bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward a molecular genetic classification of clear cell renal cell carcinoma.
Authors: Brugarolas James , Kapur Payal , Pena-Llopis Samuel , Christie Alana , Xie Xian-Jin
Published: February 2017

341

Background: Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular underpinnings are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC and that BAP1 and PBRM1mutations are largely mutually exclusive. Herein, we investigate the clinicopathological significance of these molecular subtypes. Methods: Tumors from 145 patients with primary ccRCC were sequenced for PBRM1 and BAP1. Tumors were classified into BAP1-mutated and those exclusively mutated for PBRM1. Tumors were evaluated for pathologic features, gene expression and associated outcomes. A second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) was used for validation. Results: When compared to PBRM1-mutant tumors, BAP1-mutant tumors were associated with aggressive pathological features including high Fuhrman grade and tumor necrosis. BAP1-mutant and PBRM1-mutant tumors exhibited distinct gene expression signatures. The median overall survival (OS) was shorter for patients with BAP1-mutant tumors (4.6 years; 95% CI, 2.1-7.2), than for patients with PBRM1-mutant tumors (10.6 years; 95% CI, 9.8-11.5), corresponding to a hazard ratio (HR) of 2.7 (95% CI, 0.99-7.6, p = 0.044). A similar HR was observed in the independent dataset from the TCGA (2.8; 95% CI, 1.4-5.9; p = 0.004). The BAP1-mutant group could be further subdivided into tumors with mutations exclusively in BAP1 and those with mutations in both BAP1 and PBRM1. Double mutant tumors constituted a minority (n = 4; in TCGA), and were associated with the shortest OS (HR, 10; 95% CI, 3.2-33.6). Conclusions: Our findings reveal novel biological subgroups of ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular subclassification of ccRCC that could influence treatment decisions in the future.
Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.
Authors: Choueiri Toni K. , Je Youjin , Sonpavde Guru , Galsky Matt D. , Kaymakcalan Marina , Nguyen Paul Linh , Schutz Fabio , Heng Daniel Yick Chin , Richards Christopher J.
Published: February 2017

347

Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.
Subgroup analyses of a phase III trial comparing tivozanib hydrochloride versus sorafenib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Hutson Thomas E. , Nosov Dmitry , Eisen Timothy , Lipatov Oleg N. , Tomczak Piotr , Alyasova Anna , Harza Mihai , Kogan Mikhail , Alexseev Boris Y. , Szczylik Cezary , Strahs Andrew Louis , Esteves Brooke , Berkenblit Anna , Motzer Robert John
Published: February 2017

354

Background: Tivozanib hydrochloride (T) is a potent, selective, tyrosine kinase inhibitor of all 3 VEGF receptors with a long half-life. T has shown tolerability and has extended progression-free survival (PFS) compared with sorafenib (S; median 11.9 months vs. 9.1 months; p =0.042) in a phase III trial (TIVO-1) as initial targeted therapy for pts with mRCC. We report results of PFS subgroup analyses from TIVO-1. Methods: Pts with clear-cell mRCC, prior nephrectomy, and ≤1 prior treatment for mRCC were randomized to T (n=260) or S (n=257). Cox proportional hazards model was used to evaluate PFS. Results: Significant improvement in PFS by T vs. S was observed for the following prespecified subgroups: white, Eastern Cooperative Oncology Group (ECOG) performance status 0, ≥1 year since diagnosis, no prior treatment, ≥2 metastatic sites, North America/Western Europe, baseline systolic blood pressure (SBP) ≤140 mm Hg, and baseline diastolic BP (DBP) ≤90 mm Hg. Exploratory subgroup analysis showed a similar significant improvement by T vs. S in Memorial Sloan-Kettering Cancer Center (MSKCC) favorable prognostic group, and pts who developed hypertension on study had significantly longer PFS than pts with normal BP. The improvement in PFS by T vs S was more marked for the subgroups that developed hypertension (selected subgroups shown in the table). Conclusions: PFS subgroup analyses showed a consistent advantage with T vs. S for mRCC. Clinical trial information: NCT01030783. [Table: see text]
Validation of a genomic classifier that predicts metastatic disease progression in men with high-risk pathologic features postprostatectomy.
Authors: Ghadessi Mercedeh , Bergstralh Eric J. , Erho Nicholas , Crisan Anamaria , Davicioni Elai , Buerki Christine , Mitra Anirban Pradip , Thompson Darby J. S. , Carlson Rachel , Haddad Zaid , Zimmermann Benedikt , Ballman Karla V. , Kollmeyer Thomas M. , Sierocinski Thomas , Vergara Ismael A. , Triche Timothy J. , Black Peter C. , Thompson R. Houston , Karnes R. Jeffrey , Jenkins Robert B.
Published: February 2017

36

Background: Following radical prostatectomy (RP), 30-40% of patients have adverse pathology and are deemed at high risk for metastatic progression. The objective of this study was to validate the ability of Decipher, a genomic classifier (GC), to improve prediction of metastatic disease progression compared with clinical variables in order to better identify candidates for therapy intensification. Methods: A previously developed 22-feature GC model was validated in a prospectively designed case-cohort study of a clinically high-risk population (i.e., with one or more adverse pathological features) of 1,010 RP patients treated at Mayo Clinic between 2000-2006. A random sample of 20% of the cohort was subjected to microarray analysis and GC scores were generated for 219 patients. The primary endpoint, the c-index for predicting metastatic disease progression (i.e., positive bone or CT scans) was evaluated in a blinded analysis. Cox modeling and decision curve analyses were used to compare the performance of GC to individual clinical variables and prediction models. Results: GC had a c-index 0.79 (95% CI 0.71-0.86) that was significantly better than any single clinical variable. Cumulative incidence curves in the cohort showed that 72% of patients had low GC scores with only 3% and 6% incidence of metastatic disease at 5 and 10 years post RP. In contrast, for the 28% of patients with high GC scores, the cumulative incidence was 17% and 25% at 5 and 10 years post RP. Decision curve analysis showed that the GC model had higher overall net benefit compared to clinical variables over a wide range of ‘decision-to-treat’ thresholds for risk of metastasis. In multivariable modeling with clinicopathologic variables, GC remained the only significant independent predictor of metastasis (HR=1.51, for each 0.1 unit increment, p<0.001). Conclusions: GC can better predict metastatic disease progression compared with clinical variables and may select among patients with adverse pathology a majority that is in fact at low risk for metastasis.
Efficacy and safety data from patients with advanced renal cell cancer treated with tivozanib hydrochloride after progression on sorafenib.
Authors: Motzer Robert John , Nosov Dmitry , Tomczak Piotr , Berkenblit Anna , Esteves Brooke , Strahs Andrew Louis , Hutson Thomas E.
Published: February 2017

364

Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life and has shown superior efficacy, measured as progression-free survival (PFS), as first-line, targeted therapy vs. sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (J Clin Oncol2012;30[suppl]:Abstract 4501). Patients who progressed (PD) on sorafenib could receive tivozanib in an open-label, prospective multicenter extension study of TIVO-1. We report preliminary efficacy and safety data for patients who had PD on sorafenib and subsequently received tivozanib in this extension study. Methods: Patients with PD on sorafenib, per RECIST version 1.0, were eligible to receive tivozanib dosed at 1.5 mg/day PO for 3 weeks followed by a 1-week rest, in repeated 4-week cycles, until PD or unacceptable toxicity. Patients were to have been no more than 4 weeks from last dose of sorafenib until initiation of tivozanib, and have an ECOG performance status of ≤2. Dose adjustments were performed as previously reported. Objectives included assessing objective response rate (ORR), duration of response, PFS for tivozanib following PD on sorafenib, and overall survival. Results: As of January 20, 2012, 127 patients (72.4% male) were evaluable for response. Median age was 59.0 years (range: 23–85 years). ORR was 7.9% (95% CI 3.8–14.0%; partial response [PR]=7.9%; stable disease [SD]=65.4%; PD=18.9%), and 71.3% of patients showed tumor shrinkage. Median duration of PR was 11.1 months (95% CI ≥7.5 months). Median duration of SD was 12.7 months (95% CI ≥7.4 months). Median PFS was 5.6 months (95% CI 5.4–9.1 months). Median OS was not yet reached. Most commonly reported treatment-emergent adverse events (all grades/Grade ≥3) were hypertension (22.4%/10.2%), asthenia (11.0%/3.1%), fatigue (11.0%/3.9%), palmar-plantar erythrodysesthesia (11.0%/1.6%), and diarrhea (10.2%/1.6%). Conclusions: Tivozanib has anti-tumor activity after PD on sorafenib. The adverse-event profile of tivozanib after sorafenib is similar to that observed in TIVO-1. Clinical trial information: NCT01076010.
Ten-year follow-up of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with interferon alfa-2b (IFN) as first-line therapy: Results from a randomized trial.
Authors: Conter Henry Jacob , Wood Christopher G. , Matin Surena F. , Tamboli Pheroze , Millikan Randall E. , Jonasch Eric , Tannir Nizar M.
Published: February 2017

365

Background: We previously reported on improved tolerability and maintained efficacy of low-dose IFN in pts with mRCC treated in the cytokine era (Tannir, et al. Cancer 2006). Although VEGFR targeted agents have supplanted cytokines for most pts, IFN, in combination with bevacizumab, is a standard front-line therapy for good-risk and intermediate-risk clear-cell RCC. Methods: Between March 2002 and December 2003, a total of 118 pts (59/arm) were randomized to receive IFN 0.5 million units (MU) twice/day [IFN1] or 5 MU/day [IFN5]. Patients who were progression-free and tolerating therapy well continued IFN for a total of 5 years. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), overall survival (OS), safety, and quality of life (QOL). Results of PFS, ORR, safety, and QOL were previously reported. We provide here updated OS and long-term outcome of complete responders (CR). Results: At 10 years of follow-up, >95% of participants have died. There was no significant difference in OS between the 2 arms (HR=1.32, 95% CI: 0.91-1.91), but favored IFN1 (median OS 2.1 years vs. 1.5 years, log-rank test p=0.14). Compared with IFN5, IFN1 was less toxic and was associated with better QOL. Two nephrectomised pts, 1 from each arm, 1 with multiple hepatic and lung metastases, and 1 with multiple lung and mediastinal metastases, performance status 1 and intermediate-risk clear-cell RCC, remain in unmaintained CR 10 years since starting IFN. Among pts who did not respond to IFN but remain alive, 1 patient received high-dose IL-2 and achieved durable CR; the other patient received multiple approved and investigational targeted agents sequentially. All responders to IFN had tumor regression as early as 8 wks, with PR or CR declared at 16 wks. Conclusions: IFN produces durable CRs and potential cure in about 2% of mRCC pts. Our data have implications for the front-line therapy of mRCC and suggest that IFN, like high-dose IL-2, can be discontinued after 16 wks, if a major response is not achieved. Our updated results are of interest, considering the paucity of durable CRs to VEGFR agents.
Development and internal validation of a prognostic nomogram for overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib (PAZ).
Authors: Kattan Michael W. , Chakrabarti Debasis , Bhatt Kamalnayan , Mehmud Faisal , Sternberg Cora N. , Motzer Robert John
Published: February 2017

380

Background: PAZ, an oral multikinase inhibitor, demonstrated significant improvement in PFS over placebo in patients with aRCC in a randomized, phase III trial (J Clin Oncol 2009:29; 475). The purpose of this study was to develop and internally validate a prognostic nomogram based on the outcome data from phase III trial for predicting the probability of 12-month OS for treatment-naïve and cytokine-pretreated aRCC patients who received PAZ. Methods: Statistical modeling was performed on a dataset consisting of 281 patients from the PAZ arm of the phase III trial. Missing values were first imputed using multiple imputation with chained equations. A Cox proportional hazards regression model was fit using routinely available predictors thought to be prognostic based on clinical judgment. These predictors included the neutrophil count relative to ULN, platelet count relative to ULN, LDH relative to ULN, alkaline phosphatase relative to ULN, corrected calcium, albumin, hemoglobin, ECOG performance status, months from diagnosis to treatment, number of metastatic sites, and presence of lung, liver and bone metastases. Bootstrap-corrected estimates of discrimination and calibration in the small were calculated following 1,000 resamples. The Cox model was plotted as a nomogram. Results: A prognostic nomogram was developed and internally validated for predicting the probability of 12-month OS in aRCC patients based on a Cox regression model using 13 predictor variables. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of OS. The bootstrap-corrected concordance index, a measure of discrimination, was 0.70. When examining the nomogram, albumin appeared to have the greatest potential influence on predicted OS. Months from diagnosis to treatment and corrected calcium level seemed to be the next most potentially influential predictors. Conclusions: The nomogram predicts with reasonable accuracy and should facilitate treatment decision making for patients with advanced renal cell carcinoma. Validation in a separate dataset is planned.
Effect of targeted therapy on rapid progression and early death in renal cell carcinoma.
Authors: Wu Shenhong
Published: February 2017

389

Background: Several targeted therapeutic agents have been approved for the treatment of advanced renal cell carcinoma (RCC) due to their efficacy in overall patient population. However, their effects have not been defined in patients with rapid progressive cancer, which is characterized by progression within three months and associated with poor prognosis. Therefore, we conducted a systematic review and meta-analysis of published randomized controlled clinical trials (RCTs) to assess the effect of targeted therapy on rapid progressive RCC. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October, 2012, were searched to identify relevant studies. Rapid progression was defined as progressive disease or death at three months after the initiation of clinical trial. Eligible studies included prospective RCTs in which a targeted therapy was compared to a control in RCC patients. Summary incidence of rapid progression or death, relative risk (RR), and 95% confidence interval (CI) were calculated based on the heterogeneity of included studies. Results: A total of 4,628 patients (targeted therapy: 2,461, control: 2,167) with RCC from 10 RCTs were included for analysis. The overall incidence of cancer rapid progression with the targeted therapy was 23.6% (95% CI: 19.2-28.6%). When compared to controls including interferon or placebo, the targeted therapy significantly reduced the overall risk of rapid progression (23.6% vs. 54.5%; overall RR=0.46, 95% CI: 0.38-0.54, p<0.001; versus IFN: RR=0.55, versus placebo: RR=0.38). The effect varied significantly among different agents (p<0.001), with the highest reduction seen in patients treated with pazopanib (RR=0.27; 95% CI: 0.21-0.35). There was no significant difference between mTOR and VEGF inhibitors (p=0.25). In addition, the targeted therapy significantly reduced the risk of mortality at 3 months (5.5% vs. 10.0%; RR=0.58, 95% CI: 0.41-0.81; p=0.002). Conclusions: The targeted therapeutic agents may significantly reduce the risk of rapid progression and early death in patients with renal cell cancer.
Analysis of molecular profiling of renal cell carcinoma: Identification of a 4-microRNA signature as a prognostic value in patients with stage I-II disease.
Authors: Castellano Daniel E. , Farfán Carlos A. , Angelo Gamez , Sepúlveda Juan M. , De Velasco Guillermo , Villacampa Felipe , Tejido Angel , Dominguez Mario , de la Rosa Federico , Fresno Juan A.
Published: February 2017

395

Background: Renal-cell carcinoma (RCC) accounts for 3% of all cancers and produces over 12,000 deaths every year in the EE.UU. Currently, there is a need to identify stage I/II RCC patients with high risk of relapse following nephrectomy, given that these patients do not receive adjuvant treatment and ≈ 25% of them relapse. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNA and playing an important role as regulators of gene expression during tumorigenesis. Our willing is to define a miRNA expression profile associated with a high risk of relapse in early RCC. Methods: We analyzed 113 pts. with RCC stage I-II of a local data-base who had undergone nephrectomy from 2000 to 2008. RNA was extracted from FFPE samples using RecoverAll (Ambion). RNA samples were hybridized to Human miRNA Microarray Release 14.0, 8x15K (Agilent Technologies. Data were normalized using Quantile Normalization. Only 396 miRNAs with detectable signal in at least 10% of the hybridized samples were considered for further analysis. Identification of miRNAs related with recurrence risk and subsequent developing and validation of miRNA expression-based prediction models of recurrence risk were performed in BRB-ArrayTools v4.2.1. Results: We identified a 4-miRNA expression signature that distinguishes early stage RCC patients with low and high recurrence risk (p value = 0.0013; HR = 4.68 [1.82-12.0]). Distant recurrence free survival rate at five years was 97.4 and 81.2 for the low and high recurrence risk groups respectively. High levels of miR-424 were related with a high recurrence risk (p = 0.023). Conclusions: The TNM staging system lacks accuracy to identify prognostic markers of survival in early RCC. Our results suggest that specific miRNAs are involved in the recurrence of early disease. We have found a miRNA expression signature that identifies patients with high risk of developing distant metastasis using the FFPE sample of primary tumors. High expression levels of miR-424 were related with a high recurrence risk. MiR-424 is a hypoxia induced miRNA whose expression has been related with HIF-1α and HIF-2α stabilization and angiogenesis induction.
Metabolic complications with the use of mTOR inhibitors for cancer therapy: A systematic review and meta-analysis.
Authors: Sivendran Shanthi , Ying Jian , Gartrell Benjamin Adam , Agarwal Neeraj , Boucher Kenneth M. , Choueiri Toni K. , Sonpavde Guru , Oh William K. , Galsky Matt D.
Published: February 2017

398

Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). The risk of metabolic complications with these agents is not well characterized. Methods: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. 16 eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia were extracted. Incidence rates and incident rate ratios were calculated. Results: In total, 24 trials (including 4,261 patients) were included. The average incidence rate of any grade metabolic adverse events and grade 3-4 metabolic adverse events was 0.70 per patient and 0.11 (95% CI, 0.08, 0.15) per patient respectively. Analysis of the 3,317 patients across 8 RCT’s revealed that the log incidence rate ratio (IRR) of any grade metabolic adverse events with mTOR inhibitor therapy compared with control was 1.08 (95% CI, 0.84, 1.31) using a random-effects model. The risk of grade 3-4 adverse events was also increased with an IRR of 1.52 (95% CI, 1.05, 1.99). The IRR of all grade hyperglycemia was 1.08 (95% CI, 0.76, 1.40) and of grade 3-4 hyperglycemia was 1.66 (95% CI, 1.12, 2.20). The IRR of all grade hypertriglyceridemia was 0.91 (95% CI, 0.56, 1.26) and of grade 3-4 hypertriglyceridemia was 0.70 (95% CI,- 0.43, 1.83). The IRR of all grade hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65) and of grade 3-4 hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. Conclusions: The risk of all grade and grade 3-4 metabolic adverse events are increased in patients treated with mTOR inhibitors compared with control. However, grade 3-4 metabolic adverse events remain relatively uncommon.
Changes in circulating tumor cells (CTC) and markers of inflammation after sipuleucel-T treatment.
Authors: Hepgur Mehmet , Dorff Tanya B. , Cai Jie , Pinski Jacek K. , Reed Mary , Luther Michael , Chan Betty , Quinn David I.
Published: February 2017

40

Background: Sipuleucel-T (SipT) prolongs survival of men with metastatic castrate-resistant prostate cancer (CRPC). We prospectively collected CTC, LDH, and inflammatory markers as part of an audit to investigate changes after SipT treatment compared to baseline. Methods: Men with CRPC had blood drawn routinely before and after SipT treatment. CTC were run using Veridex assay. LDH, C-reactive protein (CRP) and β2-microglobulin (β2m) were measured in a reference lab. Wilcoxon Signed Rank Test was used to compare pre- and post-treatment (median 3.5 weeks after final infusion) levels. Results: 61 men received SipT at USC from June 2010 to July 2012 and were included in the analysis. Median pre-SipT PSA level was 24.9 and 47% had Gleason 8-9; 20% had received chemotherapy. 18 men had detectable CTCs pre SipT (range 1-170). CTC count declined in 7 men, increased in 6 men, and stayed stable in 2 men (3 inevaluable); in 3 cases the change crossed men over from unfavorable ( >5) to favorable count. PSA declines were noted in 10 men (16.4%) ranging from -0.5% to 99%. Change in CTC and PSA was discordant in 4 cases of 13. When CTC stayed stable PSA increased in 5 and decreased in 5 cases. Median CRP was 0.5 pre and 0.23 post SipT (p=0.025) and β2m was 1.74 pre and 2.01 post (p=0.02). Increased CRP was correlated with decreased CTC (r=0.7, p=0.003 Spearman test) but β2m changes were not (r=0.45, p=0.08 Spearman) and there was no correlation between changes in the inflammation markers and PSA decline. LDH did not change significantly. The relationship between infusion reaction, eosinophilia and inflammatory markers will be presented. Conclusions: We found that CTC counts can decline after SipT treatment, including conversion from unfavorable to favorable range, and can change independently of PSA. Correlation of CTCs with outcomes in a prospective study is warranted to explore this as a potential biomarker. [Table: see text]
Plasma MN (carbonic anhydrase IX) and outcome in sunitinib-treated metastatic renal cell cancer.
Authors: Lamparella Nicholas E. , Ali Suhail M. , Leitzel Kim , Carney Walter P. , Lipton Allan
Published: February 2017

405

Background: The transmembrane protein MN (carbonic anhydrase IX)(CAIX) catalyzes the hydration of carbon dioxide to carbonic acid and decreases pH. In cancer, up-regulation of CAIX gene expression occurs under hypoxic conditions within tumors. Significant levels of CAIX protein have been detected in a variety of cancers including kidney, cervix, lung, bladder, colon, breast, liver, gall bladder, and pancreas. Methods: Pretreatment plasma CAIX and VEGF-A levels were determined from 52 metastatic renal cell cancer patients enrolled in a phase III first-line trial of sunitinib vs. interferon alpha (IF). The CAIX and VEGF-A ELISAs (WILEX/Oncogene Science, Cambridge MA) were used for determination of plasma biomarker levels. 51 of 52 patients had an MSKCC score of 0 or 1. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with both continuous and dichotomous (median) plasma CAIX and VEGF levels. Results: Pretreatment plasma CAIX levels averaged 371 pg/ml, with a median of 194 pg/ml and 25th and 75th percentile values of 125 and 298 pg/ml, respectively. In the whole population, higher plasma CAIX was significant on a continuous basis for predicting reduced PFS (p < 0.007) and shorter OS (p <0.0001). When analyzed using the median as cutpoint, the elevated plasma CAIX cohort trended for reduced PFS (p = 0. 13) and had a significantly reduced OS (HR 2.77, p = 0.026) (median 94 vs. 115 weeks). In univariate analysis plasma VEGF-A did not predict for PFS or OS when analyzed as a continuous or dichotomous variable. In multivariate analysis for PFS (including treatment arm, CAIX, and MSKCC score), treatment with sunitinib (vs. IF) (p = 0.006) and lower plasma CAIX (p = 0.04) resulted in a significantly longer PFS. In multivariate analysis for OS, again treatment with sunitinib (vs. IF) (p=0.037), and lower plasma CAIX (p < 0.0001) resulted in a significantly longer OS. Conclusions: Elevated pretreatment plasma CAIX predicted for reduced PFS and overall survival in metastatic renal cancer patients. In addition, sunitinib was superior to interferon, regardless of plasma CAIX status.
Discovery and validation of the nuclear export protein CRM1 (XPO1) as a new target for the treatment of renal cell carcinoma (RCC).
Authors: Wettersten Hiromi Inoue , Kauffman Michael , Shacham Sharon , Landesman Yosef , Yang Joy , Evans Christopher , Weiss Robert
Published: February 2017

411

Background: The currently available targeted therapies for RCC have had limited success, so it is imperative to discover new therapeutic approaches for metastatic RCC. In a search for new such targets, we have identified inhibitors of CRM1 (XPO1, exportin1), the major karyopherin that mediates the export of most tumor suppressor proteins from the nucleus. To expand our initial work on the first generation of CRM1 inhibitors, we now evaluate KPT-330, an orally available Selective Inhibitor of Nuclear Export (SINE), the best tolerated among a series of CRM1 inhibitors that is currently in phase I clinical trials. Methods: The RCC cell lines (Caki-1 and 786-O) and a primary normal human kidney (NHK) cell line were treated with KPT-330, and MTT assays were performed. The cells were subjected to immunofluorescence and immunoblotting for appropriate proteins. Caki-1 xenograft mice were treated with KPT-330 for 15 days, and tumor volume was assessed. Results: KPT-330 selectively attenuated CRM1 levels and caused dose-dependent toxicity (EC50 < 1 µM) through apoptosis in all RCC cells. In untreated RCC cells, p21 was localized in the nucleus, where it likely functions as a cell cycle arrest protein, and in the cytosol, where it functions as an anti-apoptotic protein. However, in NHK cells, p21 was confined to the nucleus. KPT-330 increased p53 and p21 and confined them to the nucleus in both NHK and RCC cells. KPT-330 given orally inhibited RCC growth in xenograft mice (85.3 % inhibition, p < 0.001). Moreover, KPT-330 showed synergism with a Bcl-2 inhibitor ABT-737 in vitro, indicating the potential for combination therapy with a CRM1 inhibitor and Bcl-2 inhibitor. In vivo studies to test the combination of KPT-330 with Bcl-2 inhibitors are ongoing. Conclusions: We introduce a new therapeutic approach for RCC treatment based on the inhibition of the nuclear export of key tumor suppressors. Inhibition of CRM1 causes forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.
Effect of PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, on proliferation in renal cell carcinoma at nanomolar concentrations and prediction of sensitivity by molecular markers.
Authors: Logan Joshua E. , Mostofizadeh Nikayeh , Desai Amrita J. , Von Euw Erika Maria , Conklin Dylan , Konkatkit Veerauo , Hamidi Habib , Eckardt Mark A. , Anderson Lee , Cheng Hsiao-Wang , Ginther Charles , Taschereau Eileen , Christensen James G. , Belldegrun Arie S. , Slamon Dennis J. , Kabbinavar Fairooz F.
Published: February 2017

413

Background: Cell cycle dysregulation is prevalent in renal cell carcinoma (RCC). PD-0332991 is an orally active, potent, and selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, blocking retinoblastoma (Rb) phosphorylation at nanomolar concentrations. Methods: 28 RCC and immortalized kidney cell lines were used to examine the effects of PD-0332991 on proliferation to determine the half maximal inhibitory concentration (IC50). Effects of PD-0332991 on cell-cycle, apoptosis, and Rb phosphorylation were assessed with flow cytometry and western blot analysis for five of the cell lines: RCC-HB and SW 156 (sensitive/malignant), R444 and Hs 891.T (resistant/malignant), and CCD 1103 (resistant/immortalized non-malignant). Molecular markers for response prediction were studied using array CGH and gene expression profiling. Results: Concentration-dependent inhibition of proliferation was identified in response to PD-0332991, with IC50values ranging from 25.0nM up to 700nM; five cell lines were identified as completely resistant at 1000nM. PD-0332991 induced G0/G1 cell cycle arrest, as well as induction of late apoptosis in SW 156, and Rb phosphorylation was blocked in a time-dependent fashion in both sensitive cell lines, while resistant lines were unaffected. Genotype and expression data of CDKN2A and CDKN2B were combined and a consensus was made regarding p16 and p15 status; significant association between loss and sensitivity to PD-0332991 was identified for p16 (p = 0.027). For CCND1, CCNE1, E2F1, Rb, CDK4, and CDK6 no amplifications or homozygous deletions were identified by array CGH; cell lines were then classified as having high or low expression for each of these markers. E2F1 had low expression levels significantly associated with response to PD-0332991 (p = 0.041). Conclusions: PD-0332991 shows anti-proliferative activity in RCC through blockade of the cell cycle. The decreased expression of molecular markers p16 and E2F1 predict for sensitivity to PD-0332991 in RCC.
CpG island hypermethylation of corticotropin-releasing hormone-binding protein in kidney cancer and association with clinicopathological parameters.
Authors: Tezval Hossein , Atschekzei Faranaz , Dubrowinskaja Natalia , Merseburger Axel S. , Peters Inga , Becker Jan , Bedke Jens , Kruck Stephan , Stenzl Arnulf , Kuczyk Markus A. , Serth Juergen
Published: February 2017

414

Background: Significance of Urocortin (Ucn or UcnI), Ucn2, Ucn3, and their receptors, Corticotropin Releasing Factor Receptor 1 and 2 (CRFR1 and CRFR2), and the binding protein, Corticotropin-Releasing Hormone-Binding Protein (CRHBP) in oncology is growing rapidly. Recently we found that the UCN system may also be a relevant structure in renal cell cancer. Here we investigate whether CRHBP CGI methylation occurs in cc-RCC and whether its methylation is associated with clinicopathological parameters of patients. Methods: Tumoral tissues of 109 patients with renal cell cancer and their corresponding normal tissues have been used. Combined bisulfite restriction analysis (COBRA) for detection of relative degree of CpG island (CGI) methylation and pyrosequencing have been performed. Results: We found an approximately five-fold increase in mean methylation of the CRHBP CGI for tumor tissues (p < 0.00005). Higher DNA methylation of the CRHBP CGI showed a positive correlation with advanced disease as well (p = 0.024). Conclusions: To our knowledge we report for the first time the CGI methylation of CRHBP in clear cell renal cell carcinoma indicating a contribution of epigenetic alteration of CRHBP to RCC tumorigenesis. Moreover, our results suggest CRHBP as a potential molecular marker for assessment of progression and aggressiveness of tumors.
Interstitial lung diseases during treatment with sunitinib or mTOR inhibitors in metastatic renal cell carcinoma.
Authors: Ivanyi Philipp , Fuehner Thomas , Adam Meike , Eichelberg Christian , Herrmann Edwin , Merseburger Axel S. , Grünwald Viktor
Published: February 2017

420

Background: Targeted therapies are the mainstay for metastatic renal cell carcinoma (mRCC) treatment. Interstitial lung disease (ILD) represents an adverse event (AE) of such therapies while its incidence and management is poorly defined. Here, the experience on ILD with targeted agents in mRCC is reported. Methods: Retrospective analysis of mRCC patients receiving sunitinib, everolimus, or temsirolimus at three German tertiary centers between January 2006 and August 2009 was performed, accessing ILD incidence, management, and outcomes. Results: In total 26 ILD patients were identified out of 306 mRCC patients (8.5%) treated with targeted therapies. Median treatment duration to ILD diagnosis was 3.8 (range 0.98-21.5) months. ILD occurred in 6 of 204 sunitinib treated patients (2.9%), and in 20 of 102 mTOR inhibitor (mTORi) treated patients (19.6%). Cough represents the predominant symptom (69.2%, n=18). Chest CTs revealed 4 patterns: interstitial (n=13), nodular (n=3), ground glass opacities (n=8), or complex patterns (n=2). Pulmonary function tests (PFT) illustrates frequently a restrictive disorder (n=9), often accompanied by a diminished diffusion capacity (n=8). In 53.8% (n=14) a bronchoscopy with broncho-alveolar-lavage (BAL) was performed (lymphocytic cellularity n=6, eosinophilic cellularity n=4). Dose reduction (42.3%, n=11), temporary interruption (46.2%, n=12), or treatment withdrawal (53.8%, n=14) occurred frequently. Nine patients (34.6%) received steroids. Continuation of targeted therapies was maintained in 65.4% (n=17). No patient died from ILD. Conclusions: ILD represents a frequent AE with targeted therapies and also occurs in sunitinib treated patients. For diagnosis of ILD chest CTs are mandatory, whereas PFT and BALs are important subsidiary tools. Clinical relevance of ILD may vary and management of ILD ranges from watch and wait to termination of treatment and steroid pulse therapy. Severe complaints were more frequently associated with eosinophilic BAL, often required an aggressive treatment. However, in most patients, temporary interruption and/or dose reduction with subsequent continuation of targeted therapy remain sufficient to manage ILD.
Incidence and outcome of interstitial lung disease (ILD) with everolimus treatment for metastatic renal cell carcinoma.
Authors: Hongo Fumiya , Oishi Masakatsu , Ueda Takashi , Kimura Yasunori , Nakamura Terukazu , Naya Yoshio , Mikami Kazuya , Miki Tsuneharu
Published: February 2017

427

Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p < 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.
Immune cell repertoire in patients with indolent metastatic renal cell carcinoma.
Authors: Zhu Hui , Rayman Pat A. , Elson Paul , Rapp Sarah , Garcia Jorge A. , Dreicer Robert , Gilligan Timothy D. , Shepard Dale Randall , Finke James , Rini Brian I.
Published: February 2017

429

Background: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely influences tumor progression. An ongoing prospective trial of observation in metastatic RCC patients prior to systemic therapy is investigating circulating immune cell populations. Methods: Asymptomatic patients with low volume metastatic disease are enrolled and followed until starting initial systemic treatment. Peripheral blood specimens are collected at the time of enrollment and again at the time of initiating therapy. The immune parameters measured include CD3+ and CD4+ INF-γ producing T cells (INF-γ+ T), CD4+CD25+FoxP3+ regulatory T-cells (Treg), and CD33+HLADr-CD15+CD14- neutrophilicmyeloid-derived suppressor cells (N-MDSC). Similar immune parameters were recorded for treatment-naïve patients prior to immediate systemic therapy and healthy volunteers on separate IRB-approved protocols. Results: 25 patients are enrolled in the study, of whom 14 started systemic therapy and had immune function analyzed for this report. Patient characteristics included 100% male, median age 74. 13 patients were favorable or intermediate risk by both MSKCC and Heng prognostic criteria; one patient was poor-risk. The median observation period was 13.9 months. The median tumor burden at the time of enrollment was 3.6 cm, which increased 38% during the observation period. As shown in the table below, the observation group had lower levels of Tregand N-MDSC, and higher levels of INF-γ+ T compared to the treatment group. In contrast, the observation group’s INF-γ+ T was similar to that of controls although N-MDSC was elevated. Conclusions: Metastatic RCC patients with indolent disease have low levels of Tregand N-MDSC, and a relatively preserved immune cell repertoire compared to patients requiring immediate therapy. [Table: see text]
The molecular relationship among concurrent prostate cancer foci.
Authors: VanderWeele David James , Taxy Jerome B. , Stadler Walter Michael , White Kevin P.
Published: February 2017

43

Background: Prostate cancer management is influenced by how one views prostate cancer progression and how one calculates the risk of prostate cancer metastases and death. Currently this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. NCCN guidelines endorse surveillance for many of these tumors. Malignancies with a Gleason score of 8-10 exhibit aggressive behavior and are considered high risk. Methods: Prostate cancer is usually multifocal, and these concurrent foci are often histologically distinct. In this study the molecular relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects. In two subjects a lymph node metastasis was also examined. Laser capture microdissection was used to isolate these multiple matched foci, and somatic mutations were identified using exome sequencing. Results: We obtained an average of 40-fold median coverage of the exome, with an average high confidence mutation rate of 0.64/Mb, excluding nonsynonymous mutations. Seventy of 80 (0.875) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 17 of 79 (0.215) high confidence somatic mutations in the high grade focus were private. Eight of the 79 (0.101) were shared with low grade foci, and 62 (0.785) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations was consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.
Progression-free survival (PFS) and overall survival (OS) in patients receiving three targeted therapies (TTs) for metastatic renal cell carcinoma (mRCC).
Authors: Verzoni Elena , Iacovelli Roberto , Rizzo Mimma , Felici Alessandra , Cascinu Stefano , Di Lorenzo Giuseppe , Cerbone Linda , Ortega Cinzia , Masini Cristina , Giganti Maria Olga , Lorusso Vito , Messina Caterina , Atzori Francesco , De Vincenzo Fabio , Sacco Cosimo , Boccardo Francesco , Valduga Francesco , Massari Francesco , Tassi Renato , Procopio Giuseppe
Published: February 2017

431

Background: In recent years, TTs have improved the prognosis of mRCC patients (pts). Despite a non-negligible number of pts received 3 TTs in clinical practice, no TTs have been evaluated as third-line. Aim of this study is to investigate the clinical outcome in pts who received 3 TTs. Methods: Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was sent to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type and length of first-, second- and third-line were collected; MSKCC risk class was calculated before starting the first-line. Sequences were evaluated by class (TKI-TKI-mTOR vs. TKI-mTOR-TKI) or by drug (Su-So-Ev vs. Su-Ev-So). Median PFS, OS and Time to Strategy Failure (TTSF: from start of first- to end of thrid-line) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. Cox model was used to explore predictors of TTSF and OS. The study had the ethical approval. Results: 2,065 pts were screened and 281 pts (13%) were treated with 3 TTs. No differences were found between TKI-TKI-mTOR and TKI-mTOR-TKI groups. The TTSF was 36.5 (30.5–42.6) mos vs. 29.3 (23.6–34.9) mos (p=0.059), and the OS was 50.7 (40.6–60.8) vs. 37.8 (34.2–41.5) mos (p=0.004), for TKI-TKI-mTOR and and TKI-mTOR-TKI, respectively. TTSF for Su-So-Ev was 32.1 vs. 30.4 mos for Su-Ev-So (p=0.006). The median OS was not reached in the group treated with Su-So-Ev compared to 35.6 (95%CI, 31.6–39.6) mos in the group treated with Su-Ev-So (p<0.001). The univariate and multivariable Cox analyses for TTSF and OS showed that the only predictive factor is the primary resistance to 1st line (HR: 3.15, 95%CI, 1.98-4.99; p<0.001). The Prognostic factors are the initial MSKCC group (HR: 2.07, 95% CI, 1.41 -3.05; p<0.001), the sequence of therapy (HR: 2.59, 95% CI, 1.59-4.22; p<0.001) and the primary resistance to first line (HR: 2.20, 95% CI, 1.16-4.11; p<0.001). Conclusions: We report as the sequential treatment with two antiangiogenic inhibitors followed by an mTOR inhibitor could increase survival and the control disease in metastatic renal cell carcinoma.
Outcome of active surveillance prior to systemic target therapy in patients with metastatic renal cell carcinoma.
Authors: Matsubara Nobuaki , Mukai Hirofumi , Naito Yoichi , Itoh Kuniaki
Published: February 2017

444

Background: The clinical course of metastatic renal cell carcinoma (mRCC) has a wide spectrum that ranges from indolent to rapidly progressive disease. Initial active surveillance (AS) followed by deferred systemic target therapy might be a treatment option in a subpopulation of patients with indolent mRCC. However, very few studies have been published about AS and its outcome as well as potential predictive factor that might be associated with indolent mRCC. Here, we report clinical outcomes of mRCC patients who initially were monitored by AS. Methods: We retrospectively reviewed and analyzed the clinical and pathological data of mRCC patients who initially were monitored by planned AS prior to systemic therapy due to asymptomatic or slowly progressive disease at National Cancer Center Hospital East between 2000 and 2011. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Results: A total of 29 patients were eligible for this analysis. The median age at diagnosis was 69 years, and all patients had a good general condition with a performance status of 0 or 1. A total of 65% of patients had recurrent disease and 35% were in stage 4. All of the patients had undergone nephrectomy, and 86% had clear cell carcinoma. None of the patients was categorized into a poor risk group according to both MSKCC and Heng criteria. The median follow-up period was 35.4 months. During the follow-up period, disease progression was observed in 72% of patients but only 14% died. The median PFS time was 26.1 months. After disease progression was observed, only 58% of these patients received treatment or intervention. The median OS have not been reached yet, but 12, 24 and 48 months OS rates were 96.4, 88.7 and 83.8%, respectively. Conclusions: PFS and OS of patients who underwent AS were extremely favorable. For these indolent subpopulations, AS might be a treatment option, so toxic and expensive systemic target therapy could be deferred for a significant period of time without prognostic disadvantage. However, further observational study with a larger sample size might be needed in order to identify the exact subpopulation eligible for AS.