Renal Cell Cancer Patients Research Articles

MicroRNA-Mediated Metabolic Reprograming in Renal Cancer.

Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key “metabomiRs” that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism).

212P - Immunotherapy with nivolumab in metastatic renal cell carcinoma patients in India: Bringing a change in clinical practice

BackgroundThe standard practice for management of metastatic renal cell cancer (mRCC) patients in India has been sunitinib or pazopanib in the first line setting, and everolimus at progression. Nivolumab in the second line setting, showed a median overall survival (OS) of 26 months, 2year OS rate of 52% and objective response rate(ORR) of 26%; which was better than everolimus in the Checkmate 025 study. There is sparse data about nivolumab in Indian RCC patients. MethodsThis is a single centre, retrospective analysis, which included mRCC patients who received nivolumab between April 2016 to April 2019. The endpoints were ORR, OS and adverse events (AEs). Results31 patients of mRCC received nivolumab at 3 mg/kg or flat dose of 240mg. Median age was 60 years (22-82 years). There were 27 males and 4 females. 4 patients received first line nivolumab, and 27 patients as second line. 16 patients had earlier received sunitinib, 10 pazopanib, and 1 sorafinib. 3 patients (9.7%) achieved complete response(CR), 8(25.8%) achieved partial response, 8(25.8%)had stable disease and 12(38.7%)had progressive disease. The 3 patients with CR, received 18 doses, after which their treatment was stopped; and they continue to be in CR at followup of 36, 32 and 26 months respectively. 10 patients have completed more than 12 cycles. OS at 1 year is 60% and median OS has not been reached. The common AEs were fatigue in 8(25.8%), hypothyroidism in 6(19.3%), skin rash in 4(12.9%) and pneumonitis in 3(9.7%) patients. Colitis, arthritis, immune retinopathy, and myocarditis was each seen in 1 patient. Treatment was discontinued in 3 patients who developed grade 3 AEs. ConclusionsWith an ORR of 35.5%, nivolumab has replaced everolimus, and has become our standard second line regimen in mRCC. Achieving an OS at 1 year of 60% is the best we have seen in the second line setting. The most exciting impact has been the durable long lasting response seen (duration ranging 2-3 years) even after discontinuing treatment, in our 3 CR patients. This has prompted us to make 1 year of treatment as a standard duration of nivolumab for responding patients at our center; enabling us to reduce cost of treatment. It is very well tolerated; but a careful watch should be kept for immune related AEs. Legal entity responsible for the studyAmit Rauthan. FundingHas not received any funding. DisclosureA. Rauthan: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

1274P - A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients

BackgroundNivolumab is currently administered in a weight-based or fixed-flat dosing regimen. Approved fixed-flat dosing regimens have been solely based on simulations from dose-finding clinical trials. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported, suggesting that nivolumab dosing needs further optimization. In this study, we determined nivolumab pharmacokinetics (PK) and assessed the relationship between nivolumab clearance (CL) and tumor response in patients with NSCLC, melanoma, and renal cell cancer (RCC). MethodsIn this prospective observational cohort study (MULTOMAB trial; Dutch Trial Registry NL6828), individual estimates of nivolumab CL and the impact of baseline covariates were determined using population-PK (PPK) modeling. The study was approved by the independent ethics committee (MEC 16-011). All patients provided written informed consent. Stratified by tumor type, CL was related to best overall response (RECIST v1.1) using ANOVA and post-hoc samples t-test. ResultsIn total 1,715 nivolumab serum concentrations were analyzed from 221 patients who were treated with monotherapy nivolumab (NSCLC n=158; melanoma n=48; RCC n=14; mesothelioma n=1). The baseline parameters gender, body surface area (BSA), and serum albumin had a significant effect on nivolumab CL and were internally validated in the PPK model. Women had 22% lower CL than men, Patients with BSA > 2.2 m2 or with baseline albumin <37.5g/L had >20% higher CL than the population mean. For NSCLC, CL was 42% higher in patients with progressive disease (mean: 0.24; 95%CI: 0.22-0.27L/day) compared to patients with partial/complete response (0.17; 0.15-0.19). Although a similar trend was observed in RCC, no CL-response relationship was observed in melanoma patients. ConclusionsWe generated the first real-world PPK model of nivolumab, in which covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab CL. A significant CL-response relationship was observed in patients with NSCLC, but not in patients with melanoma. Individualized dosing regimens might therefore increase nivolumab efficacy in patients with NSCLC. Clinical trial identificationMULTOMAB trial; Dutch Trial Registry NL6828. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA.A.M. Van der Veldt: Advisory / Consultancy: BMS. J.G. Aerts: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.

Efficacy and safety profile of nivolumab for Japanese patients with metastatic renal cell cancer.

Nivolumab, which has a promising anti-tumor efficacy and a manageable safety profile, has being rapidly introduced in metastatic renal cell cancer therapy in Japan. We evaluated the efficacy and adverse events of nivolumab in real world clinical practice in Japan. The medical records of 45 consecutive patients who started treatment with nivolumab, up to September 2018, were reviewed and statistically analyzed. The median follow-up period was 22.3months. The best responses were a complete response in three patients (8%), a partial response in 14 patients (36%), stable disease in 14 patients (36%), and progressive disease in eight patients (20%). The median progression-free survival period and 1 year progression-free survival rate were 14.9months and 54.5%, respectively. The estimated overall survival period and 1-year and 2-year overall survival rates from initiation of nivolumab were not reached, and 91.1%, and 86.2%, respectively. Twenty-seven patients (60%) experienced adverse events including four (10%) severe adverse events (Grade 3 or 4). The most common adverse event was rash (n = 9, 20%). Five patients discontinued nivolumab therapy, because of an adverse event (Grade 3 diarrhea, one patient; Grade 2 fatigue, one patient; Grade 3 uveitis, two patients; and Grade 3 adrenal insufficiency, one patient). Nivolumab has a relatively favorable efficacy and safety profile for Japanese metastatic renal cell cancer patients in clinical practice.

Association between ACYP2 polymorphisms and the risk of renal cell cancer.

BackgroundKidney cancer is the predominant form of malignancy of the kidney and accounts for approximately 3%–4% of all cancers. Renal cell cancer (RCC) represents more than 85% of kidney cancer. It has been reported that genetic factors may predispose individuals to RCC. This study evaluated the association between Acylphosphatase 2 (ACYP2) gene polymorphisms and RCC risk in the Han Chinese population.MethodsTwelve single‐nucleotide polymorphisms (SNPs) in ACYP2 were genotyped using the Agena MassARRAY platform from 293 RCC patients and 495 controls. The Chi‐squared test, genetic models, haplotype, and stratification analyses were used to evaluate the association between SNPs and the risk of RCC. The relative risk was estimated using the odds ratio (OR) and 95% confidence interval (CI).ResultsWe observed that the rs6713088 allele G (OR = 1.26, 95% CI: 1.03–1.53, p = .023) and rs843711 allele T (OR = 1.29, 95% CI: 1.06–1.57, p = .010) were associated with increased RCC risk. Genetic model analyses found that rs843711 was significantly associated with an increased RCC risk under the recessive model and log‐additive model after adjusting for age and gender. Haplotype analysis showed that the haplotype “TTCTCGCC” (OR = 0.67, 95% CI: 0.48–0.94, p = .021) was associated with a decreased risk of RCC in the Han Chinese population. Stratification analysis also found that rs6713088 and rs843711 were significantly associated with increased RCC risk.ConclusionIn summary, the results suggested that ACYP2 polymorphisms could be used as a genetic marker for RCC. Additional functional and association studies are required to validate our results.

The Impact Of Succinate Dehydrogenase Gene (SDH) Mutations In Renal Cell Carcinoma (RCC): A Systematic Review.

IntroductionRenal cell cancer (RCC) syndrome is linked to Krebs cycle compartments and their coding genes' alterations like succinate dehydrogenase genes (SDHx). Here we present a systematic review of the SDH genes’ mutations and their impact on both RCC diagnosis and prognosis.MethodsThis systematic review includes any study in which tissue samples of RCC are considered in correlation with the SDHx mutations, microsatellite instability (MSI), and protein expression. For this purpose, a systematic search of MEDLINE (PubMed), Scopus, Embase, and Web of Science databases was conducted and finally 5384 articles were recruited. All studies' content was checked to find the related ones which were 145 articles, which with data extraction were limited to nineteen.ResultsThe final selected nineteen studies investigating the SDHx role in RCC tumor genesis were included, among which fifteen were mutation analysis, three were just SDHx protein expression, and two were MSI and mutation analysis studies. A total of 432 RCC patients were reported by SDH mutations, and 64 patients with MSI and SDH expression change were reported in 514 surgically resected renal epithelial tumors. The most common mutation was the single nucleotide variant rs772551056 (c.137G>A) of SDHB. For SDHC, c.380A>G presented in 48 RCC patients, and for SDHA a novel germline mutation c.2T>C: p.M1T in an occasional case of gastrointestinal stromal tumor intricate with RCC.ConclusionRCC as an aggressive type of kidney cancer needs some biomarkers to be diagnosed exactly. It was shown recently that the succinate dehydrogenase gene variations can provide this diagnostic and prognostic biomarker. For this purpose, SDHB rs772551056 associated with its protein expression alterations can be taken into account. It is possible that a novel mutation of SDHA (c.2T>C: p.M1T) can provide evidence of GIST associated with RCC as well.

Multi-omic analysis of uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer patients

Multi-omic analysis of uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer patients

Development of a Highly Sensitive Technique for Capturing Renal Cell Cancer Circulating Tumor Cells

Purpose: Liquid biopsy is becoming increasingly important as a guide for selecting new drugs and determining their efficacy. In urological cancer, serum markers for renal cell and urothelial cancers has made the development of liquid biopsy for these cancers strongly desirable. Liquid biopsy is less invasive than conventional tissue biopsy is, enabling frequent biopsies and, therefore, is considered effective for monitoring the treatment course. Circulating tumor cells (CTCs) are a representative liquid biopsy specimen. In the present study, we focused on developing our novel technology for capturing renal cell cancer (RCC)-CTCs using an anti-G250 antibody combined with new devices. Basic experiments of our technology showed that it was possible to detect RCC-CTC with a fairly high accuracy of about 95%. Also, RCC-CTC was identified in the peripheral blood of actual RCC patients. Additionally, during the treatment course of the RCC patient, change in the number of RCC-CTC was confirmed in one case. We believe that the technology we developed will be useful for determining the treatment efficacy and drug selection for the treatment of renal cell cancer (RCC). In order to solve issues such as thresholds setting of this technology, large-scale clinical trials are expected.

A Prospective Observational Study of Renal Cell Cancer Patients Treated With Nivolumab Plus Ipilimumab in the Real World Setting in Japan

A Prospective Observational Study of Renal Cell Cancer Patients Treated With Nivolumab Plus Ipilimumab in the Real World Setting in Japan

A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients

BackgroundNivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC).MethodsIn this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type.ResultsTwo-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m2 and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22–0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15–0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma.ConclusionsBased on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied.

Abstract 2289: Prognostic impact of progastrin levels in blood compared to MSKCC based clinical prognosis in metastatic renal cell cancer patients

Abstract Background and Aims: Progastrin is a tumor promoting peptide which is detectable in the blood of patients with different cancers (Prieur et al. AACR 2017, Prieur et al. ASCO 2017). Progastrin gene is a direct target of the WNT/ß-catenin oncogenic pathway involved in tumorigenesis of many organs, but it is unknown if it has any prognostic significance in metastatic renal cell cancer (mRCC) patients. We evaluated progastrin as a prognosis marker along with known markers of prognosis in mRCCC. Methods: 145 patients with mRCCC were enrolled in this study and blood samples were drawn after consent. Progastrin was measured using the ELISA cancerREAD®. Progastrin concentrations in the 145 mRCCC patients (test set) was assessed against 213 samples from asymptomatic volunteers from the French blood establishment (control set). The prognostic impact of progastrin levels was determined with overall survival (OS) using Cox proportional hazards and also compared to MSKCC based clinical prognosis (good;intermediate; poor). Statistical significance was considered at P≤0.05. Results: The median follow-up of the cohort was 5.45 years (IQR: 1.87-9.95) and at the time of analysis 98/145 patients had died from disease progression. Plasma progastrin was detected in 95% of the patients (cut-off value 1 pM, range 0 to 272 pM, median value of 7.2 pM; IQR 3.20-19.71) compared to the control set (median value=0.61 pM; IQR 0.00-1.58). The Receiver Operating Characteristic analysis indicated an area under the curve of 0.92 (p&amp;lt;0.0001; 95% CI 0.89 to 0.94). At the univariate level, MSKCC scores (good; intermediate; poor categories) in this cohort was associated with OS and was prognostic (p&amp;lt;0.0001). We detected progastrin levels were higher with MSKCC score poor prognostic (p&amp;lt;0.0002) (median 30.39 pM; IQR 9.31-57.20). Elevated progastrin was also independently associated with poor survival (p&amp;lt;0.0001) and a multivariate model of MSKCC taken with progastrin levels remained significantly associated with poor survival (p&amp;lt;0.0001). Conclusion: Elevated progastrin levels in mRCCC is correlated with poor survival and further refines clinically used MSKCC prognostic scores. Progastrin assay is a simple and inexpensive blood test that might define subsets of mRCCC patients with poor survival who need to be identified for aggressive treatments. Citation Format: Manish Kohli, Winston Tan, Lea Payen, Carole Langlois-Jacques, Pierre Liaud, Delphine Maucort-Boulch, Dominique Joubert, Alexandre Prieur. Prognostic impact of progastrin levels in blood compared to MSKCC based clinical prognosis in metastatic renal cell cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2289.

THE IMPACT OF ANTIANGIOGENIC TREATMENT OF METASTATIC RENAL CELL CARCINOMA ON CENTRAL BLOOD PRESSURE AND PULSE WAVE VELOCITY

Objective:The aim of the study was to assess early and late changes of central blood pressure (BP), augmentation index (AI) and pulse wave velocity (PWV) in renal cell cancer (RCC) patients treated inhibitors of angiogenesis. We also assessed reversibility of these effects.Design and method:35 patie

Long noncoding RNA ZFPM2-AS1 promotes the tumorigenesis of renal cell cancer via targeting miR-137.

Recently, long noncoding RNAs (lncRNAs) have attracted more attention for their roles in tumor progression. The aim of this study was to investigate the role of lncRNA ZFPM2 antisense RNA 1 (ZFPM2-AS1) in the progression of renal cell cancer (RCC), and to explore the possible underlying mechanism. Expression levels of ZFPM2-AS1 in both RCC cells and 50 paired tissue samples were detected by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR). Moreover, the relationship between lncRNA ZFPM2-AS1 expression level and clinic-pathological characteristics as well as patients' disease-free survival rate was explored, respectively. Furthermore, cell proliferation assay, wound healing assay and transwell assay were performed to investigate the role of lncRNA ZFPM2-AS1 in vitro. In addition, Western blot assay, Luciferase reporter gene assay and RNA immunoprecipitation assay were used to explore the possible underlying mechanism. The expression level of ZFPM2-AS1 in tumor tissues was significantly higher than that of corresponding normal tissues. ZFPM2-AS1 expression was associated with lymph node metastasis, tumor stage and survival time of RCC patients. Moreover, the overexpression of ZFPM2-AS1 significantly promoted the growth, invasion and migration of tumor cells, whereas remarkably inhibited cell apoptosis in vitro. Further experiments revealed that miR-137 was a direct target of ZFPM2-AS1. In addition, miR-137 expression in tumor tissues was negatively correlated with ZFPM2-AS1 expression. Our findings indicated that ZFPM2-AS1 could promote metastasis and proliferation, whereas inhibiting the apoptosis of RCC via targeting miR-137. This study might provide a new vision for interpreting the mechanism of RCC development.

MiR-33a inhibits cell growth in renal cancer by downregulation of MDM4 expression.

Background MicroRNA‐33a (miR‐33a) plays the role of the tumor suppressor gene by regulating the expression level of downstream genes. However, the effects of miR‐33a in renal cell cancer (RCC) remain unknown. Our study was designed to investigate the expression level and potential function of miR‐33a in RCC.MethodsRT‐qPCR was applied to measure the levels of miR‐33a in RCC tissues and cell lines. Western blotting and luciferase reporter assay were used to detect the relationship between miR‐33a and Mouse double minute 4 (MDM4) in RCC cells. CCK‐8 and flow cytometry were applied to detected cell viability and cell cycle. Animal models and TUNEL assay were applied to detect the effect of miR‐33a on the growth of RCC and cell apoptosis.ResultsWe found that the levels of miR‐33a were significantly decreased in RCC tissues and cell lines. Moreover, the low expression of miR‐33a in RCC patients indicated a shorter overall survival (OS). Notably, MDM4 as a direct target of miR‐33a in RCC, the expression level of MDM4 was significantly increased in RCC cells group than the control group. Furthermore, miR‐33a overexpression significantly inhibited RCC cells growth than the control group, while the inhibitory effects of miR‐33a were reversed upon the overexpression of MDM4. Luciferase reporter assays showed that there was a direct interaction between miR‐33a and 3′ UTR of MDM4 mRNA. In vivo, tumor volumes and weight were significantly decreased in the transfected miR‐33a mimics group than the control group.ConclusionTaken together, our study indicates that miR‐33a inhibits RCC cell growth by targeting MDM4.

Impact of antibiotics and proton pump inhibitors on clinical outcomes of immune check point blockers in advanced non-small cell lung cancers and metastatic renal cell cancer.

e20520 Background: Studies have suggested that antibiotics can negatively influence efficacy of immune check-point blockers (ICB) but the results are inconsistent. The impact of concomitant proton pump inhibitors (PPI) is not known. We evaluated whether antibiotic and PPI use in patients with advanced non-small-cell lung cancer (NSCLC) and metastatic renal cell cancer (RCC) affects ICB efficacy. Methods: We identified advanced NSCLC and RCC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding systemic antibiotics and PPI use &lt; 1 month or during ICB treatment were collected. The primary outcome was progression free survival (PFS) per response evaluation criteria in solid tumors (RECIST 1.1). Secondary outcomes were overall survival (OS) and objective response rate (ORR). Logistic regression and cox proportional hazards model were used for statistical analysis. Results: 87/148 (58%) and 40/55 (72%) patients received antibiotics and 57/148 (39%) and 17/55 (31%) received PPI &lt; 1 month or during ICI therapy in NSCLC and RCC respectively. In RCC, antibiotic use was associated with inferior PFS (2.9 v 5.0 months, HR = 2.3 95%CI 1.0-5.0; p = 0.04) but OS and ORR were not affected. In NSCLC, antibiotic exposure was associated with superior PFS (5.0 v 2.5 months, HR = 0.5, 95% CI 0.3-0.7; p &lt; 0.01), OS (13.0 v 8.0 months, HR = 0.5, 95% CI 0.3-0.8; p &lt; 0.01) and ORR (33% v 11%, OR = 4.6, p &lt; 0.01). On univariate analysis, there was trend towards inferior OS in NSCLC (9.0 v 13.0 months, p = 0.05) with PPI use. PPI use was not associated with other primary or secondary outcomes in both the cohorts. The antibiotic effect remained significant for PFS in NSCLC and RCC in multivariate analysis. Conclusions: Antibiotic use significantly affected PFS in both NSCLC and RCC. PPI use did not affect outcomes. In contrast to previous studies, this is the first study to show that antibiotic use was associated with favorable outcomes in NSCLC. More studies are needed to explain this association. Future clinical trials with ICB should consider stratification of patients based on antibiotic exposure.

Molecular profile of early-stage and advanced-stage of renal cell cancer in China.

e16071 Background: The mutation spectrum has been extensively studied in Renal Cell Cancer (RCC), a heterogeneous disease. While major investigations have focused on metastatic RCC (mRCC). This study intended to explore the molecular characteristics between early-stage (stage I/Ⅱ) and advanced-stage (Ⅲ/Ⅳ) of RCC patients (pts). Methods: 36 tumor specimens were obtained from individual pts diagnosed RCC, including 22 tissues paired with blood samples. Somatic mutations were identified via targeted next generation sequencing with Acornmed panel including 808 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and chromosomal rearrangements. Clinical data of a cohort from TCGA who had RCC was collected and analyzed. Results: Among the 36 pts enrolled, 61% were early-stage group and 39% were advanced-stage group. The most frequently mutated genes in RCC were VHL (50%), PBRM1 (14%), BAP1 (11%), TP53 (11%) and PIK3CA (6%). Truncating mutations were the most frequent alterations accounting for 66% (33/50) of genetic alterations. Mutations in VHL, BAP1, PBRM1 and TP53 were shared by both early and advanced RCC. While mutations in PIK3CA, CDKN2C, EGFR, FAMCA, GRIN2A, KDM6A, SOX17, TSC1 and APC were only detected in early stage group. KNSTRN, KRAS, MYD88, NF2, ATM, PTEN and STAT5B mutations were only detected in advanced group. Among 22 plasma samples, genomic alterations were detected in 40.9% (9/22) of pts postoperatively, such as TP53, PIK3CA, PTEN, and APC. Functional annotation clustering revealed that 4/9 in these genes were tumor suppressors, which negatively regulated apoptosis. Pts with genomic alterations in TP53 (p = 0.0034), PIK3CA (p = 0.0015) or PTEN (p = 0.00017) had worse OS significantly (TCGA). Conclusions: VHL, PBRM1, BAP1 were the most important driver genes mainly detected in all stages of RCC. The heterogeneity between early and advanced-stage may be related with clinical status. Gene alterations in plasma ctDNA postoperatively should have the potential to stratify patients with different prognostic outcome.

Stereotactic radiotherapy for stage I renal cell carcinoma: Overall survival and treatment trends compared to thermal ablation and surgical resection.

e16111 Background: Stereotactic radiotherapy (SRT) is a non-invasive treatment modality that is currently evaluated for use in renal cell cancer (RCC). We aimed to evaluate current utilization of SRT for stage I RCC and compare associated overall survival with thermal ablation (TA) and partial nephrectomy (PN). Methods: The 2004-2015 United States National Cancer Database was searched for histopathologically approved stage I RCC treated with PN, cryoablation (CRA), radiofrequency- or microwave-ablation (RFA/MWA) or SRT. Patients were propensity score matched to account for potential confounders. Overall survival (OS) was evaluated with Kaplan-Meier plots, log-rank tests and Cox proportional hazards models. Results: A total of 91,965 patients were included (SRT n = 174; PN n = 82,913; CRA n = 5,446; RFA/MWA n = 3,432).Stage I SRT patients tended to be older females with fewer comorbidities and treated at non-academic centers in New England states. After propensity score matching, a cohort of n = 660 patients was obtained with well-balanced distribution of confounders between the different treatment strategies. In the matched cohort, OS following SRT was inferior to PN and thermal ablation (PN vs. SRT HR = 0.33, 95% CI: 0.22-0.50, p &lt; 0.001; CRA vs. SRT HR = 0.44, 95% CI: 0.30 – 0.66, p &lt; 0.001; RFA/MWA vs. SRT HR = 0.53, 95% CI: 0.36-0.77, p &lt; 0.001). OS following CRA was comparable to PN (HR = 1.35, 95% CI: 0.84-2.18, p = 0.216), while OS following RFA/MWA was inferior to PN (HR = 1.61, 95% CI: 1.01-2.56, p = 0.046). OS rates are summarized in table 1. Conclusions: Only a minority of RCC patients receive SRT. In stage I RCC, current renal SRT protocols yield lower overall survival compared to thermal ablation and resection, while CRA and PN show comparable outcomes. Based on the current body of evidence, SRT for RCC should be reserved for clinical trials or exceptional clinical circumstances.[Table: see text]

The role of p53 isoforms’ expression and p53 mutation status in renal cell cancer prognosis

ObjectivesTo analyze p53 mutations and gene expression of p53, ∆40p53, and ∆133p53 isoforms in renal cell cancer (RCC) tissues and normal adjacent tissue (NAT) and to associate them to clinical features and outcome. Patients and methodsForty-one randomly selected patients, with primary, previously untreated RCC, with complete clinicopathohistological data were analyzed. NAT samples were available for 37 cases. Expression of p53, ∆40p53 and ∆133p53 was determined using RT-qPCR. A functional yeast-based assay was performed to analyze p53 mutations. ResultsMore than half (56.1%) of patients harbored functional p53 mutations, and they were significantly younger than those with wild type (WT) p53 (P = 0.032). Expression of p53, ∆40p53, and ∆133p53 was upregulated in mutant (MT) p53 RCC compared to WT p53 RCC tissues. However, there was no difference in expression of these isoforms between MT p53 RCC tissues and NAT. Expression of ∆133p53 was significantly downregulated in WT p53 tissues compared to NAT (P = 0.006). Patients that harbored functional p53 mutation had better overall survival (hazard ratio 4.32, 95% confidence interval 1.46–18.82, P = 0.006). Multivariate analysis demonstrated that tumor stage and p53 mutation might be used as independent prognostic marker for overall survival in RCC patients. ConclusionsOur findings support the specific events in the carcinogenesis of RCC. p53 isoforms can be differentially expressed depending on p53 mutational status.

SGK2 promotes renal cancer progression via enhancing ERK 1/2 and AKT phosphorylation.

Increasing studies reported that the serum- and glucocorticoid-inducible kinases (SGKs) contributed to the tumorigenesis of various cancer. In this article, we are aiming to explore the function of SGK2 in renal cell cancer (RCC). In this study, the SGK2 expression was quantified by Western blot (WB) in multiple RCC cell lines. And in vitro SGK2 knockdown and overexpression experiments were also performed. In addition, molecular function analysis was performed using FunRich software V3. The Cancer Genome Atlas (TCGA) database was retrieved to verify the association between the SGK2 expression and the prognosis of RCC patients. We found that SGK2 was up-regulated in RCC tissues compared with adjacent normal tissues, and the SGK2 expression also increased in various RCC cell lines compared to that in the normal epithelial cell line HK-2. Meanwhile, the SGK2 expression was significantly associated with the survival rate of RCC patients. Functional experiments showed that silencing SGK2 expression inhibited RCC cells proliferation, migration, colony formation and invasion abilities in vitro, whereas opposite results were uncovered after overexpressing SGK2 in RCC cells. Furthermore, functional analyses showed that SGK2 related genes were associated with protein serine/threonine kinase activity, guanosine triphosphatase (GTPase) activity, guanyl-nucleotide exchange factor activity, and motor activity. Protein interaction analysis identified that growth factor receptor-bound protein 2 (GRB2), one of the most important upstream components in the growth factor signaling pathway, was significantly enriched in SGK2 related genes. In addition, the WB assay validated that SGK2 could promote the phosphorylation of ERK 1/2 and AKT. Our results suggested that SGK2 promoted RCC progression by mediating the phosphorylation of extracellular regulated protein kinases (ERK) 1/2 and Protein kinase B (AKT/PKB), indicating that SGK2 might serve as a potential prognostic marker and therapeutic target for renal cancer patients.

HSR19-108: A Meta-Analysis of Randomized Controlled Trials (RCTs) for Efficacy and Safety of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors (VEGF-TKIs) Adjuvant Therapy in High-Risk Renal Cell Cancer (RCC)

Background: Four large RCTs (ASSURE, S-TARC, PROTECT, ATLAS) tested adjuvant VEGF-TKI therapy in high risk RCC. The results were variable for efficacy and there were concerns for increased toxicity and decline in quality of life (QoL). We performed an updated meta-analysis including results of ATLAS trial to asses a risk-benefit for adjuvant post-operative treatments in high risk RCC patients by assessing reported disease-free survival (DFS), overall survival (OS), and toxicity endpoints. Methods: Literature search was done using Medline, CENTRAL, and Embase. The DerSimonian and Laird random effects model was used to pool estimates for DFS, OS, and common side effects across the 4 trials. A subgroup analysis was performed for sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q statistic and was quantified with I2 test. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: The 4 RCTs included 4,820 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR=0.916; 95% CI, 0.832–1.009 and OS HR=1.09; 95% CI, 0.886–1.150). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N=1,909; HR=0.90; 95% CI, 0.67–1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR=5.110; 95% CI, 3.765–6.935), diarrhea (RR=10.725; 95% CI, 4.672–24.622), fatigue (RR=3.310; 95% CI, 1.879–5.829), hypertension (RR=4.274; 95% CI, 3.452–5.292) and palmar/plantar dysesthesia (RR=20.53; 95% CI, 9.006–46.801) was observed. There was no statistically significant heterogeneity amongst included trials. QoL endpoints were inconsistently reported. Risk of bias was low. Conclusions: This pooled analysis provides further evidence that there is no OS or DFS benefit associated with adjuvant TKI treatment. There was a significantly increased risk of grade 3 or 4 toxicity in greater than half of the patient population leading to decline in QoL during TKI therapy. Carefully selected very high-risk patients who can tolerate these agents without dose modifications may benefit from adjuvant TKI approach.