Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene-fusion: A Long Response to mammalian target of rapamycin (mTOR) Inhibitors

Fernández, Oliver R. Rua; Cornejo, R.A. Escala; Martín, Miguel; Muñoz, María García; Plaza, Patricia; Dominguez, Aracely Rocío García; Hernández, Juan Jesús Cruz

doi:10.1016/j.urology.2018.03.032

Cited by 18 publications

(10 citation statements)

References 17 publications

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“…As a result, tRCC patients are typically treated with therapies originally developed for clear cell RCC (ccRCC) 16 , including vascular endothelial growth factor receptor inhibitors (VEGFR-TKI), multikinase inhibitors (cabozantinib), mTOR inhibitors, or immune checkpoint inhibitors (ICIs). Although some responses to each of these classes of agents have been reported in tRCC, outcomes have been variable between series, and it remains unclear which class(es) of therapeutics are best suited to the biology of tRCC [17][18][19][20][21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

Bakouny

Sadagopan

Ravi

et al. 2021

Preprint

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Translocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8+ tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

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Section: Introductionmentioning

confidence: 99%

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

Bakouny

Sadagopan

Ravi

et al. 2021

Preprint

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“…Additionally, Solano et al reported a case demonstrating the therapeutic efficacy of pazopanib, a similar anti-VEGF agent [ 1 ]. Alternatively, some studies have suggested that the mammalian target of rapamycin (mTOR) inhibitors is a treatment option for Xp11.2 tRCC [ 21 ]. Malouf et al reported an objective response rate of 33.0% for an mTOR inhibitor in patients with metastatic Xp11.2 tRCC [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Malouf et al reported an objective response rate of 33.0% for an mTOR inhibitor in patients with metastatic Xp11.2 tRCC [ 22 ]. Additionally, the therapeutic benefits of mTOR inhibitors have been demonstrated in a patient with Xp11.2 tRCC who did not show a favorable response to first-line VEGF inhibitor treatment [ 21 ]. Based on the current literature, targeted molecular therapies, including VEGF receptor inhibitors and mTOR inhibitors, have therapeutic advantages over immunotherapy in Xp11.2 tRCC [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

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Gene Expression Analysis of Aggressive Adult Xp11.2 Translocation Renal Cell Carcinoma at Clinical Stage T1N0M0 to Identify Potential Prognostic and Therapeutic Biomarkers

et al. 2022

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Xp11.2 translocation renal cell carcinoma (tRCC), involving transcription factor E3 (TFE3) gene fusions, is a rare and aggressive RCC variant when present in adults and has been recently recognized as a unique entity in RCC. Biomarkers and treatment guidelines do not exist for patients with aggressive Xp11.2 tRCC. The aim was to identify and evaluate therapeutic biomarkers for aggressive Xp11.2 tRCC. RNA sequencing was performed using formalin-fixed, paraffin-embedded tissues from 11 adult patients with clinical T1N0M0 Xp11.2 tRCC, including three patients with aggressive characteristics (recurrence or cancer-specific death after nephrectomy). Thirty genes were differentially expressed between the aggressive and non-aggressive groups, even after adjustment, and were associated with KEGG pathways related to the aggressiveness of Xp11.2 tRCC. PIK3R2, involved in various KEGG pathways, including the PI3K/AKT/mTOR pathway, was overexpressed in the Xp11.2 tRCC cell lines UOK120 and UOK146. The PI3K pathway inhibitor LY294002 showed a significant therapeutic benefit. This study provides the first candidate biomarker, PIK3R2, for aggressive clinical T1N0M0 Xp11.2 tRCC. Furthermore, this study is the first to recommend a targeted drug, LY294002, for aggressive Xp11.2 tRCC based on the molecular pathophysiology.

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“…Moreover, in the study of Wang in 2018, the DNA and RNA sequencing of Xp11 tRCC were reported, revealing novel gene fusions and presenting other potential targets for treatment [87]. Recent studies have shown that vascular endothelial growth factor receptor-targeted agents and mammalian target of rapamycin inhibitors play an important role effects in the treatment of metastatic TFE3 RCC [97][98][99][100][101]. Other targeted agents and immune checkpoint inhibitors are currently being tested and developed [102][103][104].…”

Section: Discussionmentioning

confidence: 99%

Factors Associated with Survival From Xp11.2 Translocation Renal Cell Carcinoma Diagnosis—A Systematic Review and Pooled Analysis

Wu¹,

Chen²,

Zhang³

et al. 2021

Pathol. Oncol. Res.

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Purpose: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a rare subtype of renal cell carcinoma (RCC), characterized by translocations of Xp11.2 breakpoints, involving of the transcription factor three gene (TFE3). The aim of our study was to comprehensively characterize the clinical characteristics and outcomes, and to identify risk factors associated with OS and PFS in Xp11.2 tRCC patients.Methods: Literature search on Xp11.2 tRCC was performed using databases such as pubmed EMBASE and Web of Science. Studies were eligible if outcomes data (OS and/or PFS) were reported for patients with a histopathologically confirmed Xp11.2 tRCC. PFS and OS were evaluated using the univariable and multivariable Cox regression model.Results: There were 80 eligible publications, contributing 415 patients. In multivariable analyses, the T stage at presentation was significantly associated with PFS (HR: 3.87; 95% CI: 1.70 to 8.84; p = 0.001). The median time of PFS was 72 months. In the multivariable analyses, age at diagnosis (HR: 2.16; 95% CI: 1.03 to 4.50; p = 0.041), T stage at presentation (HR: 4.44; 95% CI: 2.16 to 9.09; p < 0.001) and metastasis status at presentation (HR: 2.67; 95% CI: 1.12 to 6.41; p = 0.027) were all associated with OS, with a median follow-up time of 198 months.Conclusion: T stage at presentation is the only factor that is associated with both PFS and OS in patients with Xp11.2 tRCC. Also, patients over 45 or with metastases are more likely to have poorer OS.

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Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene-fusion: A Long Response to mammalian target of rapamycin (mTOR) Inhibitors

Cited by 18 publications

References 17 publications

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

Gene Expression Analysis of Aggressive Adult Xp11.2 Translocation Renal Cell Carcinoma at Clinical Stage T1N0M0 to Identify Potential Prognostic and Therapeutic Biomarkers

Factors Associated with Survival From Xp11.2 Translocation Renal Cell Carcinoma Diagnosis—A Systematic Review and Pooled Analysis

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