RESUMO
INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single-agent cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD-1/PD-L1-blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD-1/PD-L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non-cross-resistant. METHODS: The current phase 2 trial treated patients with PD-1/PD-L1 blockade-resistant metastatic urothelial cancer with single-agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate. RESULTS: Twenty-six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune-related hepatitis. CONCLUSIONS: High dose CTLA-4 blockade in patients with PD-1/PD-L1-resistant metastatic urothelial cancer has modest activity and is associated with treatment-related toxicity similar to prior reports.
Assuntos
Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Carcinoma de Células de Transição , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Antígeno CTLA-4 , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
PURPOSE OF REVIEW: Cisplatin-based combination chemotherapy has been a standard of care in the perioperative management of muscle-invasive bladder cancer for years, but several novel therapies are under active investigation. This review aims to provide an update on recent relevant literature and a forward look at the future landscape of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer patients who opt for radical cystectomy. RECENT FINDINGS: The recent approval of nivolumab as adjuvant therapy established a new treatment option for high-risk patients with muscle-invasive bladder cancer after radical cystectomy. Several phase II studies of chemo-immunotherapy combinations and immunotherapy alone have reported pathological complete responses in the 26-46% range, including studies in cisplatin-ineligible patients. Randomized studies of perioperative chemo-immunotherapy, immunotherapy alone, and enfortumab vedotin are ongoing. Muscle-invasive bladder cancer remains a challenging disease associated with significant morbidity and mortality; however, increasing options in systemic therapy and an increasingly personalized approach to cancer treatment suggest continued future improvements in patient care.
Assuntos
Cisplatino , Neoplasias da Bexiga Urinária , Humanos , Cisplatino/uso terapêutico , Quimioterapia Adjuvante , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Terapia Combinada , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Músculos/patologia , Invasividade NeoplásicaRESUMO
OBJECTIVES: We sought to assess if adding a biopsy proven histologic subtype to a model that predicts overall survival that includes variables representing competing risks in observed, biopsy proven, T1a renal cell carcinomas, enhances the model's performance. METHODS: The National Cancer Database was assessed (years 2004-2015) for patients with observed T1a renal cell carcinoma who had undergone renal mass biopsy. Kaplan-Meier curves were utilized to estimate overall survival stratified by histologic subtype. We utilized C-index from a Cox proportional hazards model to evaluate the impact of adding histologic subtypes to a model to predict overall survival for each stage. RESULTS: Of 132 958 T1a renal masses identified, 1614 had biopsy proven histology and were managed non-operatively. Of those, 61% were clear cell, 33% papillary, and 6% chromophobe. Adjusted Kaplan-Meier curves demonstrated a difference in overall survival between histologic subtypes (P = 0.010) with greater median overall survival for patients with chromophobe (85.1 months, hazard rate 0.45, P = 0.005) compared to clear cell (64.8 months, reference group). Adding histology to a model with competing risks alone did not substantially improve model performance (C-index 0.65 vs 0.64 respectively). CONCLUSIONS: Incorporation of histologic subtype into a risk stratification model to determine prognostic overall survival did not improve modeling of overall survival compared with variables representing competing risks in patients with T1a renal cell carcinoma managed with observation. These results suggest that performing renal mass biopsy in order to obtain tumor histology may have limited utility. Future studies should further investigate the overall utility of renal mass biopsy for observed T1a kidney cancers.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biópsia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Nefrectomia , Estudos Retrospectivos , Medição de RiscoRESUMO
BACKGROUND: FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance. METHODS: 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients. RESULTS: Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response. CONCLUSIONS: Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.
Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/metabolismo , Estudos Retrospectivos , Análise de Sequência de DNA , Análise de Sequência de RNA , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologiaRESUMO
Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Idoso , Aminoquinolinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/administração & dosagem , Butilaminas/administração & dosagem , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Receptores CXCR4/antagonistas & inibidores , Resultado do Tratamento , Microambiente TumoralRESUMO
BACKGROUND: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. METHODS: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. FINDINGS: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. INTERPRETATION: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. FUNDING: None.
Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Idoso , Carcinoma de Células Renais/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Estudos RetrospectivosRESUMO
BACKGROUND: The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. Palbociclib is an oral, selective inhibitor of CDK 4/6 that restores Rb function and promotes cell cycle arrest. METHODS: In this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Primary endpoint was progression-free survival at 4 months (PFS4) using a Simon's two-stage design. Next-generation sequencing including Rb pathway alterations was conducted. RESULTS: Twelve patients were enrolled and two patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. No responses were seen. Median PFS was 1.9 months (95% CI 1.8-3.7 months) and median overall survival was 6.3 months (95% CI 2.2-12.6 months). Fifty-eight percent of patients had grade ≥3 hematologic toxicity. There were no CDKN2A alterations found and no correlation of Rb pathway alterations with clinical outcome. CONCLUSIONS: Palbociclib did not demonstrate meaningful activity in selected patients with platinum-refractory metastatic UC. Further development of palbociclib should only be considered with improved integral biomarker selection or in rational combination with other therapies.
Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Inibidor p16 de Quinase Dependente de Ciclina/genética , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Análise de Sequência de DNA , Resultado do Tratamento , Neoplasias Urológicas/genéticaRESUMO
BACKGROUND: Women with advanced bladder cancer have inferior survival compared with men. However, women treated on clinical trials do not appear to have a survival disadvantage. Less frequent administration of systemic chemotherapy in women with advanced bladder cancer may contribute to their inferior survival. METHODS: The authors identified patients diagnosed with stage IV bladder cancer from 1998 through 2010 using the National Cancer Data Base, a national outcomes database that includes 70% of all newly diagnosed cancer cases in the United States. Sex differences in demographics, systemic chemotherapy administration, and overall survival (OS) were compared. RESULTS: A total of 23,981 patients were identified (35% of whom were female). Compared with men, women were older, more likely to be black, and less likely to be insured (P<.01 for all). The Charlson-Deyo comorbidity score did not differ between men and women. Women were less likely to receive systemic chemotherapy than men (45% vs 52%; adjusted relative risk, 0.91 [95% confidence interval (95% CI), 0.88-0.94]). Women had a lower median OS compared with men (8.0 months [95% CI, 7.7-8.3 months] vs 9.8 months [95% CI, 9.5-10.0 months]; P<.001). OS remained lower for women on multivariable analysis, even after adjusting for the administration of systemic chemotherapy (hazard ratio for death, 1.11 [95% CI, 1.08-1.15]). CONCLUSIONS: Women are less likely than men to receive systemic chemotherapy for advanced bladder cancer and this difference may partially account for the poorer OS observed in women. However, OS remains lower in women independent of chemotherapy use, and may be related to unmeasured comorbidities, functional status, or tumor biology. Cancer 2016;122:2012-20. © 2016 American Cancer Society.
Assuntos
Tratamento Farmacológico/estatística & dados numéricos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Tratamento Farmacológico/métodos , Feminino , Disparidades em Assistência à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Caracteres Sexuais , Análise de Sobrevida , Estados Unidos , Neoplasias da Bexiga Urinária/patologia , Adulto JovemRESUMO
BACKGROUND: Historically, African American (AA) patients with renal cell carcinoma (RCC) have had inferior survival compared with Caucasian patients. Recent studies suggest that the survival disparity between races may be worsening since the advent of targeted therapies for RCC. In this study, survival rates among AA and Caucasian patients with advanced RCC are examined over time to determine whether a disparity in survival persists in the targeted therapy era. METHODS: The authors identified patients with stage IV RCC in the National Cancer Data Base and compared survival between AA and Caucasian patients during the periods before (1998-2004) and after (2006-2011) the advent of targeted therapy. RESULTS: In total, 48,846 patients were identified, and 10% were AA. Three-year survival among both AA and Caucasian patients improved between the 2 periods (P < .01 for both), with no interaction observed between race and improved survival over time (P = .15). The adjusted hazard ratio (HR) for death among AAs compared with Caucasians was 1.13 (95% confidence interval, 1.08-1.19) in the post-targeted therapy era, which was unchanged from the pretargeted therapy era (adjusted HR, 1.10; 95% confidence interval, 1.04-1.15). The adjusted HR was similar when the analysis was restricted to those who received systemic therapy. CONCLUSIONS: Both AA and Caucasian patients with advanced RCC have had a significant improvement in survival since the advent of targeted therapy. However, AA patients maintain a survival disadvantage compared with Caucasians independent of treatment received, potentially related to unmeasured comorbidities, disease burden, or tumor biology. Cancer 2016;122:2988-2995. © 2016 American Cancer Society.
Assuntos
Carcinoma Papilar/mortalidade , Carcinoma de Células Renais/mortalidade , Etnicidade/estatística & dados numéricos , Disparidades em Assistência à Saúde , Neoplasias Renais/mortalidade , Terapia de Alvo Molecular , Grupos Raciais , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Carcinoma Papilar/patologia , Carcinoma Papilar/terapia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , População Branca/estatística & dados numéricosRESUMO
Systemic chemotherapy is integral to the management of muscle-invasive and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy has been increasingly utilized for muscle-invasive BCa over the past several years, and several options for cisplatin-based regimens have emerged. Adjuvant chemotherapy may be considered for select patients who did not receive neoadjuvant therapy. Systemic chemotherapy added to radiotherapy is a critical component of a bladder-preserving approach and superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa for more than three decades. Novel targeted agents are in development fueled by the recent molecular characterization of BCa. Recent trials of immunotherapy have demonstrated the possibility of a less toxic and potentially more effective treatment for metastatic disease. It is an extremely exciting time for BCa research, and much needed improvements in systemic treatment are most certainly on the horizon.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Humanos , Imunoterapia , Terapia Neoadjuvante , Radioterapia , Neoplasias da Bexiga Urinária/patologiaRESUMO
PURPOSE OF REVIEW: The number of cases of muscle-invasive bladder cancer is increasing along with the age of the population. Management of muscle-invasive bladder cancer in the elderly is complex, requiring a multidisciplinary team approach and a comprehensive assessment of each individual patient. RECENT FINDINGS: A geriatric assessment should be used to inform treatment decisions in elderly patients with bladder cancer. There is increasing evidence to support aggressive therapy in appropriate elderly patients, including radical cystectomy and neoadjuvant chemotherapy. Adjuvant chemotherapy also has a role in patients with high-risk disease after cystectomy. A bladder preservation approach with trimodality therapy is a well tolerated and effective alternative to cystectomy in appropriately selected patients. SUMMARY: Treatment decisions should not be based on chronologic age alone and advanced age should not preclude aggressive or curative therapy. The recent molecular characterization of bladder cancer and several recent immunotherapy trials provide hope of a more targeted approach to treatment of bladder, potentially improving both effectiveness and tolerability of treatment regimens in the elderly.
Assuntos
Cistectomia , Terapia Neoadjuvante , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fatores Etários , Idoso , Quimioterapia Adjuvante , Cistectomia/efeitos adversos , Humanos , Terapia Neoadjuvante/efeitos adversos , Invasividade Neoplásica , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaRESUMO
The use of prostate-specific membrane antigen-positron emission tomography (PSMA-PET) is becoming more widespread for the diagnosis and management of prostate cancer. Here we report a case of oligometastatic renal cell carcinoma (RCC) to the testes diagnosed incidentally on PSMA-PET imaging. This case demonstrates the potential for diagnosis of nonprostate disease with PSMA-PET imaging, as well as the promising nature of PSMA-PET for the diagnosis and surveillance of RCC. In addition, this case report discusses the rare occurrence of oligometastatic RCC to the testis.
RESUMO
In bladder urothelial carcinoma, ERBB2 mutations have been associated with favorable response to platinum-based neoadjuvant chemotherapy. However, this association has not been reported in upper tract urothelial carcinoma (UTUC). We describe an excellent response to cisplatin-based chemotherapy in metastatic UTUC with an ERBB2 mutation. Our patient is a 54-year-old female with metastatic UTUC who received systemic cisplatin and gemcitabine. Postchemotherapy imaging demonstrated decreased size of pyelocaliceal mass and decreased retroperitoneal adenopathy compared to initial imaging. Surgical pathology from consolidative resection showed 3 mm residual renal tumor and no viable lymph node disease. Genomic testing demonstrated an ERBB2 gain of function mutation.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Platina , Cisplatino/uso terapêutico , Genes erbB-2 , Mutação , Neoplasia Residual , Resposta Patológica Completa , Receptor ErbB-2/genéticaRESUMO
We present the case of a patient with X-Linked Hypophosphatemia (XLH) and an inflammatory myofibroblastic tumor (IMT) of the bladder which prompted further investigation into the possible relationship between XLH and IMT i.e. a case of Occam's Razor or Hickam's Dictum?
RESUMO
BACKGROUND: Platinum-based neoadjuvant chemotherapy (NAC) is standard for patients with muscle-invasive bladder cancer (MIBC). Pathologic response (complete: ypT0N0 and partial: Assuntos
Cisplatino
, Neoplasias da Bexiga Urinária
, Humanos
, Terapia Neoadjuvante/métodos
, Gencitabina
, Nivolumabe/uso terapêutico
, Proteômica
, Microambiente Tumoral
, Neoplasias da Bexiga Urinária/tratamento farmacológico
, Neoplasias da Bexiga Urinária/patologia
, Biomarcadores Tumorais
, Músculos/patologia
, Imunoterapia
, Invasividade Neoplásica
, Cistectomia
RESUMO
Radiation therapy (RT) for prostate cancer has been associated with an increased risk for the development of bladder cancer. We aimed to integrate clinical and genomic data to better understand the development of RT-associated bladder cancer. A retrospective analysis was performed to identify control (CTRL; n= 41) and RT-associated (n=41) bladder cancer patients. RT and CTRL specific features were then identified through integration and analysis of the genomic sequencing data and clinical variables. RT-associated bladder tumors were significantly enriched for alterations in KDM6A and ATM, while CTRL tumors were enriched for CDKN2A mutation. Globally, there was an increased number of variants within RT tumors, albeit at a lower variant allele frequency. Mutational signature analysis revealed three predominate motif patterns, with similarity to SBS2/13 (APOBEC3A), SBS5 (ERCC2/Smoking) and SBS6/15 (MMR). Poor prognostic factors in the RT cohort include, a short tumor latency, smoking status, the presence of the smoking and XRT mutational signatures, and CDKN2A copy number loss. Based on the clinical and genomic findings, we suggest, at least two potential pathways leading to RT-associated bladder cancer; the first, occurs in the setting of field cancerization, related to smoking or pre-existing genetic alterations and leads to the development of more aggressive bladder tumors, and the second, in which RT initiates the oncogenic process in otherwise healthy urothelium, leading to a longer latency and less aggressive disease.
RESUMO
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (Assuntos
Desoxicitidina
, Gencitabina
, Imunoterapia
, Terapia Neoadjuvante
, Neoplasias da Bexiga Urinária
, Humanos
, Neoplasias da Bexiga Urinária/tratamento farmacológico
, Neoplasias da Bexiga Urinária/imunologia
, Neoplasias da Bexiga Urinária/terapia
, Neoplasias da Bexiga Urinária/patologia
, Terapia Neoadjuvante/métodos
, Desoxicitidina/análogos & derivados
, Desoxicitidina/uso terapêutico
, Desoxicitidina/administração & dosagem
, Imunoterapia/métodos
, Masculino
, Cisplatino/uso terapêutico
, Cisplatino/administração & dosagem
, Feminino
, Anticorpos Monoclonais Humanizados/uso terapêutico
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Inibidores de Checkpoint Imunológico/uso terapêutico
, Idoso
, Pessoa de Meia-Idade
, Invasividade Neoplásica
, Interleucina-9/metabolismo
, Antígeno B7-H1/metabolismo
, Biomarcadores Tumorais/sangue
, Resultado do Tratamento