Administering immunotherapy after anti-vascular targeted therapy improves overall survival of patients with metastatic clear cell renal cell carcinoma
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PROVIDER: S-EPMC11242332 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:ImportanceClinical trials have shown an overall survival (OS) benefit associated with first-line immunotherapy (IT) and combination targeted therapy (TT) and IT regimens compared with TT among patients with metastatic clear cell renal cell carcinoma (RCC). Generalizability of these findings in a real-world cohort outside of a clinical trial setting is unclear.ObjectiveTo assess the association of first-line TT, IT, and combination TT and IT regimens with OS in a real-world cohort of patients with metastatic clear cell RCC.Design, setting, and participantsThis retrospective propensity-matched cohort study identified 5872 patients with metastatic clear cell RCC in the National Cancer Database from January 1, 2015, to December 31, 2017, who received first-line TT, IT, or combination TT and IT and were not treated on a clinical trial protocol. Patients were stratified by first-line systemic treatment. Statistical analysis was conducted from October 1 to December 1, 2020.Main outcomes and measuresThe primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. After 1:1:1 nearest-neighbor caliper matching of propensity scores, survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates.ResultsThe final study population included 5872 patients (TT group: n = 4755 [81%]; 3332 men [70%]; median age, 64 years [interquartile range, 57-71 years]; IT group: n = 638 [11%]; 475 men [74%]; median age, 61 years [interquartile range, 54-69 years]; and combination TT and IT group: n = 479 [8%]; 321 men [67%]; median age, 62 years [interquartile range, 55-69 years]), and the matched cohort included 1437 patients (479 per treatment group). Patients in the IT and combination TT and IT groups were younger than those in the TT group, had fewer comorbid conditions (Charlson-Deyo score of 0, 480 of 638 [75%] in the TT group, 356 of 479 [74%] in the IT group, and 3273 of 4755 [69%] in the combination TT and IT group), and were more often treated at academic centers (315 of 638 [49%], 216 of 479 [45%], and 1935 of 4755 [41%], respectively). Both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC (IT group: hazard ratio [HR], 0.60 [95% CI, 0.48-0.75]; P < .001; combination TT and IT group: HR, 0.74 [95% CI, 0.60-0.91]; P = .005). No survival difference was seen between the IT and combination TT and IT groups (combination TT and IT: HR, 1.24 [95% CI, 0.98-1.56]; P = .08).Conclusions and relevanceThis study suggests that both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC. These findings are similar to those identified in recently reported clinical trials, lending confidence to the broader applicability of these findings outside of a clinical trial setting.
| S-EPMC8150693 | biostudies-literature
Project description: Not available
| S-EPMC8797268 | biostudies-literature
Project description:Renal cell carcinoma (RCC) is a type of cancer with an increasing rate of morbidity and mortality and is a serious threat to human health. The treatment of RCC, especially kidney renal clear cell carcinoma (KIRC), has always been the focus of clinical treatment. Using The Cancer Genome Atlas (TCGA) database as a starting point, we explored the feasibility of applying the pyroptosis mechanism to KIRC treatment by searching for cancer markers associated with pyroptosis and cancer treatment signatures. The obtained samples were clustered using unsupervised clustering analysis to define the different KIRC subtypes with different pyroptosis expression levels. Based on this, a gene expression analysis was performed to explore the carcinogenic mechanism that is markedly related to pyroptosis. The Genomics of Drug Sensitivity in Cancer database and single sample gene set enrichment analysis (ssGSEA) algorithm were used to analyze the different treatment methods of the current prominent KIRC to determine whether pyroptosis plays a role. Finally, LASSO regression was used to screen for related genes and construct a model to predict patient prognosis. The expression levels of GSDME, CASP3, CASP4, CASP5, CHMP3, and CHMP4C were incorporated into the model construction. After verification, the prediction accuracy of the 3-, 5-, 7- and 10 years survival rates of our prognostic model were 0.66, 0.701, 0.719, and 0.728, respectively. Through the above analysis, we demonstrated the feasibility of pyroptosis in the clinical treatment of KIRC and provided novel ideas and suggestions for the clinical treatment of KIRC.
| S-EPMC9252305 | biostudies-literature
Project description:Accumulating pieces of evidence suggested that immunotypes may indicate the overall immune landscape in the tumor microenvironment, which were closely related to therapeutic response. The purpose of this study was to classify and define the immune subtypes of clear cell renal cell carcinoma (ccRCC), so as to authenticate the potential immune subtypes that respond to immunotherapy. Transcriptome expression profile and mutation profile data of ccRCC, as well as clinical characteristics used in this study were obtained from TCGA database. There were significant differences in the infiltration of immune cells, immune checkpoints, and antigens between ccRCC and para-cancerous tissues. According to immune components, patients with ccRCC were divided into three immune subtypes, with different clinical and molecular characteristics. Compared with other subtypes, IS2 showed cold immune phenotype, and was associated with better survival. IS1 represented complex immune populations and was associated with poor overall survival (OS) and progression free survival (PFS). Further analysis indicated that expression of immune checkpoints also differed among the three subtypes, and was abnormally up-regulated in IS3. Pathway enrichment analysis indicated that the mTOR signaling pathway was abnormally enriched in IS3, while the TGF_BETA, ANGIOGENESIS and receptor tyrosine kinase signaling pathways were abnormally enriched in IS2. Furthermore, there was an abnormal enrichment of the epithelial-to-mesenchymal transition (EMT) signaling pathway in IS1, which may be associated with a higher rate of metastasis. Finally, SCG2 was screened as a specific antigen of ccRCC, which was not only related to poor prognosis, but also significantly associated with immune cells and immune checkpoints. In conclusion, the immune subtypes of ccRCC may provide new insights into the tumor biology and the precise clinical management of this disease.
| S-EPMC9512512 | biostudies-literature
Project description:BackgroundRecently, increasing study have found that DNA methylation plays an important role in tumor, including clear cell renal cell carcinoma (ccRCC).MethodsWe used the DNA methylation dataset of The Cancer Genome Atlas (TCGA) database to construct a 31-CpG-based signature which could accurately predict the overall survival of ccRCC. Meanwhile, we constructed a nomogram to predict the prognosis of patients with ccRCC.ResultThrough LASSO Cox regression analysis, we obtained the 31-CpG-based epigenetic signature which were significantly related to the prognosis of ccRCC. According to the epigenetic signature, patients were divided into two groups with high and low risk, and the predictive value of the epigenetic signature was verified by other two sets. In the training set, hazard ratio (HR) = 13.0, 95% confidence interval (CI) 8.0-21.2, P < 0.0001; testing set: HR = 4.1, CI 2.2-7.7, P < 0.0001; entire set: HR = 7.2, CI 4.9-10.6, P < 0.0001, Moreover, combined with clinical indicators, the prediction of 5-year survival of ccRCC reached an AUC of 0.871.ConclusionsOur study constructed a 31-CpG-based epigenetic signature that could accurately predicted overall survival of ccRCC and staging progression of ccRCC. At the same time, we constructed a nomogram, which may facilitate the prediction of prognosis for patients with ccRCC.
| S-EPMC7686748 | biostudies-literature
Project description:BACKGROUND:The genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications. METHODS:We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours. RESULTS:The cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases. CONCLUSIONS:These data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.
| S-EPMC5943584 | biostudies-literature
Project description:The treatment of advanced and metastatic kidney cancer has been revolutionized by the development of targeted systemic therapies. Despite the growing number of available agents approved for use against clear cell renal cell carcinoma, patients with non-clear histologies, constituting approximately 1 in 4 cases of kidney cancer, have not received the same attention. The majority of clinical trials testing novel targeted therapies have excluded non-clear subtypes, providing limited therapeutic options for patients with these diagnoses and their oncologists. This review will focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma: papillary I and II, chromophobe, and collecting duct. The unique genetic and molecular profiles of each distinct non-clear kidney cancer subtype will be described, as these differences are integral to the development and effectiveness of the novel agents used to treat them. Trials focusing on non-clear kidney cancer, or those that treated clear cell tumors along with significant numbers of non-clear subtypes, will be discussed. The role of cytoreductive nephrectomy and the use of neoadjuvant and adjuvant targeted therapy will be reviewed. Lastly, areas of future research will be highlighted.
| S-EPMC3003336 | biostudies-other
Project description:BackgroundThere is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy.ObjectiveTo explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome.Design, setting, and participantsMultiple frozen samples from primary tumours were taken from sunitinib-naïve (n=22) and sunitinib-treated mccRCC patients (n=23) for protein analysis. A cohort (n=86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings.InterventionThree cycles of sunitinib 50mg (4 wk on, 2 wk off).Outcome measurements and statistical analysisReverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression.Results and limitationsDifferential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26-0.87; p=0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed.ConclusionsCA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort.Patient summaryDrug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy.
| S-EPMC4410300 | biostudies-literature
Project description:BackgroundEndogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. While the dysregulation of ERV transcription has been linked to immune cell infiltration in various cancers, its relationship with immune checkpoint inhibitor (ICI) response in solid tumors, particularly metastatic clear-cell renal cell carcinoma (ccRCC), remains inadequately explored.MethodsThis study analyzed patients with metastatic ccRCC from two prospective clinical trials, encompassing 181 patients receiving nivolumab in the CheckMate trials (-009 to -010 and -025) and 48 patients treated with the ipilimumab-nivolumab combination in the BIONIKK trial. ERV expression was quantified using the ERVmap algorithm from RNA sequencing data. Our primary objective was to correlate ERV expression with progression-free survival, with overall survival and time-to-second-treatment survival as secondary endpoints. We used bootstrap methods with univariate Cox regression on 666 substantially expressed ERVs to evaluate their prognostic significance and stability.ResultsOur analysis centered on two ERVs, E4421_chr17 and E1659_chr4, which consistently exhibited opposing prognostic impacts across both cohorts. We developed a stratification system based on their median expression levels, categorizing patients into four ERV subgroups. These subgroups were further consolidated into a three-tier risk model that significantly correlated with ICI treatment outcomes. The most responsive ERV risk category showed enhanced endothelial cell infiltration, whereas the resistant category was characterized by higher levels of myeloid dendritic cells, regulatory T cells, myeloid-derived suppressor cells, and markers of T-cell exhaustion. Notably, this ERV-based classification outperformed traditional transcriptomic signatures in predicting ICI efficacy and showed further improvement when combined with epigenetic DNA methylation markers.ConclusionsOur findings introduce a dual ERV-based stratification system that effectively categorizes patient risk and predicts clinical outcomes for ccRCC patients undergoing ICI therapy. Beyond enhancing the predictive precision of existing transcriptomic models, this system paves the way for more targeted and individualized approaches in the realm of precision oncology.
| S-EPMC11784120 | biostudies-literature
Project description: Not available
| S-EPMC7541406 | biostudies-literature