bluuebunny/crossref_metadata_2025 huggingface dataset:
United States trends in patterns of care in clinical stage I testicular cancer: Results from the National Cancer Database (1998-2011).
Authors: Jeldres Claudio , Nichols Craig R. , Pham Khanh , Daneshmand Siamak , Kollmannsberger Christian K. , Hayes-Lattin Brandon M. , Wolff Erika , Odem-Davis Katherine , Porter Christopher R.
Published: February 2017

369

Background: There has been significant evolution in worldwide guidelines for management of clinical stage I (CS1) testicular cancer where active surveillance (AS) strategies are now considered a first choice, especially for patients with lower recurrence risk after orchiectomy. Conversely, local therapies for CS1 such as primary retroperitoneal lymphadenectomy (RPLND) in non-seminoma and regional radiation in seminoma are phasing out of recommendations. In the US, there have been no comprehensive efforts to measure uptake of guideline recommendations and modern patterns of care for early-stage testicular cancer. Methods: Access to the testicular cancer data set within the National Cancer Data Base (NCDB) was granted to Virginia Mason Medical Center (A SWOG affiliated cancer research program) for this retrospective cohort study. We identified all patients with CS1 testicular cancer between 1998 and 2011. Management options after orchiectomy such as adjuvant radiotherapy, adjuvant chemotherapy, RPLND, or AS were analyzed using cross tabulation and trend analysis. Results: Within the NCDB, of 75,902 patients with testicular cancer, 31,208 and 13,301 were diagnosed with CS1 seminoma and non-seminoma, respectively. For CS1 seminoma, AS use increased from 25.2% in 1998 to 55.8% in 2011. Similarly adjuvant chemotherapy use also increased (1.9 % to 16.7%). Conversely, use of adjuvant radiation decreased from 72.9% to 27.5%. For CS1 non-seminoma, AS remained the main treatment modality ranging between 58.8% and 66.2%. The use of adjuvant chemotherapy increased (28.3% in 2011) and the rate of primary RPLND constantly decreased down to 12.9% that same year. Interestingly, 50.3% of patients with CS1 non-seminoma and negative lympho-vascular invasion status had chemotherapy rather than AS. Trends analyses were statistically significant for all treatment modalities (p<0.05). Conclusions: Active surveillance as a management strategy has increased and is currently the most common treatment modality used for both CS1 seminoma and non-seminoma in the US. Regional therapies in CSI seminoma and non-seminoma are decreasing but persist even in patients with a low risk of recurrence.
Dose calculation and tolerability of adjuvant AUC 7 carboplatin in 100 patients with stage I seminoma.
Authors: Basso Umberto , Diminutto Alberto , Morelli Franco , De Giorgi Ugo , Perin Alessandra , Fraccon Anna Paola , Lo Re Giovanni , Rizzi Anna , Sava Teodoro , Valcamonico Francesca , Zustovich Fable , Massari Francesco , Maruzzo Marco , Zanardi Elisa , Zattoni Filiberto , Zagonel Vittorina
Published: February 2017

374

Background: Administration of carboplatin AUC 7 has become a standard adjuvant option to be discussed with pts following orchiectomy for stage I seminoma, as alternative to radiotherapy on retroperitoneal lymphnodes or observation. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial by Oliver et al. (Lancet, 2005), but dose ranges were not reported. Oncologists use different methods to estimate GFR and to calculate this unusually high dosage of carboplatin, and fear of toxicity may induce arbitrary dose reductions and potentially compromise the outcome. Methods: In 9 Italian centers we conducted a retrospective review focusing on adjuvant carboplatin administration to stage I seminoma pts. Modality of dose calculation, dose reductions and toxicities were recorded. Results: Since August 2006, 100 pts have been treated, median age 35 years (range 26 to 58). Adverse prognostic factors were either T >4 cm (14% of pts) or rete testis invasion (32), both (36), none or unspecified (18). Glomerular Filtration Rated was estimated mainly by Cockroft-Gault formula (55% of pts), Jeliffe formula (27%), 24-hour urine collection (17%), MDRM (1%): median value was 106 ml/min (range 75 to 209). All Oncologists declared to use Calvert formula to calculate AUC 7 dose, and administered a median of 900 mg of carboplatin (range 690 to 1535). A dose reduction > 10% was prudentially applied to 15% of pts; a second cycle was delivered in 8 pts. Acute toxicities are outlined in table 1. After a median follow-up of 20 months, 6% of patients have relapsed (all in the retroperitoneum), none of whom had been treated with reduced dose. Conclusions: AUC 7 carboplatin dosage peaked 1,535 mg in our cohort of stage I seminoma patients with no infections and nephrotoxicity, moderate nausea-vomiting, but 5% of grade 3-4 thrombocytopenia. Prudential dose reductions appeared unfrequent and should be proscribed. [Table: see text]
Influence of social demographics and African-American race on outcomes in testicular cancer: Analysis of 75,902 patients in the National Cancer database.
Authors: Nichols Craig R. , Jeldres Claudio , Pham Khanh , Daneshmand Siamak , Kollmannsberger Christian K. , Hayes-Lattin Brandon M. , Odem-Davis Katherine , Wolff Erika , Porter Christopher R.
Published: February 2017

391

Background: While there have been substantial advances in treatment and outcomes in testicular cancer, most of the data are derived from large institutionals or clinical trials. Testicular germ cell tumors are uncommon (8,000 new patients annually in US). The incidence among patients (pts) of African origins is extremely low. Most of the conclusions regarding outcomes are based on Caucasian pts from research institutions. Information about modern outcomes in non-Caucasian races is scant and little is known about the influence of various social demographic parameters on presentation patterns and survival. Using this population-based database available through the NCDB, we sought to better understand social and racial variations in outcomes. Methods: Within the NCDB, 75,902 testicular cancer pts were available for review. Tools available through the NCDB were utilized for analysis. Herein, we evaluated social demographics (insurance type, educational achievement, annual income, type of treating institution) and racial/ethnic characteristics as they pertained to stage at presentation and survival. Results: 75,902 pts were available from the timeframe of 1998 through 2011 for aggregation of social demographic features as well as racial/ethnic characteristics. Overall survival was available on 48573 pts through 2006. Racial-ethnic breakdown at presentation was 84.1% (n=63,867) Caucasian and African-American 2.7% (n=2,083). Overall, insurance type, education (% without high school degree), income (< $ 30000 to >$46,000) and type of treating hospital were analyzed using univariate and multivariate models. Full details will be presented. Conclusions: Unfavorable presentations and outcomes in testicular cancer are seen by race and social demographics. In depth analytics are being performed to characterize the variations as related to biological/genetic differences and/or differences in social demographics. In this very large cohort, the National Cancer database demonstrates a 2-fold risk increase in death in African American pts relative to Caucasian pts with similar stage at presentation.
Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma.
Authors: Hakimi A. Ari , Ostrovnaya Irina , Jacobsen Anders , Coleman Jonathan A. , Russo Paul , Mano Roy , Sankin Alexander , Motzer Robert John , Purdue Mark , Pomerantz Mark , Freedman Matthew L , Choueiri Toni K. , Hsieh James , Klein Robert J.
Published: February 2017

395

Background: The exonic single nucleotide variant rs11762213 located in the METoncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC) (Schutz et al, Lancet Oncol 2013). We sought to validate this finding and explore the biologic implications using The Cancer Genome Atlas (TCGA) cohort. Methods: The variant call file (VCF) and expression data was available for 272 patients. We then extracted the data for rs11762213 as follows for the "normal" sample: allelic fraction for variant allele > 80% is homozygous variant while allelic fraction for variant allele 30% to 70% is heterozygous. Paired tumor-normal materials, genomic data (whole exome, RNAseq, and DNA methylation) and clinical information were acquired from publically available TCGA datasets. Kaplan-Meier method was used to estimate the survival probabilities. Cancer specific survival (CSS) was analyzed using the competing risk method and Cox proportional hazard regression was used for analysis of time to recurrence. Multivariate competing risk models were also fitted in the TCGA cohort in order to adjust for the Mayo Clinic SSIGN score. Results: Overall, the variant allele of rs11762213 was detected in 10.3% of the cohort and was associated with higher nuclear grade (p=0.03) and trended toward higher clinical stage (p=0.07). After adjusting for the prognostic SSIGN score, the risk allele remained a significant predictor for adverse cancer specific survival (CSS; p<0.0001; Odds Ratio [OR] 3.88, 95% confidence interval [CI] 1.99-7.56) and time to recurrence (TTR; p=0.003; OR 2.97; 95% CI 1.44-6.2). RNA sequencing data for MET did not reveal differences in tumor mRNA expression when stratified by risk allele, but did show differences in the normal kidney expression (p=0.02) in a smaller cohort (n=61). Conclusions: The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and could be integrated into clinical practice for prognostic stratification. Gene expression analysis suggests that inherited variation at MET influences expression of the gene in normal kidney tissue. Further external validation and biological interrogation is necessary.
Comprehensive kinase profiling to classify clear cell (cc)-renal cell carcinoma (RCC).
Authors: Mehta Amitkumar N. , Willey Christopher Douglas , Anderson Joshua , Welaya Karim Youssry , Chen Dongquan , Ghatalia Pooja , Madan Ankit , Sudarshan Sunil , Naik Gurudatta , Grizzle William E. , Choueiri Toni K. , Sonpavde Guru
Published: February 2017

409

Background: Comprehensive high throughput functional kinase activity in localized cc-RCC tumors may assist in devising a classification system and help identify potential therapeutic targets. Methods: Patients (pts) with localized tumors undergoing surgery with minimum follow-up of 18 months underwent kinomics of fresh frozen cc-RCC tumors and matched normal renal tissue using the PamStation12 high-content phospho-peptide substrate microarray system (PamGene). The protein tyrosine kinome (PTK) and serine/threonine kinome (STK) PamChips were used to measure global kinase activity. Advanced network modeling of altered phospho-peptides was performed using MetaCore while upstream kinase prediction scoring was based off of phosphonet (phosphonet.ca). Both unsupervised analyses and supervised analyses of kinomics were done guided by tumor recurrence. Kinomics of tumor and matched normal tissue were compared. Results: Of 41 evaluable pts, the median age was 61 and pathologic stage was 1, 2, 3 and 4 in 19, 1, 20 and 1 pts, respectively. Unsupervised clustering analyses of tumor kinomics showed 3 groups: A (N=12), B (N=16), C (N=13). Potential driver kinases implicated were PFTK1, PKG1 and SRC in groups A, B, and C, respectively. Network modeling of these groups identified many Process Mappings including, but not limited to Inflammation pathways (A), translation initiation (B) and immune response and cell adhesion pathways(C). 5 of 9 pts who progressed were classified as Group C, 1 progressor was in Group B, and 3 were in Group A. Supervised analysis showed decreased CDK1, RSK1-4, ERK1-2, PKG2 and AKT2 kinase activity in those who progressed compared to others. 12 tumors showed increased PIM1 and MAPKAPK3, and decreased JNK2 and CDK1 compared to adjacent normal tissue. Conclusions: Comprehensive kinomics of localized cc-RCC was used to classify tumors based on unsupervised clustering, which appeared to confer differential long-term outcomes while supervised analysis also identified potential pathways related to recurrence. Kinases amplified in renal tumors compared to adjacent normal renal tissue were also identified. Significant heterogeneity of kinases was found with no single dominant kinase across all analyses.
Deep sequencing of sarcomatoid renal cell carcinoma (sRCC) and identification of aurora kinases and mTOR as potential therapeutic targets.
Authors: Pal Sumanta Kumar , Tong Tommy , He Miaoling , Wu Huiqing , Liu Xueli , Nelson Rebecca A. , Wu Xiwei , Signoretti Sabina , Choueiri Toni K. , Jones Jeremy
Published: February 2017

411

Background: The presence of sarc elements in pts with RCC portends a poor prognosis. Some studies have focused on epithelial-to-mesenchymal transition (EMT) as a driver of sarc ccRCC; however, the potential role of other targetable entities is unknown. Methods: From an institutional database, we identified 13 pts with metastatic sarc ccRCC and 13 pts with metastatic ccRCC lacking sarc elements matched by age and risk group. All patients had available FFPE tissue derived from nephrectomy. For a limited sample of 5 pts with sarc ccRCC, RNA sequencing was performed on microdissected cc, sarc, and benign renal cortical sections from FFPE blocks. Reads were aligned to hg19 genome with Tophat v2.0. IHC was used to explore expression of implicated genes in the entire matched cohort of 26 pts. Results: With respect to RNA sequencing analysis for 5 pts with sarc ccRCC, reads had between 4% and 24% exon coverage. Hierarchical clustering demonstrated that most samples were clustered by patient, not by disease state (i.e., sarc vs non-sarc), suggesting that inter-patient variation is large. However, comparisons between cc and sarc components for these 5 pts demonstrated a significant increase in cell growth pathways, with the most highly enriched gene ontology pathways being M-phase, cell cycle, mitosis and aurora kinase pathways. No EMT-related pathways were found to be enriched. IHC assessments of VEGF and mTOR pathways were performed, given their purported role in RCC cell growth. While no differences were noted in pVEGFR2, higher pS6K staining was noted in both the sarc and non-sarc components of pts with sarc ccRCC relative to pS6K staining in tumor tissue derived from ccRCC pts lacking sarc elements (p<0.05 for both). No differences in EMT marker expression were noted (specifically, E-cad, N-cad and Twist); IHC assessments for aurora kinases A and B will be reported. Conclusions: Although cytotoxic agents and VEGF-directed therapies have been explored in sarc ccRCC, the finding of mTOR pathway activity underscores the need to examine mTOR inhibitors in this disease. Furthermore, emerging agents targeting aurora kinases may have a role in sarc ccRCC.
High-dose interleukin-2 registry, PROCLAIM: Modern data on toxicities and outcomes.
Authors: Lowder James N , Aung Sandra , Wong Michael K.K. , Daniels Gregory A. , Kaufman Howard , McDermott David F. , Morse Michael
Published: February 2017

430

Background: High dose interleukin-2 is an FDA-approved treatment for metastatic melanoma (mM) and renal cell carcinoma (mRCC) that consistently delivers durable CRs in up to 10% of patients. Concerns of treatment related toxicities are a major barrier to IL-2 administration. Nonsystematic reviews show that HD IL-2 therapy is safe, however treatment protocols have evolved to a series of best practices within over 60 HD IL-2 centers in the US. Methods: In order to capture current practices and generate modern data on toxicities and outcomes, PROCLAIM, a HD IL-2 observational database, was initiated in 2011. One goal of the registry is to survey real world HD IL-2 clinical experience used in the treatment of patients with mM, mRCC or other metastatic malignancies. A retrospective cohort was initiated for hypothesis generation and to inform the prospective cohort which has currently > 470 patients enrolled. We report here on the retrospective data comprising 267 patients (mRCC,97) treated between 2007-2012. Results: Analysis of the retrospective data show that no deaths were reported, compared to the historic mortality rate of 4% (n=255 mRCC)(Fyfe,1995). Toxicites are acute and abate rapidly after cessation of IL-2. Center-specific reasons for stopping dosing to end a cycle, as well as tolerance of elevated creatinine levels varied significantly. There were striking differences between the median number of doses administered per cycle per center, clustering around 4-6 vs. 8-14. There appears to be a trend towards higher and more durable responses with higher dose density per cycle. Conclusions: HD IL-2 can be a safe and effective immunotherapy that can be given over a short duration and delivers consistent durable therapeutic responses. The rapid resolution of its toxicities allows for its use with other therapies either in sequence or in combination; trials are currently in progress.
Growth kinetics and outcomes of cT1b renal masses under active surveillance.
Authors: Mehrazin Reza , Smaldone Marc C. , Kutikov Alexander , Tomaszewski Jeffrey J. , Li Tianyu , Viterbo Rosalia , Greenberg Richard E. , Chen David Y. T. , Uzzo Robert G.
Published: February 2017

440

Background: The natural history of untreated T1b renal masses is poorly understood. We assessed the growth kinetics and outcomes of ≥cT1b cortical renal tumors which continue to remain on radiographic AS compared to those who underwent definitive surgery after a period of AS. Methods: Prospectively maintained, renal tumor database was reviewed to identify enhancing solid and cystic masses managed expectantly from 2000-2012. cT1a masses, transitional cell carcinoma or those suspected for metastatic disease were excluded from analysis. Localized tumors > 4.0 cm (≥T1b) that were radiographically followed for > 6 months were included for analysis. Clinical and pathological records were reviewed to determine tumor growth rate and clinical outcomes in those remained on AS or those who underwent delayed intervention. Mean for tumor size on presentation, annual linear tumor growth rate (LGR), Charlson comorbidity index (CCI), and follow-up (FU) were calculated. Chi−square test & Logistic regression were used for uni- and multi-variable analyses. Results: Of 457 pts managed with AS, 67 cT1b tumors (in 63 patients) were identified. 43 pts (67%) were managed solely with AS, while 21 pts (33%) progressed to intervention. The median age at presentation pts managed with AS and intervention was 77 and 60 yrs respectively (p=0.0002), while no difference was observed in median CCI (3 vs. 2, p=0.6). No difference was observed in tumor size at presentation between pts managed with AS and those undergoing delayed intervention (5.9 vs. 5.4 cm, p=0.8). In contrast, the mean LGR significantly differed between pts managed expectantly and pts progressed to intervention (0.37 vs. 0.73 cm/yr; p=0.02). On MVA, age (OR=0.9,CI:0.8−0.98) and LGR (OR=11,CI:1.8−60) were significant predictors of surgical intervention. With a mean FU period of 38.9 ± 24.0 months (6−105), 9 pts died (14%) from other cause and no pt progressed to metastatic disease. Conclusions: Localized cT1b≥ renal masses show comparable growth rates to small tumors managed expectantly with low rates of progression to metastatic disease with short term follow up. An initial period of AS to determine tumor growth kinetics is a reasonable option in select pts with significant competing risks and limited life expectancy.
Phase I study of pazopanib in combination with interferon alfa in patients with advanced renal cell carcinoma (RCC) and other primary tumors: A Spanish Oncology Genitourinary Group (SOGUG) study.
Authors: Garcia del Muro Xavier , Duran Ignacio , García-Donas Jesús , Rodriguez-Moreno Juan Francisco , Gil-Martin Marta
Published: February 2017

450

Background: Pazopanib is a VEGF receptor inhibitor active in the treatment of advanced RCC treatment, and Interferon has been a long-standing treatment option for metastatic RCC with a modest overall survival benefit. The purpose of this study is to assess the feasibility and safety of the combination of pazopanib and interferon in the treatment of advanced RCC and other tumor types. Methods: This is a phase I study of the combination of pazopanib and interferon alfa-2A. It has been developed in a 3+3 standard escalating design with cohorts of 3-6 patients (pts) to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD). Pazopanib is given po daily and interferon is given subcutaneously 3 times a week. Dose levels 1, 2, 3, 4 and 5 corresponded to pazopanib 400, 600, 800, 800 and 800 mg per day plus interferon 3, 3, 3, 6 and 9 million U. Patients with previously treated RCC and also other primary tumors could be included. Results: 19 pts were included and treated in 4 dose levels. Patients’ median age was 60 years old, 13 men and 6 women. Six of them were diagnosed with RCC; other pts presented metastatic tumors as ovarian carcinoma, peritoneal mesothelioma, breast cancer (2), liposarcoma, breast angiosarcoma, uterine sarcomas (3), endometrial carcinoma (3) and melanoma. MTD was reached at level 4, and the RD was Pazopanib 800mg with IFN 3MUI. Three pts experienced DLT, one in level 2 and two in level 4: grade 4 transaminitis, grade 3 transaminitis and grade 3 liver hematoma, respectively. Other toxicities (grade 3 and 4) included anemia, neutropenia, thrombocytopenia, asthenia, arthromialgia, anorexia, diarrhea and Raynaud’s syndrome. Additional mild but common toxicities were fever and proteinuria. One partial response was observed in a uterine sarcoma patient. In RCC, 4 pts achieved stable disease lasting a median of 5 cycles. Conclusions: Combination of pazopanib and interferon alfa is feasible and safe, allowing administration of active doses of both agents. A phase II study to assess this combination activity in RCC is assured. Clinical trial information: NCT01513187.
Multicenter phase II clinical trial of everolimus in Japanese patients with unresectable or metastatic renal cell carcinoma (mRCC) after failure of treatment with first-line tyrosine kinase inhibitor (TKI) therapy.
Authors: Ozono Seiichiro , Oyama Masafumi , Nozawa Masahiro , Fujimoto Kiyohide , Kishida Ken , Tokuda Noriaki , Kimura Go , Nishimura Kazuo , Matsubara Akio , Matsuyama Hideyasu , Sugiyama Takayuki , Kamba Tomomi , Kume Haruki , Masumori Naoya , Oya Mototsugu , Kanayama Hiro-Omi , Naito Seiji , Hinotsu Shiro , Shimozuma Kojiro , Akaza Hideyuki
Published: February 2017

455

Background: Everolimus has shown the efficacy and the safety in the phase III trial (RECORD-1) in patients with mRCC after failure of Vascular Endothelial Growth Factor Receptor-TKI. However, 26% of patients received two TKIs (sunitinib and sorafenib) as previous therapy in RECORD-1. In addition, as pre-treatment before TKI, 65% of patients received cytokine therapy and 13% of patients received chemotherapy. Therefore, there is still no clear evidence of everolimus as second line setting after failure of 1st-line TKI therapy. Methods: This study is an open-label, multi-center, single-arm, phase II trial. Primary endpoint is progression-free survival (PFS), and secondary endpoints are overall survival, objective response rate, time-to-treatment-failure, safety and quality of life (EORTC QLQ-C30, FKSI-DRS, EQ-5D). Key eligibility criteria are RCC with clear cell component, patients who received one TKI as first line therapy, patients who did not receive cytokine and chemotherapy and ECOG performance status 0-1. Results: 57 patients were enrolled from 02/11 to 12/12. Median age was 63 years, common sites of metastasis were lung (32.7%) and bone (12.2%), 79.6% had previous nephrectomy, previous TKI therapy were sunitinib (69.4%), sorafenib (22.4%) and axitinib (8.2%). Median PFS was 4.4 months (95% confidence interval: 3.7-6.0). 8.2% had partial response and 57.1% had stable disease according to RECIST v.1.0. The incidence of adverse events (AEs) of all grades was 95.9%. Major AEs were stomatitis (49.0%), hypertriglyceridemia (26.5%) and hypercholesterolemia (24.5%). Serious AEs were stomatitis (10.2%), interstitial lung disease (6.1%) and rash (6.1%). There were no treatment related deaths. All QOL scores were not changed at 2 months, while dyspnea and global health scores of EORTC QLQ-C30 and FKSI-DRS score were worsened at 4 months. Conclusions: This study is a first report of everolimus as second line setting after failure of 1st-line TKI. Further study and long-term follow-up would be warranted. Clinical trial information: UMIN000004742.
Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC).
Authors: Agarwal Neeraj , Parikh Kinjal , Tantravahi Srinivas Kiran , Crispin Hilda , Van Atta Joan , Batten Julia Anne , Sageser Daniel , Samlowski Wolfram E. , Grossmann Kenneth F. , Wang Junfeng , Stenehjem David D.
Published: February 2017

461

Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB ( OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2. Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer. Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table. Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC pts. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling pts for treatment with HD IL-2. [Table: see text]
Genome-wide profiling of histone 3 lysine 36 trimethylation in clear cell renal cell carcinoma.
Authors: Ho Thai Huu , Lee Jeong-Heon , Nateras Rafael Nunez , Castle Erik P. , Stanton Melissa L. , Joseph Richard Wayne , Bryce Alan H. , Carballido Estrella M. , Parker Alexander S. , Zhang Zhiguo , Ordog Tamas
Published: February 2017

464

Background: Although the von Hippel-Lindau (VHL) tumor suppressor gene is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. We hypothesize that loss of SETD2 methyltransferase activity alters the genome wide pattern of H3K36 trimethylation (H3K36me3) in ccRCC, and contributes to the cancer phenotype. Methods: To generate a genome-wide profile of H3K36me3 in frozen nephrectomy samples and RCC cell lines, we optimized a chromatin immunoprecipitation (ChIP) protocol for the isolation of DNA associated with H3K36me3. H3K36me3 is associated with open chromatin and an H3K36me3-specific antibody was used for immunoprecipitation of endogenous H3K36me3-bound DNA. ChIP PCR primers were optimized for active genes, such as actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and a “gene desert” on chromosome 12 (negative control). ChIP libraries were then generated from 3 paired uninvolved kidney and RCC and 2 RCC cell lines. In order to identify H3K36Me3 upregulated regions in uninvolved kidney and RCC, reads from the ChIP sequencing were mapped to the human genome using Burrows-Wheeler Aligner and SICER algorithms. Results: Using ChIP PCR, we found that active genomic regions were enriched 15-30 fold over the negative controls indicating that the quality and yield of immunoprecipitated DNA/chromatin complexes from frozen tissue was sufficient for ChIP sequencing. A preliminary ChIP sequencing analysis of RCC cell lines and frozen ccRCC tissue indicates that H3K36me3 enriched DNA sequences were mapped to exons (31.3%) compared to introns (13.5%, p<0.001), consistent with the role of H3K36me3 in transcription. Conclusions: Genomic regions enriched for H3K36Me3 binding were identified from patient-derived tissue and RCC cell lines. Current efforts are focused on comparing the H3K36me3 profiles between matched tumor and uninvolved kidney ChIP libraries to generate a genome wide map of dysregulated H3K36me3 modifications.
Searching for circulating microRNAs in genitourinary tumors.
Authors: Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Veiga Francisco Gomez , Valladares Ayerbes Manuel , Quindós Varela Maria , Fernandez Nunez Natalia , Molina Diaz Aurea , Santamarina Cainzos Isabel , Anton Aparicio Luis Miguel
Published: February 2017

468

Background: Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information in genitourinary tumors (GT). The aim of this work was identify aberrantly expressed miRNAs potentially useful for CTC detection in blood samples from patients with GT to assess their potential clinical significance, and to gain a greater understanding of the mechanisms driving tumor progression. Methods: We examined blood levels of 92 microRNAs in 113 metastatic patients: prostate (mP), renal cell carcinoma (mRCC), bladder tumors (mB) and healthy volunteers (HV) (N=18) using SYBR-green-based microRNA RT-qPCR arrays (Exiqon). Array design was made by literature review and bioinformatics approach using free databases. Relative Expression Software Tool (REST) and SPPS 21.0 were used to data processing and analysis. Results: microRNAs differential expressed between tumors and HV (only up-regulated miRNAs are shown in Table). Conclusions: microRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. These results suggest that our bioinformatic approach is an useful high-throughput method to identified tumors-associated miRNAs. The selected miRNAs should be further evaluated for their potential as markers for CTC detection, prognosis and therapeutic outcome. Further studies of precision and sensitivity on these markers in this GT population will clarify its role as novel stable blood-based markers. [Table: see text]
CCP score and risk stratification for prostate cancer patients at biopsy.
Authors: Crawford E. David , Shore Neal , Scardino Peter T. , Davis John W. , Tward Jonathan D. , Harrison Lowndes , Moyes Kelsey , Fitzgerald Lisa , Stone Steven , Brawer Michael K.
Published: February 2017

47

Background: New prognostic markers for prostate cancer play an important role in addressing the controversies of over diagnosis and treatment. The cell cycle progression score (CCP) (Prolaris, Myriad Genetic Laboratories, Inc.) is a new RNA-based marker, which improved the prediction of prostate cancer aggressiveness in eight separate cohorts. Each one-unit increase in CCP score corresponds with approximately a doubling of the risk of the studied event (recurrence or death from prostate cancer). In this analysis, we characterized the CCP score distribution from our initial CCP signature commercial testing. Methods: Our current laboratory database was evaluated for patients whose biopsy was analyzed with the CCP test and whose clinicopathologic data was collected by the ordering physician. Formalin fixed, prostate biopsy tissue from 1,648 patients diagnosed with adenocarcinoma ordered by more than 300 physicians were analyzed. The CCP score was calculated by measuring the RNA expression of 31 cell cycle progression genes normalized to 15 housekeeping genes. Results: Of the 1,648 samples that contained sufficient carcinoma (more than 0.5mm linear extent), 1,604 (97.3%) provided quality RNA for analysis. This retrospective analysis showed a normal distribution for the CCP score ranging from −2.9 to 3.1. Correlation with Gleason score was r=0.35. A relative classification of cancer aggressiveness based on CCP of approximately1,200 patients from multiple cohorts was developed to interpret how the patient’s CCP score compared to that of patients within the same AUA risk category. The thresholds between each of the five intervals are one unit of CCP score apart, with the "consistent" interval centered at the median CCP score. Based on the CCP score, 27.9% of men had a less aggressive cancer compared to the clinicopathologic prediction and were assigned to a lower risk group while 27.6% of patients had a more aggressive cancer. Conclusions: The CCP signature test is a novel assay that can improve risk stratification for men with prostate adenocarcinoma independent of the Gleason score and prostate-specific antigen level. Over 50% of men initially tested in the commercial assay were assigned to a different risk category than predicted by clinicopathologic features alone.
Biomarker analysis from a phase III trial (GOLD) of dovitinib (Dov) versus sorafenib (Sor) in patients with metastatic renal cell carcinoma after one prior VEGF pathway–targeted therapy and one prior mTOR inhibitor therapy.
Authors: Escudier Bernard J. , Porta Camillo , Squires Matthew , Szczylik Cezary , Kollmannsberger Christian K. , Melichar Bohuslav , Rha Sun Young , Esteban Emilio , Bjarnason Georg A. , Vogelzang Nicholas J. , Sternberg Cora N. , Shi Michael , Marker Mathab , Motzer Robert John
Published: February 2017

473

Background: In the GOLD trial, Dov did not improve progression-free survival (PFS) or overall survival (OS) over Sor. An exploratory objective of the study was to investigate plasma and tumor biomarkers to predict outcome. Methods: Plasma samples were obtained longitudinally throughout the study, and biomarkers were assessed by immunoassay. Primary archival tumor samples were assessed by immunohistochemistry. Log-rank tests, stratified by baseline MSKCC risk group, for difference in Kaplan-Meier curves between biomarker category (low/high based on </≥ median baseline values) within treatment arm were performed. Hazard ratios (HRs) were estimated from Cox proportional hazards models. Results: Plasma samples were available from 561 patients (Dov, n = 281; Sor, n = 280), and tumor samples were available from 341 patients (Dov, n = 181; Sor, n = 160). Baseline plasma biomarker levels were not predictive of Dov or Sor PFS or OS. However, strong prognostic effects, particularly for OS, were observed. High baseline cKIT and low baseline FGF2, HGF, PlGF, sVEGFR1, VEGFA, and VEGFD were associated with better OS for both Dov and Sor (Table). Changes from baseline in a number of plasma biomarkers were observed following treatment with Dov and Sor, consistent with VEGFR/FGFR inhibitory effects. Prognostic effects were also observed for low FGFR2 (PFS) and low FGF2 (OS) expression in archival tumors. Conclusions: Baseline plasma biomarkers are prognostic but not predictive in the third-line setting. Clinical trial information: NCT01223027. [Table: see text]
The impact of body mass index on treatment recommendations for patients with intermediate risk prostate cancer.
Authors: Yamoah Kosj , Whittemore Alice S. , Malkowicz S. Bruce , Spangler Elaine , Kattan Michael W. , Dicker Adam , Rebbeck Timothy R.
Published: February 2017

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Background: To evaluate the clinical utility of body mass index (BMI) in predicting adverse pathologic outcomes, hence the need for radiation therapy (RT) following radical prostatectomy (RP) for men with organ-confined prostate cancer. Methods: We compared BMI and preoperative risk factors to adverse pathologic risk factors (RP-risk) that dictate the use of RT following RP. Multivariate analysis was used to determine whether BMI provides clinically relevant information in predicting RP-risk for additional RT as well as biochemical outcome. Results: Patients with elevated BMI had higher RP-risk (p=0.002). Specifically, extraprostatic extension, p less than 0.001; positive surgical margins, p=0.005; and a trend towards worse seminal vesicle invasion, p=0.08. Elevated BMI did not correlate with preoperative risk groupings (p=0.38). However, in patients with intermediate-risk disease BMI greater than 29kg/m2 was strongly associated with higher RP-risk (p=0.03) and higher rate of pathologic upgrading of tumors (p<0.004). Intermediate risk patients with BMI greater than 29kg/m2had a two-fold increased risk of requiring RT following RP based on greater than or equal to two adverse pathologic factors (15% vs. 34%). After controlling for known preoperative risk factors, BMI was an independent predictor of RP-risk for additional RT (p=0.006) and biochemical recurrence (p=0.03). Conclusions: BMI of greater than 29kg/m2 is an independent predictor of adverse RP-risk requiring additional RT, particularly in patients with intermediate risk disease. This select group of patients may be best treated with definitive radiation therapy to prevent the additional toxicity from adjuvant or salvage RT following RP. We propose including BMI in clinical decision-making for appropriate treatment recommendation for patients with intermediate risk prostate cancer.
Long-term clinical and toxicity outcomes of hypofractionated intensity-modulated radiation therapy for clinically localized prostate cancer.
Authors: Kotecha Rupesh , Weller Michael A. , Marwaha Gaurav , Hearn Jason , Kupelian Patrick , Reddy Chandana A. , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D.
Published: February 2017

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Background: As an alternative to dose-escalated conventionally fractionated radiotherapy, hypofractionation capitalizes on the unique radiobiology of prostate cancer cells. This study reports the long-term clinical outcomes and late treatment-related toxicities in patients with clinically localized prostate adenocarcinoma treated with hypofractionated radiation therapy at a single tertiary-care institution. Methods: Between 1996 and 2008, 822 patients were treated with hypofractionated intensity modulated radiation therapy (IMRT) (70 Gy in 2.5 Gy/fraction) directed to the prostate gland with or without coverage of the seminal vesicles over a 5.5 week period. Actuarial rates of biochemical relapse free survival by the nadir + 2 definition (bRFS), distant metastasis free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes were available and measured according to the National Cancer Institute Common Toxicity Criteria (v3) in 773 (94%) of the patients. Results: The median follow-up was 8.5 years (range: 0-14.2 years). The overall 10-year bRFS, DMFS, and OS rates were 69.6%, 86.4%, and 71.7%, respectively. By National Comprehensive Cancer Network (NCCN) low-, intermediate-, and high-risk groups, the 10-year bRFS rates were 86.9%, 74.1%, and 41.3%, respectively. The rate of grade 2 or worse late genitourinary (GU) and gastrointestinal (GI) toxicity rates were 17.2% and 5.6 %. Only 1.4% of patients experienced late equal to or greater than grade 3 GU toxicity and 1.0% experienced late greater than or equal to grade 3 GI toxicity. Of those who had any toxicity during the follow-up period, 47% and 65% of patients experienced resolution or improvement in their GU and GI symptoms, respectively. Conclusions: Hypofractionated IMRT for localized prostate cancer provides excellent long-term relapse-free survival rates that are comparable to historical studies using conventional fractionation. With modern IMRT and image guidance, HFRT has an acceptably low incidence of late GU and GI toxicities, and appears to be a suitable treatment alternative to conventional fractionation.
A weighted-adjusted indirect comparison of everolimus (EVE) versus axitinib (AXI) in second-line metastatic renal cell carcinoma (mRCC) patients who previously failed sunitinib therapy.
Authors: Sherman Steven A. , Wang Xufang , Amzal Billy , Casciano Roman , Gao Haitao , Stergiopoulos Sotirios G. , Calvo Emiliano
Published: February 2017

491

Background: Both EVE and AXI have been approved for second-line treatment of mRCC after VEGFR-TKI therapy failure. No head-to-head clinical trial has compared clinical outcomes between EVE and AXI in this setting. This study aims to compare progression free survival (PFS) from two phase III clinical trials among mRCC patients with SUN as their only prior antineoplastic therapy and subsequently treated with EVE in the RECORD-1 trial vs. AXI in the AXIS trial, after adjusting for cross-trial differences. Methods: A weighted-adjusted indirect comparison using patient-level data from RECORD-1 and summary data from the AXIS trial publication was performed to align baseline characteristics from both trials and compare PFS (central review). A subset of N=43 second-line SUN -refractory mRCC patients treated with EVE were identified in RECORD-1 to correspond to a similar subset of patients (N=194) treated with AXI in AXIS. Logistic regression was used to identify factors predicting PFS in RECORD-1. The RECORD-1 subset was weighted to align the distributions of these key factors (i.e., MSKCC risk, gender, and time on prior SUN) with the AXIS subset. Weights were calculated for each patient using the following equation: Wi = [Pi (AAXIS)/Pi (ARECORD-1)] * [Pi (BAXIS)/Pi (BRECORD-1)] * [Pi (CAXIS)/Pi (CRECORD-1)], where A=Gender, B=MSKCC risk, and C=time on prior SUN. A weighted median PFS estimate with 95% bootstrap confidence interval (CI) and corresponding Kaplan-Meier (KM) curve were derived for EVE patients. Results: After weighting, the three key baseline characteristics were mostly comparable between the two studies, with the exception of MSKCC where a higher proportion of poor risk patients was evident in RECORD-1 (42%) vs. AXIS (33%). A median PFS of 5.1 months (95% CI: 3.6-10.7) was observed for weighted EVE patients compared to 4.8 months (95% CI: 4.5-6.4) reported in AXIS. Conclusions: The PFS estimates suggest similar efficacy between EVE and AXI in SUN-refractory mRCC patients. Further research is needed to confirm these results, which should be interpreted as those from an observational study.
Second-line prescribing preferences (PPrefs) of U.S.-based medical oncologists’ (MOs) following first-line TKI in patients with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Ryan Charles J. , Green Mark R. , Britton Susan L. , Buettner Arden , Lankford Maria , Neely Douglas
Published: February 2017

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Background: During 2013 we assessed PPrefs for 2nd line therapy among 294 MOs based on age and outcome with 1st line TKI management for mccRCC using a validated, proprietary, live, case-based market research tool. A core case scenario with 3 1st line therapy outcomes - objective response; stable disease (SD); progressive disease (PD) -was constructed. Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case–43 y.o.with recurrent disease in lung and bone 4 years after nephrectomy for ccRCC. PS 1. No brain mets. CrCl 79 ml/min. Scenarios tested (S1, S2, etc.): S1: 9 month objective PR with sunitinib/pazopanib 1st line. S2: 4 months stable disease with pazopanib 1st line. S3: Progression at 8 weeks with sunitinib 1st line. Results: Data from events 1 - 3 are shown in Table. Conclusions: Majority of 2nd line prescribing is mTOR-based with everolimus preferred over temsirolimus. Use of a TKI as 1st salvage after 1st line TKI is preferred by 38–51% of MOs when 1st line response is an extended objective PR. There is very limited preference for sequential TKIs when the best initial response is SD for < 6 months or PD as best response. Current no specific TKI is the dominant PPrefs among MOs in this 1st salvage setting. [Table: see text]
Sequential treatment of advanced or metastatic renal cell carcinoma (mRCC): What is effective? Data from the German RCC registry.
Authors: Mueller Lothar , Goebell Peter J. , Lueck A. , Overkamp Friedrich , Vogt Michele , Marschner Norbert
Published: February 2017

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Background: In addition to Bevacizumab+Interferon, current treatment options of mRCC imply two major intracellular modes of action and thus classes of therapies: the four approved tyrosine kinase inhibitors (TKI) Sunitinib, Sorafenib, Pazopanib, Axitinib and the two inhibitors of the mammalian target of rapamycin (mTOR) Temsirolimus, Everolimus (EVE). With their availability efficacy of sequential treatment has become a central question of clinical research. While clinical trials recruit highly selected patients (pts) and usually focus on a single line of therapy, collected data of clinical registries may represent all patients and all sequential therapies. Methods: Starting in 12/2007 the registry aims to enrol a total of 1500 patients from more than 120 oncology and urology outpatient centres collecting data on all systemic treatments, outcome, patient and tumour characteristics. Here, the effectiveness of two 1st – 2nd-line sequential treatments, TKI–TKI vs TKI–EVE, was investigated with a multivariate cox proportional hazards model considering potential confounding variables (age, comorbidity, body mass index (BMI), duration of 1st-line therapy, Motzer’s score and type of sequential treatment). Results: At the time of analysis, 481 pts had received sequential 1st- and 2nd-line treatment between 2007 and 2012. In total, 70% of pts received 1st-line TKI-treatment. 46% of these pts received the sequential treatment TKI–TKI, 25% received TKI–EVE. In the multivariate analysis, high BMI (HR 0.946, 95% CI 0.9018-0.9923, p<.05) and a long duration of 1st-line-therapy (HR 0.9967, 95% CI 0.9956-0.9979, p<.001) had a significant positive impact on OS, whereas high risk Motzer`s score (HR 8.9992, 95% CI 2.4231-33.4228, p<.01) had a significant negative impact on OS. However, the type of sequential treatment had no impact on OS (HR 1.0658, 95% CI0.6463-1.7576, p=0.802). Conclusions: The RCC Registry provides an overview of the current treatment reality in routine medical practice. TKI are the most frequently applied 1st-line treatments, followed by TKI or mTOR inhibitors. Our data show no difference concerning the effectiveness of the sequential treatment TKI–TKI vs TKI–EVE.