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BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma.

ABSTRACT: BACKGROUND:Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies. METHODS:In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher's Exact test). The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox's regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC. RESULTS:Of 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p?=?0.03), earlier stage at diagnosis (p?=?0.04), had no prior nephrectomy (p?=?0.04) and no immune-related adverse events (irAE) (p?=?0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p?=?0.02) and lower neutrophil:lymphocyte ratio (p?=?0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p?=?0.007) and irAE occurrence (p?=?0.02) while improved OS was significantly correlated with overweight BMI (BMI 25-30; p?=?0.03) and no brain metastasis (p?=?0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS. CONCLUSIONS:Clinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.

SUBMITTER: Labadie BW

PROVIDER: S-EPMC6878694 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma.

Labadie Brian W BW Liu Ping P Bao Riyue R Crist Michael M Fernandes Ricardo R Ferreira Laura L Graupner Scott S Poklepovic Andrew S AS Duran Ignacio I Maleki Vareki Saman S Balar Arjun V AV Luke Jason J JJ

Journal of translational medicine 20191125 1

<h4>Background</h4>Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies.<h4>Methods</h4>In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and ...[more]

PMID: 31767020

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Project description:BackgroundImmune-checkpoint-inhibitors (ICIs) have become the cornerstone of metastatic renal-cell-carcinoma (mRCC) therapy. However, data are limited regarding clinical outcomes by race. In this study, we compared the real-world outcomes between African American (AA) and Caucasian mRCC patients treated with ICIs.MethodsWe performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015-2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) defined as a complete or partial response maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. Univariate and multivariable analyses were carried out for OS and PFS by Cox proportional-hazard model and ORR by logistical-regression model. Descriptive statistics compared rates of immune-related adverse events (irAEs) and non-clear-cell-RCC (nccRCC) histology were assessed using Chi-square test.ResultsOur cohort was comprised of 38 AA and 160 Caucasian patients. Most were diagnosed with clear-cell-RCC (ccRCC) (78%) and more than half received (57%) PD-1/PD-L1 monotherapy. Most patients were intermediate or poor-risk groups (83%). Comparing to Caucasians, our AA cohort contained more females and nccRCC cases. Kaplan-Meier method showed AAs had no statistically different median OS (17 vs 25 months, p=0.368) and PFS (3.1 vs 4.4 months, p=0.068) relative to Caucasian patients. On multivariable analysis, AA patients had significantly shorter PFS (HR=1.52, 95% CI: 1.01-2.3, p=0.045), similar ORR (OR=1.04, 95% CI: 0.42-2.57, p=0.936) and comparable OS (HR=1.09, 95% CI: 0.61-1.95, p=0.778) relative to Caucasians.ConclusionsOur real-world analysis of ICI-treated mRCC patients showed that AAs experienced shorter PFS but similar OS relative to Caucasians. This similarity in survival outcomes is reassuring for the use of ICI amongst real-world patient populations, however, the difference in treatment response is poorly represented in early outcomes data from clinical trials. Thus, the literature requires larger prospective studies to validate these findings.

Project description:BackgroundImmune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are the most commonly used medications in metastatic renal cell carcinoma (mRCC). Recently, large clinical trials have shown favorable outcomes in patients treated with combined immune checkpoint plus VEGFR inhibition compared with VEGFR inhibition alone. However, the benefit among favorable risk (based on International Metastatic Renal Cell Carcinoma Database Consortium score) and elderly (age > 65 years) patients was not clear, leading to a discrepancy between United States Food and Drug Administration and European Association of Urology recommendations.Materials and methodsWe searched available literature for phase III randomized clinical trials evaluating the efficacy of combining immunotherapy plus VEGF/VEGFR inhibitors versus standard of care in patients with previously untreated mRCC. Combinations that were included in United States Food and Drug Administration recommendations or European Association of Urology guidelines were used for analysis. We performed a meta-analysis with a random effects model to evaluate the efficacy of immunotherapy-VEGFR inhibitor combinations compared with sunitinib in favorable risk and elderly patients.ResultsOur analysis demonstrated that progression-free survival (PFS) was significantly prolonged with combination therapy compared with sunitinib in patients with age > 65 years (hazard ratio, 0.66; 95% confidence interval, 0.52-0.84; P = .001). The PFS in favorable risk disease was improved with combination therapy compared with sunitinib, but the difference was not statistically significant (hazard ratio, 0.68; 95% confidence interval, 0.46-1.01; P = .055).ConclusionOur meta-analysis strengthens the trend of beneficial effect in prolonging PFS in both subgroups compared with each trial alone, indicating that favorable risk and elderly patients with mRCC likely benefit from combining programmed cell death 1 or programmed cell death-ligand 1 and VEGFR inhibition.

Project description:BackgroundImmune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Biomarkers for mRCC patients treated with ICI are limited, and body composition is underutilized in mRCC. We investigated the association between body composition and clinical outcomes in ICI-treated mRCC patients.MethodsWe performed a retrospective analysis of 79 ICI-treated mRCC patients at Winship Cancer Institute from 2015-2020. Baseline CT images were collected at mid-L3 and segmented using SliceOMatic v5.0 (TomoVision). Density of skeletal muscle (SM), subcutaneous fat, inter-muscular fat, and visceral fat were measured and converted to indices by dividing by height(m)2 (SMI, SFI, IFI, and VFI, respectively). Total fat index (TFI) was defined as the sum of SFI, IFI, and VFI. Patients were characterized as high versus low for each variable at gender-specific optimal cuts using overall survival (OS) as the primary outcome. A prognostic risk score was created based on the beta coefficient from the multivariable Cox model after best subset variable selection. Body composition risk score was calculated as IFI + 2*SM mean + SFI and patients were classified as poor (0-1), intermediate (2), or favorable risk (3-4). Kaplan-Meier method and Log-rank test were used to estimate OS and PFS and compare the risk groups. Concordance statistics (C-statistics) were used to measure the discriminatory magnitude of the model.ResultsMost patients were male (73%) and most received ICI as first (35%) or second-line (51%) therapy. The body composition poor-risk patients had significantly shorter OS (HR: 6.37, p<0.001), PFS (HR: 4.19, p<0.001), and lower chance of CB (OR: 0.23, p=0.044) compared to favorable risk patients in multivariable analysis. Patients with low TFI had significantly shorter OS (HR: 2.72, p=0.002), PFS (HR: 1.91, p=0.025), and lower chance of CB (OR: 0.25, p=0.008) compared to high TFI patients in multivariable analysis. The C-statistics were higher for body composition risk groups and TFI (all C-statistics ≥ 0.598) compared to IMDC and BMI.ConclusionsRisk stratification using the body composition variables IFI, SM mean, SFI, and TFI may be prognostic and predictive of clinical outcomes in mRCC patients treated with ICI. Larger, prospective studies are warranted to validate this hypothesis-generating data.

Dataset Information

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma.

Publications

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma.

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