bluuebunny/crossref_metadata_2025 huggingface dataset:
SPAZO2 (SOGUG): Outcomes of patients treated with pazopanib as first line in mRC according to gender in real world.
Authors: Maximiano Constanza , Puertas Alvarez Javier Luis , Maroto Rey Jose Pablo , Pinto Alvaro , Miranda Pallares Maria Jose , Suarez Cristina , Climent Miguel A. , Garcia Carbonero Iciar , Guzman Jose Carlos Villa , Borrega Pablo , De Velasco Guillermo , Fernandez Parra Eva , Crespo Guillermo , García Domínguez Rocío , Gallardo Diaz Enrique , Meana Garcia Andres , Garcia Marrero Rosa , Gonzalez Larriba Jose Luis , Perez Ramirez Sara , Arranz Arija Jose Angel
Published: February 2018

623

Background: Treatment of mRC is not affected by gender, studying possible differences in a real-world study, could increase the knowledge of toxicity and possible prognostic factors. Methods: SPAZO2 (NCT03091465) was a retrospective real-world study to analyze the effectiveness of 1st-line pazopanib and subsequent therapies in mRC. Data from 530 pt treated outside CT were collected in 50 spanish centers, and externally monitored. Ineligibility criteria: ECOG > 1, pure nonclear-cell, Hgb < 9 g/dl, renal failure, severe cardiovascular disease, chronic liver disease, or recent neoplasia Results: 530 pt were included, 67.2% men (M), mean age was 66.2 years (26-92). There were no significant differences (M vs W) in the age > 75 (24.7 vs 24.1%), clear cell carcinoma (77.2 vs 79.9%), nephrectomy (72.5 vs 68.4%), IMDC (favourable: 15.2 vs 12.1%, intermediate: 59.3 vs 64.4%, poor: 25.6 vs 23.6%), metastases (lymph nodes: 46.1 vs 43.1%, lung: 69,7 vs 67,2 %, liver: 16 vs 20.1%, bone: 27 vs 24.1%, skin/soft tissues: 1.1 vs 3,4% and CNS: 4,8% vs 6.3%). Discontinuation due to toxicity or comorbidities was 12.4 vs 9.8%. There were no differences in the second lines received (57.9 vs 56.9%), neither response, PFS and OS (table). Median follow up was 39 mo. The gender has no prognostic value when adjusted for the prognostic groups of IMDC (HR of PFS 0.96, CI 95% 0.78-1.2, HR of OS: 0.92, CI 95% 0.72-1.14). Only diarrhea and elevation of uric acid were higher in the men group. Conclusions: Pazopanib was safe and effective in both groups with similar outcome. Women had less diarrhea and less increased uric acid. There were not differences in OS or PFS. In IMDC subgroup analysis, there is a trend towards a better evolution or PFS in the poor prognosis women subgroup. Clinical trial information: NCT03091465. [Table: see text]
High dose interleukin-2 and response in 944 patients with metastatic renal cell cancer (RCC): Data from the PROCLAIM registry.
Authors: Dorff Tanya B. , Wong Michael K.K. , Clark Joseph , Daniels Gregory A. , Curti Brendan D. , Morse Michael , Kaufman Howard , McDermott David F. , Quinn David I. , Zang Peter , Gregory Nancy C. , Eifler Lisa Maria , Thomas Stephen , White Marci , Singh Jatinder , Dutcher Janice P.
Published: February 2018

624

Background: High dose interleukin-2 (HD IL2) has traditionally been dosed every 8 hours for a maximum of 14 doses each cycle. We evaluated whether alternate dosing schedules and dose intensity affected achievement of complete response (CR) or partial response (PR) in the PROCLAIM registry. Methods: Patients with metastatic RCC were enrolled retrospectively and prospectively into the PROCLAIM registry to collect outcome data. Statistical methods for comparisons were done using Fisher’s and Chi Square tests. Results: From 2006-2017 the registry included 944 RCC patients; 257 (27%) women, 676 (72%) men. 844 (89%) were white. Histologic distribution: 624 (66%) clear cell, 93 (10%) medullary, 79 (8%) collecting duct, 78 (8%) chromophobe and 70 (7%) papillary. 207 (22%) had prior therapy with VEGF/mTOR. Best response was 51 (5.4%) CR and 169 (17.9%) PR; 263 (28%) progressive disease. 13 (1.4%) patients received q12 hour dosing while 830 (88%) received q8 hour dosing. 608 (64%) received 600 KIU/kg and 67 (7%) received 720 KIU/kg. Median # of doses in cycle 1 was 10 for CR and PR patients at 600 KIU/kg and 9 for those with stable or progressive disease. In the 720 KIU/kg group median #doses was 11 for CR, 8 for PR, and 7 for stable or progressive disease. In cycle 2 median doses received was 7.16 for patients with CR, 7.02 for PR and 6.76 for stable disease. Median dose intensity is similar at these two dose levels. Associations with achievement of CR/PR are summarized in the Table. Conclusions: There is no difference in response rate based on dosing schedule but the small number of subjects dosed q12 hours limits interpretation. Good performance patients possess the best opportunity for benefit from HD IL2. There is a trend for response with higher median # doses. Further studies of alternate dosing schedules are warranted. Clinical trial information: NCT01415167. [Table: see text]
Pharmacogenetic-based area-under-curve model to predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma.
Authors: Yamamoto Yoshiaki , Tsunedomi Ryouichi , Kawai Yoshihisa , Matsumoto Hiroaki , Hazama Shoichi , Nagano Hiroaki , Matsuyama Hideyasu
Published: February 2018

625

Background: Although titrated-dose axitinib offers a good objective response rate (ORR) for metastatic renal cell carcinoma (RCC), its optimal initial dose is unclear because its dosing regimen is based on a hypertensive reaction. We investigated whether axitinib pharmacogenetics were related to clinical efficacy/adverse events, and calculated a model to predict clinical efficacy and adverse events, using pharmacokinetic data based on gene polymorphisms in a phase 2 trial. Methods: We prospectively evaluated objective response and adverse events to establish a prediction model in 44 consecutive patients with advanced RCC, treated with axitinib between October 2013 and March 2017. Gene polymorphisms, including ABC transporters ( BCRP and MDR1) and UGT1A were analyzed by whole-exome sequencing, Sanger sequencing, and DNA chips. To construct the prediction model for area under curve (AUC), we used an exponential regression model with gene polymorphisms and dosage as covariates. To further validate this prediction model, we prospectively compared the calculated AUC in this model with actual AUCs in 13 additional consecutive patients. Results: Actual AUC was significantly correlated with the best ORR ( P = 0.0002), and adverse events (grade 2–3 hand–foot syndrome [ P = 0.0055]; grade 2 hypothyroidism [ P = 0.0381]); it was also significantly correlated with calculated AUC ( P < 0.0001). Calculated AUC was also significantly associated with best ORR ( P = 0.0044), grade 2–3 hand–foot syndrome ( P = 0.0191) and grade 2 hypothyroidism ( P = 0.0082). Surprisingly, hypertension was associated with neither ORR nor AUC. In the validation study, calculated AUC before axitinib treatment precisely predicted actual AUC ( P = 0.0079) in 13 additional consecutive patients. Conclusions: Our pharmacogenetics-based AUC model may offer a more benign method to determine optimal initial axitinib doses than hypertension, and could contribute to more precise treatment of individuals with advanced RCC. Clinical trial information: UMIN000011147.
Genomic alterations to refine prognostication of patients with metastatic renal cell carcinoma.
Authors: Bosse Dominick , Xie Wanling , Lalani Aly-Khan A. , de Velasco Guillermo , Voss Martin Henner , Tannir Nizar M. , Tamboli Pheroze , Appleman Leonard Joseph , Rathmell Kimryn , Heng Daniel Yick Chin , Sonpavde Guru , Signoretti Sabina , Hakimi A. Ari , Choueiri Toni K.
Published: February 2018

626

Background: The IMDC risk score is a valid and simple tool to prognosticate patients (pts) with metastatic renal cell carcinoma (mRCC). Some non-VHL common genomic alterations may be associated with outcomes. We therefore assessed the prognostic value of most commonly mutated genes in mRCC beside VHL overall, and within IMDC risk groups. Methods: We identified patients treated at Dana-Farber Cancer Institute (n = 65) or part of TCGA (n = 33) who had genomic data available and were treated with first line vascular endothelial growth factor tyrosine kinase inhibitors. Information on genomic alterations (GA) focused on PBRM1, BAP1, SETD2, KDM5C and TP53 was extracted. Cox regression was performed to assess the association of each GA with overall survival (OS), adjusting for IMDC risk groups and age. Results: Overall, 98 pts were identified. 96/98 pts had clear-cell histology. Pts distribution by IMDC risk groups was: 7% good, 58% intermediate, 27% poor and 8% unknown. Mutation rates were 27% PBRM1, 17% BAP1, 29% SETD2, 9% KDM5C and 8% TP53. In multivariable models, there was an association between GA and worse OS for BAP1 and BAP1 or TP53 combined (Table). When stratified by IMDC risk groups, GA in BAP1 or TP53 was associated with shorter median OS in poor risk pts [12.1 mo (95%CI 8.3- 24.0) v. 27.6 mo (95%CI 18.9- 53.4), aHR 4.64 (95%CI 1.32-16.4), p = 0.017] and a trend toward worse median OS in intermediate risk pts [20.5 mo (95%CI 7.4-54.6) v. 36.3 mo (95%CI 21.1, NR), aHR 2.11 (95%CI 0.94-4.74)] compared to pts without GA in BAP1 or TP53. Too few death events were observed in good risk pts to assess the prognostic value of GA in BAP1 or TP53. Conclusions: GA in BAP1 or TP53 are prognostic in mRCC and further discriminate pts with distinct outcomes within IMDC risk groups. Validation in larger dataset is ongoing. [Table: see text]
Everolimus (E) plus bevacizumab (B) is effective first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) with papillary features (PF): Results from a phase II trial.
Authors: Feldman Darren R. , Lee Chung-Han , Molina Ana M. , Knezevic Andrea , Chen Yingbei , Chaim Joshua , Coskey Devyn Taylor , Ged Yasser , Tickoo Satish , Reuter Victor E. , Patil Sujata , Xiao Han , Aghalar Jahan , Apollo Arlyn J. , Carlo Maria Isabel , Motzer Robert J. , Voss Martin Henner
Published: February 2018

627

Background: We previously reported on a phase II trial of E+B across various non-clear cell RCC histologies and observed significant activity among pts with papillary or unclassified RCC ( uRCC ) with PF (objective response rate [ORR] 39%, median progression-free survival [PFS] 12.9 months [m]; Voss, JCO, 2016). An expansion cohort limited to these two histologies was conducted to confirm the efficacy of E+B. Methods: E + B was administered at standard doses until progressive disease (PD) or intolerance to therapy. The current analysis included 19 pts with pRCC or uRCC with PF in the initial cohort and 20 pts in the expansion cohort (total n=39). The primary endpoint was 6 month PFS with secondary endpoints of ORR, median PFS, and overall survival (OS). Correlative analyses included next generation sequencing (NGS) from tumor and germline across >341 genes of interest. Results: Of 39 pts, 24 had uRCC with PF, 14 had papillary RCC, and 1 had translocation RCC with PF. Among 37 evaluable pts, the ORR was 35%; 43% for uRCC with PF and 23% for papillary RCC. Six-month PFS for all 39 pts was 78%; 82% for uRCC with PF and 68% for papillary RCC. Median PFS was 13.7m; 13.7m for uRCC with PF and 8.4m for papillary RCC (Table). With median followup of 17.6m, median OS is 33.9m. Toxicity with E+B was similar to previous reports. 33 of 39 pts had NGS performed and partial responses were observed across a wide spectrum of genomic alterations, including several recurrently seen in papillary RCC variants such as mutations in FH, MET, NF2, and ARID1a. Conclusions: The expansion cohort confirms the activity of E+B for pts with advanced papillary RCC or uRCC with PF with superior ORR, PFS, and OS compared to historical results with sunitinib for these histologies. E+B represents a new standard first-line treatment option for these pts. Clinical trial information: NCT01399918. [Table: see text]
Validation of a testosterone-deficiency symptoms rating-scale in prostate cancer patients treated with androgen deprivation therapy and radiotherapy.
Authors: O'Cathail Micheal , Little Jessica , Hosni Shaymaa , Sundar Santhanam
Published: February 2018

63

Background: Androgen deprivation therapy (ADT) plays an important role in the management of non-metastatic prostate cancer (NMPC). We prospectively assessed the performance of a symptom rating scale, the aging men’s symptoms score (AMS) in relation to other validated QOL tools. Methods: Following ethics approval, 145 patients with a diagnosis of NMPC receiving ADT as part of radical treatment were enrolled after informed consent. Data was collected using the EORTC QLQ-C30, the AMS and the International Index of Erectile Function score (IIEF-5) questionnaires at baseline, 3 months (post ADT) and after ADT was stopped. Results: Eighty six (58.1%) patients had ADT for <9 months, 7 (4.7%) had 9 -18 months and 55 (37.2%) had 27-36 months. A third (32.3%) of patients had moderate/severe symptoms of testosterone deficiency (TD) at baseline vs 62% and 44.4% at time points 2 & 3 (p<0.0001). Severe erectile dysfunction was common and worsened with ADT (45.3% & 74.1% respectively) and did not recover post ADT (p<0.0001). Few (1.6%) patients retained normal erectile function at the end of the study vs 15.6% at baseline. Self-reported QoL using EORTC QLQ C30 (Q.30) remained high at all time points (80.8%, 76.2%,75.8% respectively for a score of 5-7, 7 =very good, 1=very poor). Conclusions: TD due to ADT resulted in significant symptoms only in a subset of patients and not all symptoms resolved post ADT. However, self-reported QoL remained unaffected indicating that andropause symptoms may not affect QoL in radically treated prostate patients. This prospective data validates AMS scale and it could be used in routine clinical practice to assess TD symptoms in this group. [Table: see text]
Phase1 clinical trial of high doses of Seleno-L-methionine (SLM), in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.
Authors: Zakharia Yousef , Garje Rohan , Brown James A. , Nepple Kenneth Gerard , Dahmoush Laila , Gibson-Corley Katherine , Spitz Douglas , Milhem Mohammed M. , Rustum Youcef M.
Published: February 2018

630

Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533.
Trends and morbidity for minimally invasive versus open cytoreductive nephrectomy in the management of metastatic renal cell carcinoma.
Authors: Zlatev Dimitar V. , Ozambela Manuel , Salari Keyan , Wang Ye , Mossanen Matthew , Pucheril Daniel , Ingham Matthew D. , Chung Benjamin I. , Chang Steven Lee
Published: February 2018

632

Background: Cytoreductive nephrectomy (CN) prior to systemic therapy for metastatic renal cell carcinoma (RCC) is recommended in patients with a surgically resectable primary tumor. Traditionally performed as open surgery, the advent of laparoscopic and robotic surgery provides a minimally invasive alternative to CN with a potential for accelerated recovery and earlier initiation of systemic therapy. We sought to compare the trends and morbidity of laparoscopic, robotic, and open CN for patients with metastatic RCC. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we identified 24,145 patients who underwent elective radical nephrectomy for metastatic RCC in the United States between 2003 and 2015. Comparative analysis between laparoscopic, robotic, and open CN was performed with propensity weighting on rates of 90-day complications, blood transfusion, intensive care unit (ICU) admission, prolonged length of stay (LOS), discharge destination, 90-day readmission, operative time, and direct hospital costs. Results: Over the course of the study period, the rates of open CN decreased from 76.7% to 66.4%, laparoscopic CN decreased from 22.3% to 11.4%, and robotic CN increased from 0.6% to 22.1%. Compared to open CN, the laparoscopic approach was associated with a 30% decreased odds of 90-day major complications (OR 0.70, 95% CI 0.50 - 0.97, p < 0.05). Compared to open CN, both laparoscopic and robotic approaches were associated with significantly decreased odds of blood transfusion (OR 0.46 and 0.38, respectively), ICU admission (OR 0.57 and 0.48, respectively), and LOS (OR 0.50 and 0.35, respectively). Direct costs were lowest for laparoscopic CN. Conclusions: Compared to open CN, minimally invasive CN is associated with decreased rates of blood transfusion, ICU admission, and LOS. Laparoscopic CN is additionally associated with decreased major complications and direct costs compared to open CN. When technically feasible, the utilization of minimally invasive CN, especially laparoscopic, may be associated with improved outcomes, decreased costs, and accelerated recovery prior to systemic therapy in patients with metastatic RCC.
S-TRAC trial: Sensitivity analyses of disease-free survival (DFS).
Authors: George Daniel J. , Pantuck Allan J. , Motzer Robert J. , Ravaud Alain , Escudier Bernard , Staehler Michael D. , Serfass Lucile , Krishnaswami Sriram , Casey Michelle , Lechuga Mariajose , Koch Gary , Figlin Robert A.
Published: February 2018

633

Background: DFS has been frequently used as endpoint in the adjuvant setting and was the primary basis of approval for adjuvant cancer therapies. In S-TRAC, adjuvant sunitinib demonstrated a significant improvement of DFS vs. placebo in patients with locoregional renal cell carcinoma (RCC) based on blinded independent central review. DFS was defined as time from randomization until recurrence or death from any cause or second cancer. In the absence of a standard definition of DFS in RCC, multiple sensitivity analyses were performed to confirm the robustness of the DFS results from S-TRAC. Methods: Two analyses considered the time to recurrence including and excluding RCC specific deaths and contralateral kidney recurrence. Additional analyses used the same event and censoring rules as the primary analysis but considered earliest dates of relapse for equivocal new lesions later determined to be unequivocal -to align with RECIST 1.1 criteria for new lesions- and some alternative dates for secondary malignancies. Other sensitivity analyses evaluating alternative event and censoring rules as well as the imbalance in censoring in the first year in the primary analysis will also be presented. Results: The HR from select sensitivity analyses are presented in the Table. Conclusions: Results of sensitivity analyses with alternative definitions of DFS in S-TRAC demonstrated the robustness of the primary DFS analysis, with consistent HRs (0.76-0.81) favoring sunitinib. Clinical trial information: NCT00375674. [Table: see text]
Comparison of tumor mutational burden (TMB) in PBRM1/BAP1-based subsets of advanced renal cell carcinoma (aRCC).
Authors: Pal Sumanta K. , Madison Russell , Chung Jon , Agarwal Neeraj , Bergerot Paulo Gustavo , Bosse Dominick , Sokol Ethan , Hartmaier Ryan James , Miller Vincent A. , Ross Jeffrey S. , Choueiri Toni K. , Ali Siraj Mahamed
Published: February 2018

634

Background: Using IHC, Joseph et al (J Urol 2016) propose that 40.1%, 48.6%, 8.7% and 1.8% of patients (pts) can be characterized as PBRM1+BAP1+, PRBM1-BAP1+, PBRM1+BAP1- and PBRM1-BAP1-, respectively. We sought to confirm consistency of the frequency of genomic alterations (GAs) and IHC data and to compare TMB across subsets. Methods: DNA was extracted from 40 microns of FFPE sections from pts with aRCC. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. TMB was determined on 1.2 million Mb of sequenced DNA; results are reported in subsets segregated by presence or absence of PBRM1 and BAP1 alteration. Results: 648 consecutive pts (459:189 M:F) with clear cell RCC (ccRCC) were assessed with a median age of 58, and 368 consecutive pts (254:114 M:F) with non-clear cell RCC (nccRCC) were assessed with a median age of 57. Mutations in BAP1 and PBRM1 were found more frequently in ccRCC vs nccRCC (P < 0.05 for both). In pts with ccRCC, average TMB was highest in pts with co-occurring PBRM1 and BAP1 GAs (4.87 muts/Mb), and lowest in pts lacking both GAs (2.77 muts/Mb) (P < 0.05). TMB was similar across PBRM1/BAP1-based subsets amongst pts with nccRCC. Conclusions: As anticipated, the frequency of PBRM1/BAP1-mutated subsets by CGP is inversely related to the frequency of subsets with PBRM1/BAP1 loss by IHC from previous reports. In addition to these confirmatory findings, this large series identifies that pts with dual PBRM1/ BAP1 GAs (associated with the worst prognosis) had the highest TMB. [Table: see text]
Comprehensive genetic characterization of TFE3-positive renal cell carcinoma.
Authors: Jeong Chang Wook , Cho Jae So , Lee Moses , Choi Murim , Song Cheryn , Lee Sangchul , Ku Ja Hyeon , Kwak Cheol , Kim Hyeon Hoe
Published: February 2018

635

Background: MiT family translocation renal cell carcinoma (RCC) is very rare variant which has translocation of Xp11.2/TFE3 gene or t(6;11)/TFEB gene. Xp11.2 translocation RCC is predominantly reported in younger age and has aggressive features. However, its pathophysiology or genetic characteristics are rarely understood. The aim of the study is to describe the comprehensive genetic characteristics of TFE3-positive RCC diagnosed by immunohistochemistry. Methods: We identified patients who were clinically diagnosed as Xp11.2 translocation RCC by immunostaining positive of TFE3 from two tertiary referral hospitals. Among them, a total of 19 patients whose fresh frozen tissue and normal DNA were achieved were included in the analysis. Whole exome sequencing (WES) was performed to evaluate somatic mutations and copy-number variation (CNV). We also performed RNAseq on the TFE3-positive RCC, 7 clear cell RCC, and 4 normal kidney tissue for comparison. Fusion partners were identified and clustering analysis was done by RNAseq. Results: Mutational landscape of TFE3-positive RCC is unique by low somatic mutation rate and very rare COSMIC variants. High prevalence of CNV with loss of 3p, 6q, 9, gain of 5, 7, and 12 were most frequent. We identified NONO, RBM10, SFPQ, ASPSCR1 and PRCC as fusion partner as previously described. We could not find TFE3 fusion in 6 out of 19 patients by RNAseq, and they were older and had more mutations than the others. They were also genetically clustered with clear cell RCC. Oxidative reducatase pathway was upregulated and immune response and cell adhesion were downregulated by gene ontology results from heatmap clusters. These may promote metastasis, resistant to immunity and cell survival in poorer condition which could be potential mechanism of Xp11.2 translocation RCC aggressiveness. Conclusions: TFE3-positive RCC showed distinctive mutation pattern with low somatic mutation and rare common driver gene. One-third clinically diagnosed Xp11.2 translocation RCC (6/19) did not have real gene fusion even in TFE3 overexpression. They were older and had more somatic mutations than the others. Furthermore, they were clustered with clear cell RCC.
Effects of cabozantinib on bone turnover markers in patients with metastatic renal cell carcinoma.
Authors: Ratta Raffaele , Verzoni Elena , Pantano Francesco , Grassi Paolo , Martinetti Antonia , Morelli Daniele , Sottotetti Elisa , Mennitto Roberta , Fucà Giovanni , Prisciandaro Michele , De Braud Filippo G. , Santini Daniele , Procopio Giuseppe
Published: February 2018

638

Background: In-vitro studies have shown that cabozantinib has a strong inhibitory action on osteoclast differentiation and bone-resorption activity. The aim of this analysis was to investigate the effects of cabozantinib on bone turnover markers in patients (pts) with metastatic renal cell carcinoma (mRCC). Methods: We included mRCC pts treated with cabozantinib within the Italian Managed Access Program (MAP) at the Istituto Nazionale Tumori of Milan (Italy). Plasma samples from every patient were collected at baseline and after 3 and 6 months of treatment. The bone resorption markers C-terminal telopeptide of type I collagen (CTx) and tartrate-resistant acid phosphatase isoenzyme 5b (TRACP 5b), the osteoclastogenesis markers osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), vitamin D and parathormone (PTH) were measured by immunometric assay techniques. Data were analyzed using the RM One-Way ANOVA test with Greenhouse-Geisser correction followed by uncorrected Fisher’s LSD multiple comparison tests with individual variances computed for each comparison. Statistical tests were performed using the program GraphPad Prism (San Diego, CA). Results: Twenty-two pts have been treated with cabozantinib. Mature data were available for 11 pts. Analysis of TRACP 5b, OPG, RANKL and vitamin D did not show any significant variations during treatment with cabozantinib. CTx showed a significant reduction after 6 months of treatment (MV 171.5 pg/mL, STD 208.4) from baseline (mean value [MV] 352.2 pg/mL, standard deviation [STD] 210.1) (p = 0.0439) in the whole study population. PTH levels significantly increased after 3 months of treatment (MV 86.79 pg/mL, STD 34.99) from baseline (MV 30.77 pg/mL, STD 12.64) (p = 0.0003), while significantly decreased after 6 months (MV 75.01 pg/mL, STD 53.1) (p = 0.0174). Conclusions: Our data suggested that cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx; it was also associated with an asymptomatic transient secondary increase of parathormone. This is the first clinical evidence on effects of cabozantinib on bone metabolism in a small population of mRCC pts.
Evaluation of prostate cancer risk in men with PSA < 1.5.
Authors: Stanton Whitney N. , Crawford E. David , Arangua Paul , Hoenemeyer John , La Rosa Francisco G. , van Bokhoven Adrie , Lucia M. Scott , Poage Wendy , Werahera Priya N.
Published: February 2018

64

Background: Prostate Specific Antigen (PSA) screening remains controversial primarily because of over detection and treatment. There is an unmet clinical need to identify patients at increased risk for high-grade (HG – Gleason Score ≥7) prostate cancer (PCa) since PSA has low sensitivity. Combining PSA with well-validated prostate cancer biomarkers (PCM) can improve risk assessment. We investigated the performance of three PCMs (phi – prostate health index, 4KScore, and SelectMDx) on patients with PSA levels < 1.5 ng/mL that represent a “safe zone” where risk of any PCa is rare Methods: 652 men were screened for PCa during the annual Prostate Cancer Awareness Week at the University of Colorado Hospital. This study was supported by Prostate Condition Education Council and the Schramm Foundation. phi is evaluated using p2PSA, total PSA, and free PSA in serum. Phi < 52.7 suggests absence of HG PCa. 4KScore incorporates four kallikrein protein biomarkers: total PSA, free PSA, intact PSA, human kallikrein protein, and clinical information. A 4KScore < 20% suggests absence of HG PCa. The SelectMDx post-DRE urine test measures mRNA levels of the homeobox C6 and distal-less homeobox 1 biomarkers. SelectMDx score of 0% indicates absence of HG PCa. Results: No patients with a PSA < 1.5 had SelectMDx > 0% and/or phi > 52.7. One patient had a 4KScore of 27%, indicating a risk for HG PCa. For patients with PSA between 1.5-3.99, 2.9% (4/135), 7.4% (4/54), and 2.3% (2/85) had positive phi, 4KScore, and SelectMDx results, respectively. Conclusions: Men with PSA <1.5 ng/mL are at very low risk for HG PCa. Men with PSA between 1.5-3.99 with positive PCM results may be referred for further evaluation. [Table: see text]
Treatment trends of localized renal cell carcinoma by hospital type: A NCDB analysis.
Authors: Cahn David B. , Handorf Elizabeth , Edwards Daniel C. , Kidd Laura , Geynisman Daniel M. , Kadow Brian T. , Greenberg Richard E. , Viterbo Rosalia , Chen David , Kutikov Alexander , Uzzo Robert , Smaldone Marc C.
Published: February 2018

641

Background: Weighing operative, oncologic and comorbid risks guide treatment recommendations for localized kidney cancers. We hypothesize that individualized surgical decision making may also be influenced by surgical center and volume. Methods: The National Cancer Database (NCDB) was queried for patients 18-80 years old with pT1a-T2bN0M0 RCC, treated by partial (PN) or radical nephrectomy (RN), or ablation (ABL) from 2004-2014. After adjusting for clinicopathologic characteristics, we evaluated the association of hospital volume (vol) and center classification with receipt of PN. High vol was defined as the top 10% in treatment volume. Results: 142,090 patients met inclusion criteria, where 58% (n = 82,498) and 41% (n = 58,873) were treated by RN and PN, respectively, and 1% (n = 719) by ABL. The utilization of PN increased over time (2004: 24% vs 2014: 53%; p < 0.001). Stratified by tumor stage, 60% (n = 47,484) of pT1a and 24% (n = 9,906) of pT1b tumors were treated by PN. On multivariate analysis, patients treated at a high-vol center (OR 1.89, 95% CI 1.57-2.28) had a greater likelihood of receiving a PN when compared to treatment elsewhere. Additionally, compared to a community cancer program, treatment at a comprehensive community cancer center (OR 1.39, 95%CI 1.23-1.57), academic/research (OR 1.67, 95%CI 1.47-1.90), or integrated network cancer program (OR 1.48, 95%CI 1.24-1.77) had a higher likelihood of receiving a PN. The median distance travelled was 9.8 and 18.1 miles, for treatment at non high vol and high vol centers, respectively. An inverse correlation was noted between increasing tumor stage and receipt of PN, compared to pT1a tumors (pT1b [OR 0.22, 95%CI 0.20-0.23], pT2a [OR 0.06, 95%CI 0.05-0.06], pT2b [OR 0.03, 95%CI 0.02-0.03]). Conclusions: In the NCDB, despite increased utilization of PN at higher vol centers, the majority of localized renal tumors are still treated with RN. Smaller tumor size, treatment at a higher vol centers, comprehensive community cancer centers, academic/research programs, or integrated network cancer programs increase the likelihood of receipt of PN. Evaluation of population based trends aid in understanding localized RCC surgical management and may help quality improvement efforts.
Association of dividing pathologically upstaged T3a renal cell carcinoma with improved alignment of outcomes: A call for TMN revision.
Authors: Hamilton Zachary , Capitanio Umberto , Pruthi Deepak K. , Bindayi Ahmet , Larcher Alessandro , Ryan Stephen , Reddy Madhumitha , Yim Kendrick , Bloch Aaron , Field Charles , Berquist Sean , Ballon-Landa Eric , Liss Michael , McGregor Thomas B , Montorsi Francesco , Derweesh Ithaar
Published: February 2018

642

Background: Incidental pathological upstaging to pT3a disease can occur after surgical treatment of clinical T1 and T2 Renal Cell Carcinoma (RCC), and upstaged pT3a disease is associated with worsened outcomes. Oncologic and survival outcomes within the pT3a category are heterogeneous. We investigated recurrence and survival outcomes in pT3a disease, and aimed to better categorize this cohort for improvement on current TMN staging. Methods: Multi-center retrospective analysis of patients with renal cell carcinoma (cT1-3aN0M0) from 1987-2016. After initial comparison of outcomes between pT1, pT2 and pT3a, patients were substratified within the pT3a category based on presenting clinical stage. Comparison was drawn between pT1, pT2 and the subdivided pT3a group (cT1 → pT3a, cT2 → pT3a, and cT3a → pT3a). Primary outcome was recurrence free survival (RFS). Secondary outcome was overall survival (OS). Kaplan−Meier (KM) analysis was utilized. Results: 2640 patients were analyzed (2125 cT1, 448 cT2, 67 cT3a, mean follow up 67.8 months). Rate of incidental T3a upstaging from cT1-2 was 14.7%. Compared to pT1-2 disease, patients with incidental pT3a upstaging had higher rate of recurrence (7.5% vs. 29.6%, p < 0.001) and all-cause mortality at last follow up (15.9% vs. 25.4%, p < 0.001). With regards to RFS, when pT3a was subdivided based on presenting clinical stage, significant differences in RFS emerged which aligned differently. Compared to 5 year RFS of pT1 (94.4%), cT1 → pT3a aligned with pT2 (76.6% and 81.2%, p = 0.346) while cT2 → pT3a aligned with cT3a → pT3a 47.4% and 44.0%, p = 0.815). With regards to OS, a similar alignment was noted for 5 year OS after subdivision, where pT1 was 89.9%, while cT1 → pT3a correlated with pT2 (79.8% and 83.1%, p = 0.640) and cT2 → pT3a correlated with cT3a → pT3a 67.0% and 64.2%; p = 0.893). Conclusions: Patients with cT1 → pT3a have outcomes more similar to pT2, than patients with cT2 → pT3a which align more closely to cT3a → pT3a. Future refinements of the TNM staging system for RCC should consider re-grouping cT1 → pT3a into the pT2 group. Further confirmation is requisite.
Cabozantinib (C) exposure-response (ER) modeling of efficacy and safety endpoints as a function of clearance in patients (pts) with renal cell carcinoma (RCC).
Authors: Jonasch Eric , Motzer Robert J. , Escudier Bernard , Powles Thomas , Markby David W , Nielsen Jace , Lacy Steven , Choueiri Toni K.
Published: February 2018

645

Background: C is approved for the treatment of advanced RCC after prior antiangiogenic therapy at 60 mg qd with dose reductions to 40 mg and 20 mg used to manage adverse events (AEs). In this study, ER analyses were used to evaluate the effect of C dose on progression-free survival (PFS) and safety endpoints at different apparent clearance (CL/F) values for pts in the phase 3 METEOR study (NCT01865747). Methods: Predicted steady-state C exposures were calculated for doses of 60, 40, and 20 mg in pts with CL/F values of 1.3, 2.23, and 3.3 L/hr; these values were based on population PK models and represent pts with low, average, and high CL/F, respectively. Time-to-event Cox proportional hazard ER models were used to characterize the relationship between predicted C exposure and the probability of PFS and 4 common C AEs: fatigue/asthenia (grade ≥3), palmar-plantar erythrodysesthesia (PPE; grade ≥1), diarrhea (grade ≥3), and hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg). Results: Among the 282 pts evaluated, predicted C CL/F values ranged from 0.51 to 7.24 L/hr. Predicted C exposure at the 60 mg dose ranged from 758 to 1923 ng/mL for representative pts with high and low CL/F (3.3 and 1.3 L/hr). A 60 mg dose for a high CL/F pt is predicted to yield C exposure similar to that of an average CL/F pt dosed at 40 mg (758 vs 748 ng/mL). At the 3 CL/F values evaluated, the hazard ratio (HR) for PFS modestly favored the 60 mg vs 40 mg dose, with the greatest impact on high CL/F pts (HR 1.13, 95% CI 1.10-1.16). 4 common C AEs are predicted to occur at lower rates at the 40 mg vs 60 mg dose; HRs ranged from 0.51-0.82 with the greatest effect in pts with low CL/F. Conclusions: Predicted C CL/F values and C exposures varied among pts with RCC in the METEOR study. ER models suggest that pts with high CL/F may have less favorable PFS outcomes at a starting dose of 40 mg vs the recommended 60 mg dose. Patients with low CL/F are predicted to have decreased rates of AEs at lower doses. Clinical trial information: NCT01865747. [Table: see text]
The importance of the need for better systemic therapy in the definitive treatment of high-risk prostate cancer regardless of whether the initial treatment modality was external beam radiation, I-125 brachytherapy, or radical prostatectomy.
Authors: Ciezki Jay P. , Reddy Chandana A. , Mian Omar Y. , Garcia Jorge A. , Klein Eric A. , Ulchaker James , Angermeier Kenneth , Campbell Steven C. , Stephenson Andrew J.
Published: February 2018

65

Background: While androgen deprivation therapy (ADT) is a common form of systemic therapy for treating high-risk prostate cancer (HRCaP), distant metastases development remains the predominate form of failure. We present a description of the sites of failure after treatment of HRCaP with External Beam Radiation (EBRT), I-125 Brachytherapy (PB), or Radical Prostatectomy (RP). This is accompanied by an analysis of prostate cancer-specific mortality (PCSM) after clinical failure. Methods: The study includes 2186 patients with HRCaP according to NCCN guidelines (684 EBRT, 409 PB, and 1093 RP). The association of PCSM with clinical and pathologic variables was assessed with Fine and Gray regression with non-PCSM mortality treated as a competing event. Results: The median f/u is 52 months. Overall, there were 323 clinical failures (sites of first failures: 287 distant (DM), 34 local (LF), 2 DM + LF). The median time to the diagnosis of DM was 44 months. ADT was used in 93% of EBRT, 53% of PB and 19% of RP patients. Further details regarding the development of DM is shown in Table 1. The type of initial treatment was not associated with PCSM after DM (Table 1). The only factor significantly associated with PCSM was Gleason Score (p = 0.0372). Conclusions: DM is the primary mode of failure after definitive treatment of HRCaP. The type of initial definitive treatment did not affect PCSM after DM. The cure rates of all forms of definitive treatment of HRCaP would benefit from better systemic therapy. [Table: see text]
A phase I, open-label, dose-escalation and cohort expansion study evaluating the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma.
Authors: Faiena Izak , Zomorodian Nazy , Comin-Anduix Begonya , Sachadeva Ankush , Bot Adrian , Kabinnivar Fariouz , Said Jonathan W. , Cheung-Lau Gardenia , Pang Jia , Macabali Mignonette , Cabrera Paula , Kaplan-Lefko Paula , Berent-Maoz Beata , Liu Sandy , Pantuck Allan J. , Belldegrun Arie S. , Chamie Karim , Drakaki Alexandra
Published: February 2018

653

Background: We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC (mRCC) in this phase 1 study targeting CAIX overexpressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs produced ex-vivo from patients’ peripheral blood mononuclear cells (PBMC), by culturing with GM-CSF & IL-4, then engineered with AdGMCAIX prior to intradermal injection. The injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15, and 50 X 106 cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally q2wkX3 doses. The primary aim is safety. Secondary aims are to evaluate immune responses & antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function. Results: Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses, comprising DC expressing CAIX, CD11c and other relevant markers. No serious adverse events (SAEs) were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the 9 patients who received treatment, 1 expired of progressive disease (PD), 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have PD and are currently receiving standard-of-care therapies, and 1 has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAEs noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies, either alone, or in combination with approved therapies. Clinical trial information: NCT01826877.
Association of microbiome and plasma cytokine dynamics to nivolumab response in metastatic renal cell carcinoma (mRCC).
Authors: Maia Manuel C. , Poroyko Valeriy , Won Haejung , Almeida Lorena , Bergerot Paulo Gustavo , Dizman Nazli , Hsu Joann , Jones Jeremy , Salgia Ravi , Pal Sumanta K.
Published: February 2018

656

Background: Checkpoint inhibitors (CPI) represent a standard of care in mRCC. The relationship of the microbiome to benefit from CPIs has been suggested in clinical studies in melanoma (Wargo et al ASCO 2017). Here we provide updated evidence of association between microbiome composition, plasma cytokines and response to nivolumab in mRCC patients (pts). Methods: Stool and blood samples were prospectively collected from pts with mRCC at 3 time points relative to nivolumab treatment (baseline, week 4 and week 12) and used to assess gut microbiota composition in two different groups: responders (R; including complete/partial response and stable disease) and non-responders (P; primary progression). For stool analyses, microbial DNA was extracted, 16s rRNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina). Sequence reads were processed by Mothur software, assembled in OTUs, taxonomically annotated and used to construct dissimilarity matrices. Differentially abundant taxa were determined by METASTATS and compared between R and P. We further interrogated whether plasma cytokine profile was influenced by specific bacterial species. Results: Of 20 pts, 16 were evaluable for response. In preliminary analyses, 25,304 OTUs were attributed to 165 genera from 8 phyla. PCoA analysis reveals that the first two principal coordinates can explain 49.2% of data set variation. Subsequent k-means clustering shows an almost complete separation of microbiota in R and P groups (p = 0.07). The analysis of microbiota membership in P and R groups revealed 2 differentially abundant taxonomic units present above 1% abundance. Namely, Roseburia spp and Faecalibacterium spp were significantly elevated in R as compared to P (p < 0.05). Correlations between these bacteria and plasma cytokines will be presented at the meeting. Conclusions: Our results are the first to associate specific microbial genera to nivolumab response in mRCC, and this represents the first effort to combine analysis of the microbiome and serum cytokines. Manipulation of the stool microbiome as a means of modulating nivolumab response should be investigated.
Does treatment approach for small renal masses affect survival in patients 70 years old?
Authors: Hockman Lukas , Haden Tyler , Henderson Alex , Pokala Naveen
Published: February 2018

658

Background: With the advent of modern imaging techniques small renal masses are being diagnosed more frequently. Many of these masses are benign, and those that are malignant are often low grade and rarely affect the survival. Surveillance is more commonly being advocated as an option for these masses. This study elucidates survival following different treatment approaches. Methods: SEER 18 data from 2004-13 identified 10,477 patients 70 years and older with renal cell carcinoma and tumors greater than or equal to 3 cm. Exclusion criteria included multiple primaries, distant metastasis and node positive disease. Data was collected on demographics, treatment patterns, overall survival and cancer specific survival. Kaplan-Meier analysis and Cox regression models were used to compare outcomes. Results: After exclusion 5084 patients remained. The mean age was 76.4 years. The mean tumor size was 2.3cm. Tumor laterality was right in 2610, left in 2467, bilateral in 2 and unspecified in 5. Racial analysis identified 84% of patients as white, 9% as black and 7% as other. Gender split was 51% male. Treatment methods included 791 ablations and 3324 surgical resections (radical or partial nephrectomy). The remaining 969 patients did not have treatment (surveillance). Survival was measured at 60 and 118 months. The overall survival was 75% and 54% respectively for ALL patients, 82% and 62% for ablation, 42% and 19% for surveillance and 82% and 62% for resection. Cancer specific survival was 97% and 96% for ablation, 83% and 74% for surveillance and 96% and 94% for resection. Surgical resection or ablation significantly improved survival at 5 and 10 years (p = < 0.0001). Multivariate analysis showed survival was affected by age and year of diagnosis, but not by tumor size. Conclusions: The significant difference in overall survival suggests appropriate selection of patients for surveillance based on medical comorbidities. Treatment with curative intent improves survival in patients with greater than or equal to 3 cm renal masses, even in patients 70 years and older, and must be offered to patients without significant comorbidities.