de Próstata Resistentes à Castração , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Carboplatina/uso terapêutico , Quinases Ciclina-Dependentes/genética , Docetaxel/uso terapêutico , Humanos , Masculino , Nitrilas/uso terapêutico , 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
PURPOSE: The comparative cardiovascular risk profiles of available hormone therapies for the treatment of prostate cancer is not known. MATERIALS AND METHODS: We queried the U.S. Food and Drug Administration Adverse Event Reporting System, a retrospective, pharmacovigilance database, for cardiovascular adverse event reports in men with prostate cancer receiving gonadotropin releasing hormone (GnRH) agonists, GnRH antagonists, androgen receptor antagonists, and/or androgen synthesis inhibitors from January 2000 to April 2020. RESULTS: Cardiovascular adverse events accounted for 6,231 reports (12.6%) on hormone monotherapy and 1,793 reports (26.1%) on combination therapy. Arterial vascular events were reported most commonly, followed by arrhythmias, heart failure, and venous thromboembolism. Compared to GnRH agonists, GnRH antagonists were associated with fewer cardiovascular adverse event reports as monotherapy (adjusted reporting odds ratio [ROR]=0.70 [95% CI 0.59-0.84], p <0.001) and as combination therapy (ROR=0.47 [0.34-0.67], p <0.0001), driven by reductions in arterial vascular events. Second generation androgen receptor antagonists and abiraterone were associated with more reports of hypertension requiring hospitalization (ROR=1.21 [1.03-1.41], p=0.02 and ROR=1.19 [1.01-1.40], p=0.03, respectively), and more heart failure events when used in combination with GnRH antagonists (ROR=2.79 [1.30-6.01], p=0.009 and ROR=2.57 [1.12-5.86], p=0.03). CONCLUSIONS: In this retrospective analysis of a pharmacovigilance database, arterial vascular events were the most commonly reported cardiovascular adverse events in men on hormone therapy for prostate cancer. GnRH antagonists were associated with fewer reports of overall cardiovascular events and arterial vascular events than GnRH agonists. Additional study is needed to identify optimal strategies to reduce cardiovascular morbidity among men with prostate cancer receiving hormone therapy.
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Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Insuficiência Cardíaca/epidemiologia , Hipertensão/epidemiologia , Neoplasias da Próstata/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/efeitos adversos , Androstenos/efeitos adversos , Estudos Transversais , Bases de Dados Factuais/estatística & dados numéricos , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Insuficiência Cardíaca/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Estudos Retrospectivos , Estados Unidos/epidemiologia , United States Food and Drug Administration/estatística & dados numéricos , Adulto JovemRESUMO
Background Pazopanib is approved for metastatic renal cell carcinoma (RCC). We assessed the safety and efficacy of pazopanib with a low fat meal (LFM): <400 cal and < 20% fat or 10 g per meal. Methods A single arm study of pazopanib with a LFM in 16 adult patients with metastatic RCC with a clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤ 2, and ≤ 3 prior therapies. Pazopanib at 400 mg daily given with LFM for 12 weeks. Incremental dose increases up to 800 mg, or irreversible decreases to 200 mg, allowed every 2 weeks. Primary study endpoint was safety; adverse events (AE) measured per CTCAE version 4.0. Secondary endpoints of RECIST 1.1 response with assessment as 12 weeks; pharmacokinetic (PK) analysis at nine time points, and CYP3A4 polymorphism evaluation. Results Pazopanib with a LFM was well tolerated; 13 of 16 subjects completed all 12 weeks. Three patients withdrew due to adverse events (AEs), with five occurrences of grade 3 AEs. Conclusions Pazopanib with a LFM has acceptable safety and comparable efficacy to fasting administration. Total median pazopanib dose per subject for the study duration was 63.5% of maximum possible conventional dose. A larger study is warranted. Clinical Trial Registration Number: NCT02729194.
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Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/terapia , Dieta com Restrição de Gorduras/métodos , Neoplasias Renais/terapia , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Carcinoma de Células Renais/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Indazóis , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
PURPOSE OF REVIEW: To date, prostate cancer has been poorly responsive to immunotherapy. In the current review, we summarize and discuss the current literature on the use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer (mCRPC). RECENT FINDINGS: Sipuleucel-T currently remains the only FDA-approved immunotherapeutic agent for prostate cancer. Single-agent phase 3 vaccine trials with GVAX and PROSTVAC have failed to demonstrate survival benefit to date. Clinical trials using combination approaches, including combination PROSTVAC along with a neoantigen vaccine and checkpoint inhibitor immunotherapy, are ongoing. Checkpoint inhibitor monotherapy clinical trials have demonstrated limited efficacy in advanced prostate cancer, and combination approaches and molecular patient selection are currently under investigation. The optimal use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer remains to be determined. Ongoing clinical trials will continue to inform future clinical practice.
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Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/terapia , Extratos de Tecidos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Humanos , Imunoterapia/tendências , Imunoterapia Ativa/tendências , Masculino , Neoplasias de Próstata Resistentes à Castração/secundárioRESUMO
Tuberculosis (TB) remains an important cause of infectious morbidity in the United States (US), necessitating timely and accurate diagnosis. We report a case of concurrent pulmonary and extrapulmonary TB presenting as tuberculous otitis media in a hospitalized US patient admitted with cough, night sweats, and unilateral purulent otorrhea. Diagnosis was made by smear microscopy and rapidly confirmed by Xpert MTB/RIF-a novel, automated nucleic acid amplification test for the rapid detection of drug-susceptible and drug-resistant TB. This case adds to the growing body of evidence validating Xpert MTB/RIF as an effective tool for the rapid diagnosis of extrapulmonary TB, even in low TB-prevalence settings such as the US, when testing is performed on non-respiratory specimens.
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Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Cisplatino , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversosRESUMO
BACKGROUND: Cardiovascular (CV) disease is common among men with prostate cancer and the leading cause of death in this population. There is a need for CV risk assessment tools that can be easily implemented in the prostate cancer treatment setting. METHODS: Consecutive patients who underwent positron emission tomography/computed tomography (PET/CT) for recurrent prostate cancer at a single institution from 2012 to 2017 were identified retrospectively. Clinical data and coronary calcification on nongated CT imaging were obtained. The primary outcome was major adverse CV event (MACE; myocardial infarction, coronary or peripheral revascularization, stroke, heart failure hospitalization, or all-cause mortality) occurring within 5 years of PET/CT. RESULTS: Among 354 patients included in the study, there were 98 MACE events that occurred in 74 patients (21%). All-cause mortality was the most common MACE event (35%), followed by coronary revascularization/myocardial infarction (26%) and stroke (19%). Coronary calcification was predictive of MACE (HR = 1.9, 95% CI: 1.1-3.4, P = .03) using adjusted Kaplan-Meier analysis. As a comparator, the Framingham risk score was calculated for 198 patients (56%) with complete clinical and laboratory data available. In this subgroup, high baseline Framingham risk (corresponding to 10-year risk of CV disease > 20%) was not predictive of MACE. CONCLUSIONS: MACE was common (21%) in men with recurrent prostate cancer undergoing PET/CT over 5 years of follow-up. Incidental coronary calcification on PET/CT was associated with increased risk of MACE and may have utility as a CV risk predictor that is feasible to implement among all prostate cancer providers.
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Doenças Cardiovasculares , Infarto do Miocárdio , Neoplasias da Próstata , Acidente Vascular Cerebral , Masculino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Fatores de Risco , Estudos Retrospectivos , Recidiva Local de Neoplasia/complicações , Medição de Risco , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/terapia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Fatores de Risco de Doenças Cardíacas , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/complicações , Prognóstico , Valor Preditivo dos TestesRESUMO
PURPOSE: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. PATIENTS AND METHODS: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. RESULTS: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%-28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6-11.4) in cohort A and 4.5 months (95% CI, 3.4-13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2-12.3) in cohort A and 13.8 months (95% CI, 3.6-not reached) in cohort C. CONCLUSIONS: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.
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Quinases Ciclina-Dependentes , Inibidores de Checkpoint Imunológico , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Pessoa de Meia-Idade , Quinases Ciclina-Dependentes/antagonistas & inibidores , Idoso de 80 Anos ou mais , Mutação , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Ipilimumab/uso terapêutico , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Metástase Neoplásica , Antígeno Prostático Específico/sangue , Biomarcadores Tumorais , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions. METHODS: Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC. RESULTS: Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84-0.96). CONCLUSIONS: Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.
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Doenças Cardiovasculares , Diabetes Mellitus , Neoplasias de Próstata Resistentes à Castração , Veteranos , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Neoplasias de Próstata Resistentes à Castração/patologia , Nitrilas/uso terapêutico , Estudos Retrospectivos , Diabetes Mellitus/tratamento farmacológico , Resultado do Tratamento , Acetato de Abiraterona/uso terapêuticoRESUMO
Circulating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integrated ultra-low-pass whole genome sequencing (ULP-WGS) with urine cancer personalized profiling by deep sequencing (uCAPP-Seq) to achieve sensitive MRD detection and predict overall survival. Variant allele frequency, inferred tumor mutational burden, and copy number-derived tumor fraction levels in urine cell-free DNA (cfDNA) significantly predicted pathologic complete response status, far better than plasma ctDNA was able to. A random forest model incorporating these urine cfDNA-derived factors with leave-one-out cross-validation was 87% sensitive for predicting residual disease in reference to gold-standard surgical pathology. Both progression-free survival (HR = 3.00, p = 0.01) and overall survival (HR = 4.81, p = 0.009) were dramatically worse by Kaplan-Meier analysis for patients predicted by the model to have MRD, which was corroborated by Cox regression analysis. Additional survival analyses performed on muscle-invasive, neoadjuvant chemotherapy, and held-out validation subgroups corroborated these findings. In summary, we profiled urine samples from 74 patients with localized bladder cancer and used urine cfDNA multi-omics to detect MRD sensitively and predict survival accurately.
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Clear cell renal cell carcinomas (ccRCCs) represent â¼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.
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Carcinoma de Células Renais , Neoplasias Renais , Proteogenômica , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Resultado do Tratamento , Prognóstico , Biomarcadores Tumorais/genéticaRESUMO
Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Transcriptoma , Epigênese Genética , Proteínas Supressoras de Tumor/genética , Regulação Neoplásica da Expressão GênicaRESUMO
PURPOSE: PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. PROCEDURES: Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). RESULTS: We found great variability in FTT uptake (SUVmax range: 2.3-15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients without HRR and one with HRR mutations had similarly high PARP1 IHC expression. CONCLUSIONS: FTT-PET/CT may serve as an alternate biomarker for PARP1 expression and a potential method for PARPi treatment selection.
Assuntos
Antineoplásicos , Neoplasias da Próstata , Masculino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Projetos Piloto , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Antineoplásicos/farmacologia , Poli(ADP-Ribose) Polimerase-1/genéticaRESUMO
OBJECTIVE: To aid in the diagnosis and treatment of patients with metastatic tumor seeding, an exceedingly rare phenomenon following minimally invasive urological surgery, additional case reports are needed. MATERIALS AND METHODS: We report our experience with patients determined to have peritoneal carcinomatosis following robotic-assisted radical prostatectomy (RARP) and provide a descriptive summary of these unique cases. RESULTS: Five cases of peritoneal carcinomatosis were identified, all of which occurred relatively late-between 8 and 13 years-following RARP. Four of the 5 cases had T3 disease at the time of prostatectomy. 68Ga-PSMA PET identified peritoneal carcinomatosis in 3 of 5 cases. CONCLUSION: Certain clinical factors, such as advanced pathologic stage at the time of prostatectomy, may predict risk for carcinomatosis following RARP. Additionally, next-generation imaging modalities, such as PSMA PET, may aid in identifying these metastases and are likely to identify increasing numbers of these patients as next-generation imaging becomes more widely available. Continued documentation and classification of this atypical presentation are needed to improve our understanding and management of this phenomenon.
Assuntos
Neoplasias Peritoneais , Neoplasias da Próstata , Procedimentos Cirúrgicos Robóticos , Isótopos de Gálio , Radioisótopos de Gálio , Humanos , Masculino , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/etiologia , Neoplasias Peritoneais/cirurgia , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do TratamentoRESUMO
Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically "cold" malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents' combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.
RESUMO
The detection of circulating tumor DNA via liquid biopsy has become an important diagnostic test for patients with cancer. While certain commercial liquid biopsy platforms designed to detect circulating tumor DNA have been approved to guide clinical decisions in advanced solid tumors, the clinical utility of these assays for detecting minimal residual disease after curative-intent treatment of nonmetastatic disease is currently limited. Predicting disease response and relapse has considerable potential for increasing the effective implementation of neoadjuvant and adjuvant therapies. As a result, many companies are rapidly investing in the development of liquid biopsy platforms to detect circulating tumor DNA in the minimal residual disease setting. In this review, we discuss the development and clinical implementation of commercial liquid biopsy platforms for circulating tumor DNA minimal residual disease detection of solid tumors. Here, we aim to highlight the technological features that enable highly sensitive detection of tumor-derived genomic alterations, the factors that differentiate these commercial platforms, and the ongoing trials that seek to increase clinical implementation of liquid biopsies using circulating tumor DNA-based minimal residual disease detection.
Assuntos
DNA Tumoral Circulante , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Genômica , Humanos , Biópsia Líquida , Recidiva Local de Neoplasia , Neoplasia Residual/diagnóstico , Neoplasia Residual/genéticaRESUMO
BACKGROUND: Cyclin-dependent kinase 12 (CDK12) loss occurs in 3-7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established. OBJECTIVE: To determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (nâ¯=â¯172) or circulating tumor DNA (nâ¯=â¯145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset. RESULTS AND LIMITATIONS: The median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (medianâ¯=â¯34.9 mo, pâ¯=⯠0.004) and development of castration-resistant disease (median = 32.7 mo, pâ¯<⯠0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, pâ¯=⯠0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data. CONCLUSIONS: Our data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers. PATIENT SUMMARY: In this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ≥8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.