bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis of sarcomatoid clear-cell renal cell carcinomas reveals an immune subgroup.
Authors: Malouf Gabriel G. , Flippot Ronan , Mouawad Roger , Yao Hui , Comperat Eva , Roupret Morgan , Khayat David , Spano Jean-Philippe , Su Xiaoping , Tannir Nizar M. 
Published: September 2018

4571 Background: Integrative analysis of clear-cell renal cell carcinomas (ccRCC) has revealed four transcriptomic subgroups associated with distinct patients outcomes. Integrative analysis of sarcomatoid ccRCC which represent the most agressive forms of ccRCC remains unknown. Methods: We performed integrative analysis of sarcomatoid (n = 28) and Fuhrman grade IV ccRCC (n = 9) using whole-exome sequencing (n = 37), RNA-sequencing (n = 32), and DNA methylation profiling by Infinium 450K arrays (n = 31). Correlation with clinico-pathlogical tumor features and patients outcomes were performed. Results: The most frequent somatic mutations in sarcomatoid ccRCC were VHL (71%), PBRM1 (50%), SETD2 (21%), BAP1 (11%), and TP53 (11%). Hierarchical unsupervised clustering of gene expression revealed two transcriptomic subgroups C1 and C2 which do not differ in term of clinical features, presence of sarcomatoid dedifferentiation and patients outcomes. Furthermore, these clusters do not differ according to their genomic features ( VHL, PBRM1 and SETD2 mutations) or their mutational loads. Strikingly, C1 cluster was highly enriched for genes related to T cell receptor signaling pathway (p = 2.6x10-6) and adapative immunity (p = 8.5x10-5); in addition, the C1 « immune » subgroup was characterized by up-regulation of genes related to cell cycle. Conversely, C2 cluster revealed down-regulation of metabolic pathways (p = 7. 5x10-5). At the epigenetic level, methylome clustering revealed two distinct epi-clusters, epi-C1 (n = 10) and epi-C2 (n = 21); patients with tumors belonging to C2 epi-cluster displayed 9p loss and harbored inferior progression-free survival as compared to those in C1 epi-cluster (11 months versus NR ; P = 0.02); of note, this was independent of clinico-pathological tumor features and transcriptomic classification. Conclusions: Our data suggest that genetic and epigenetic landscapes of sarcomatoid ccRCC might not differ from grade IV ccRCC. In addition, we discovered an immune sarcomatoid ccRCC cluster. This finding provides a rationale for use of immune checkpoint inhibitors in sarcomatoid ccRCC.
Safety and efficacy of nivolumab for metastatic renal cell carcinoma (mRCC): Real world data from an Italian expanded access program (EAP).
Authors: De Giorgi Ugo , Scagliarini Sarah , Basso Umberto , Galli Luca , Mosillo Claudia , Caserta Claudia , Rossetti Sabrina , Guida Annalisa , Bearz Alessandra , Buti Sebastiano , Lo Re Giovanni , Valcamonico Francesca , Hamzaj Alketa , Cognetti Francesco , Rastelli Francesca , Fornarini Giuseppe , Porta Camillo , Del Bene Gabriella , Turci Daniele , Procopio Giuseppe ,   Italian EAP RCC Group
Published: September 2018

4577 Background: Nivolumab showed a survival benefit in a randomised phase III trial in pre-treated mRCC. The EAP provided the opportunity to treat patients (pts) in real world clinical practice before market availability of the drug clinical practice. The aim of this analysis was to evaluate the safety and activity of nivolumab in a real world setting. Methods: Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for mRCC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events using CTCAE v.4.0. Results: Totally, 389 pts were enrolled in the EAP across 95 Italian sites, median age was 65 years (range, 34-85) with 70 (18%) aged ≥ 75 yrs. Pts had a clear-cell RCC in 92% of cases, bone metastases in 50% and brain metastases in 8%, and received more than one previous line in 79% of cases. At the time of this analysis, median number of doses received was 10 (1-31) and 82 (21%) pts were treated beyond progression. Among 389 pts, 18 pts (5%) discontinued treatment due to AE. The best overall response rate was 17% including one complete and 66 partial responses, whereas 121 (31%) had stable disease. With a median follow-up of 7 months (range, 1 to 16), 6-month and 9-month survival rates were 83% and 77%, respectively. Response and survival rates were comparable among pts regardless age, presence of brain or bone metastases and number of prior therapies. Conclusions: This EAP represents the most extensive reported real-world experience with nivolumab in pre-treated RCC pts. These first data seem to confirm efficacy and safety data of the pivotal trial in a real world setting. Results in patient populations poorly (elderly or bone metastases) or not represented at all (brain metastases) in the pivotal trial encourage the use of nivolumab in these subgroups of RCC pts.
Evaluation of disease-free survival as an intermediate metric for overall survival in localized renal cell carcinoma: A trial-level meta-analysis.
Authors: Harshman Lauren Christine , Xie Wanling , Moreira Raphael Brandao , Bosse Dominick , Ruiz Ares Gustavo , Sweeney Christopher , Choueiri Toni K. 
Published: September 2018

4585 Background: Adjuvant trials aim to integrate systemic therapy earlier to increase cure rates over surgery alone. Overall survival (OS) is a critical endpoint for these studies but requires long durations to events and significant patient resources. We explored the potential use of disease-free survival (DFS) as an intermediate readout for OS in the adjuvant setting for localized renal cell carcinoma (RCC). Methods: We performed a systematic literature review following the PRISMA guidelines. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. Data on hazard ratio (HR) and 5-year event-free rate from Kaplan-Meier estimates were extracted. We performed a trial level meta-analysis and correlated these estimates for OS and DFS, weighted by the number of DFS events. R-square > 0.7 would indicate a strong correlation and potential for surrogacy. Results: Thirteen RCTs encompassing 6,473 patients treated with various forms of systemic therapy were eligible for the analyses. Minimum follow-up was 40 months. There was a moderate correlation between 5-year DFS and 5-year OS rates (R-square = 0.49, 95% CI:0.15-0.68) and between treatment effects as measured by DFS and OS hazard ratios (R-square = 0.44, 95% CI:0.00-0.69). Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5-year DFS and OS rates and between treatment effects (HRs) on these endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]
Next-generation sequencing (NGS) of tissue and cell free DNA (cfDNA) to identify somatic and germline alterations in advanced prostate cancer.
Authors: Cheng Michael L. , Abida Wassim , Rathkopf Dana E. , Arcila Maria E. , Barron David , Autio Karen A. , Zehir Ahmet , Danila Daniel Costin , Morris Michael J. , Gopalan Anuradha , Reuter Victor E. , Kantoff Philip W. , Slovin Susan F. , Robson Mark E. , Zhang Liying , Mandelker Diana , Tsui Dana , Taylor Barry S. , Solit David B. , Scher Howard I. 
Published: September 2018

5010 Background: With the goal of accelerating enrollment onto appropriate clinical trials, we performed prospective genomic characterization of pts with advanced prostate cancer. Given the long natural history and osseous disease predominance, we also analyzed plasma cfDNA to assess the feasibility of identifying targetable alterations in pts for whom adequate tumor tissue was unavailable. Methods: 1038 tumors from 896 pts along with matched normal DNA were analyzed with a capture-based NGS assay (MSK-IMPACT) targeting 341–468 genes. In 5/2015, the protocol was amended to allow pts to opt-in for a formal germline analysis of 76 genes associated with heritable cancer risk. In select pts, plasma cfDNA was collected and analyzed using the same assay. Results: Between 2/2014 and 2/2017, 576 primary tumors and 462 metastases were sequenced. The most notable finding was the high frequency of known or likely pathogenic germline and somatic mutations in genes that regulate DNA damage response (DDR). In the subset with both tumor and germline analysis, 28.84% (169/586) had a DDR mutation identified compared to only 10.65% (33/310) of pts with somatic only analysis. In the subset with tumor and germline analysis, 9.39% (55/586) had somatic only DDR mutations and 16.38% (96/586) had germline only DDR mutations, including 8 pts with two germline mutations. 3.07% (18/586) had co-occurring somatic and germline DDR mutations, with only 0.68% (4/586) involving the same DDR gene (all BRCA2). Prostate cancer had the highest tissue failure rate among the overall MSK-IMPACT solid tumor cohort, and bone biopsy-derived tissue was successfully sequenced in only 42% of pts. Profiling of cfDNA did identify somatic DDR or AR mutations in 12.5% (4/32) of pts without adequate tumor for analysis. Conclusions: This prospective genomic profiling effort identified frequent somatic and germline DDR mutations that may guide PARPi or platinum therapy. Both somatic and germline analyses were required to identify all pts with likely pathogenic DDR alterations. NGS-based cfDNA analysis is feasible in advanced prostate cancer and may identify mutations missed by tumor only sequencing.
Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups.
Authors: Macomson Brian , Lin Jennifer H , Tunceli Ozgur , Behl Ajay S. , Pericone Chris , Deshmukh Siddhant , Shore Neal D. 
Published: September 2018

5027 Background: Interventions in nmCRPC are the last defense against metastasis, which drives health care cost and mortality. To assess the value of such interventions we must analyze risk factors for metastasis and death. Methods: This was a retrospective study of data (Optum electronic health record database, 2007 – 2016) from men with a prostate cancer diagnosis, 2 rising PSA levels ≥1 week apart, castrate level ( < 50 ng/dL) testosterone (T) and no ICD-9/10 code or therapy indicating metastasis. Gleason grade (G) and PSA data up to and including nmCRPC index date (ie, date of 2nd PSA rise) were used to assign NCCN risk groups: Low (G ≤6 and PSA < 10 ng/mL), Intermediate (IM) (G = 7 or 10 ≤ PSA ≤ 20 ng/mL) or High (G ≥ 8 or PSA > 20 ng/mL). The LP/NG group comprised men with PSA < 10 ng/mL (LP) and missing G (NG). A Cox proportional hazard model, adjusted for age, race, comorbidity index score, T level, therapy type and bone scans was used to compare LP/NG, IM and High with the Low risk group. Results: Among 1008 men with nmCRPC (mean age 76 years; 12% African American), 553 developed metastases and 430 died during follow-up. Mean time to metastasis was 28, 22, 15, 13 months in the Low, LP/NG, IM, and High groups, respectively. In the Low group, 9 of 29 (31%) men developed metastases, vs 131/285 (46%) in the LP/NG group (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 0.86-3.35), 175/320 (55%) in the IM group (HR = 2.52, 95% CI: 1.28-4.91) and 238/374 (64%) in the High group (HR = 3.63, 95% CI: 1.85-7.10). Mean time to death was 32, 30, 24, 21 months in the Low, LP/NG, IM, High groups, respectively. There were 8 deaths in the Low group (27.6%), vs 101 (35.4%) (HR = 1.35, 95% CI: 0.65-2.79) in the LP/NG group, 124 (38.8%) (HR = 1.79, 95% CI: 0.87-3.70) in the IM group and 197 (52.7%) (HR = 2.96, 95% CI: 1.45-6.05) in the High group. The High risk group was more likely to develop metastasis during the first year and die within the first 2 years. Conclusions: Metastasis and death occurred earlier and more frequently in the Intermediate and High groups relative to the Low risk group. These findings may further inform diagnostic and management strategies for combating disease progression.
Androgen deprivation therapy in the treatment of prostate cancer and dementia risk: A systematic review and meta-analysis.
Authors: Nead Kevin Thomas , Sinha Sumi , Nguyen Paul L. 
Published: September 2018

5044 Background: Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we conduct a systematic review and meta-analysis on the association of ADT in the treatment of prostate cancer with the risk of dementia. Methods: We conducted a systematic review of articles reporting the outcome of dementia among individuals with prostate cancer in those exposed to ADT versus a lesser-exposed comparison group (e.g. no ADT, intermittent ADT) using the PRISMA statement guidelines. Two authors independently carried out searches in PubMed (1966–present), Web of Science (1945–present), Embase (1966–present), and PsycINFO (1806–present). The search was undertaken December 4th, 2016. We assessed the validity of each study per the Newcastle-Ottawa Scale criteria. We meta-analyzed studies reporting an effect estimate and controlling for confounding.Random- or fixed-effects meta-analytic models were used in the presence or absence of heterogeneity, respectively, per the I2statistic. Small study effects were evaluated using Egger and Begg’s tests. Results: Nine studies were included in the systematic review. Seven studies reported an adjusted effect estimate for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, which included 50,541 individuals, showed an increased risk of dementia among ADT users (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08–2.00; p = 0.02). We separately meta-analyzed studies reporting all-cause dementia (HR, 1.46; 95% CI, 1.05–2.02; p < 0.001) and Alzheimer’s disease (HR, 1.25; 95% CI, 0.99–1.57; p = 0.06). The I2statistic to evaluate the proportion of heterogeneity due to study variation was 76% (95% CI, 47–89; p < 0.001) for the primary analysis. There was no evidence of bias from small study effects (Egger, p = 0.19; Begg, p = 1.00). Conclusions: The currently available combined evidence suggests that ADT in the treatment of prostate cancer may be associated with an increased risk of dementia. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively.
Genome-wide analysis of metastases to reveal association of pathway activation with abiraterone acetate/prednisone (AA/P) primary resistance and cell cycle proliferation pathway activation with response duration in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Wang Liewei , Dehm Scott , Hillman David W. , Sicotte Hugues , Gormley Michael , Bhargava Vipul , Li Weimin , Tan Winston , Pitot Henry C. , Ho Thai Huu , Costello Brian Addis , Bryce Alan H. , Zhenqing Ye , Vedell Peter T , Barman Poulami , Jimenez Rafael E. , Carlson Rachel , Wang Liguo 
Published: September 2018

5053 Background: Genomic aberrations associated with resistance/response to AA/P are not known. In a prospective study we assessed whole-exome/RNA-seq based aberrations in CRPC metastatic biopsies for identifying molecular markers associated with primary resistance and response duration. Methods: Sequencing of metastatic biopsies was performed for analyzing molecular aberrations that predict primary resistance (defined as progression at 12-weeks of therapy (non-responders) using PSA, RECIST, bone scan criteria per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders and in genes differentially expressed between non-responders and responders using a “risk ratio” (RR) of ≥2. Cox regression models with multiple gene network pathways were used for determining association with time to treatment change (TTTC). Results: Of 92 enrolled pts 82 had complete whole-exome, RNA-seq & 12-week outcome data available for analysis. At 12-weeks 33/82 had progressed. Using a RR of ≥2, 113 genes were more frequently mutated in non-responders & 292 in responders. In non-responders, gene network analysis revealed frequent mutations in Wnt/β-catenin pathway genes; frequent deletion of negative regulators of Wnt pathway ( DKK4, SFRP2, LRP6). Gene expression analyses revealed significantly reduced expression levels of Wnt/β-catenin pathway inhibitors and increased expression levels of cell cycle proliferation (CCP) genes in non-responders. Median study follow up was 32 months during which time 58/82 pts progressed and switched treatments. Median TTTC was 10.1 months (IQR:4.4-24.1). In multivariate analysis CCP scores of ≥50 predicted shorter TTTC (HR = 2.11, 95% CI: 1.17-3.80; p = 0.01). Conclusions: In metastases Wnt/β-catenin pathway activation is associated with primary AA/P resistance and increased CCP with acquired drug resistance. These findings offer molecular based predictive biomarkers in CRPC stage treatment. Clinical trial information: NCT#01953640.
Effect of Ga-68 PSMA-11 PET on management in patients with recurrent prostate cancer.
Authors: Hope Tom , Aggarwal Rahul Raj , Greene Kirsten L , Chee Bryant , Tao Dora , Feng Felix Yi-Chung , Chang Albert , Cooperberg Matthew R. , Ryan Charles J. , Small Eric Jay , Carroll Peter 
Published: September 2018

5057 Background: PET imaging of prostate specific membrane antigen (PSMA) has been shown to have a higher sensitivity and specificity compared to conventional imaging. The objective was to evaluate the impact of PSMA PET on the management of prostate cancer patients with biochemical recurrence following local therapy. Methods: In our initial Ga-68-PSMA-11 PET protocol (NCT02611882), 150 patients with biochemical recurrence were imaged. 63 patients were imaged using PET/CT (GE Discovery VCT) and 63 patients using PET/MRI (GE Signa 3.0T PET/MRI). 110 patients received Lasix injections. Referring clinicians filled out a pretreatment management form and a management form based on the imaging results. Changes in management were graded as major, minor, no change or unknown based upon the responses. Results: We received both pre and post imaging forms in 126 patients, for an 84% response rate. The average PSA in the population was 5.9 ± 5.4 ng/mL with an average doubling time of 9.7 ± 11.0 months, and 60 patients had a PSA of less than 2.0 at the time of imaging. The average time between prior treatment and imaging (RP and/or radiation) was 5.3 ± 5.4 years, with 46 patients imaged within two years of their most recent treatment. 43 patients had a prior prostatectomy, 41 prior radiation, and 33 patients had both. 103 patients (82%) had disease localized on PSMA imaging. Of the 126 patients, 67 (53%) of the imaging studies resulted in a major change in management. The most common major change was converting from active surveillance to radiation therapy (15 patients, 12%), changing from ADT to radiation therapy (16 patients, 13%), and converting from radiation therapy to either active surveillance (6 patients, 5%) or to ADT alone (3 patients, 2%). 10 patients (8%) had a minor change, 42 patients (33%) had no change, and 7 patients (6%) had an unknown change in management. Conclusions: The results of our surveys demonstrate a substantial impact of PSMA PET on the intended patient management. The majority of changes involved converting a targeted therapy to systemic treatment or systemic treatment to a targeted therapy. Prospective studies are warranted to determine whether directed treatment towards PSMA-avid lesions affects long-term disease outcomes. Clinical trial information: NCT02611882.
Comprehensive molecular profiling of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue-based prognostic biomarkers.
Authors: Salami Simpa Samuel , Hovelson Daniel H , Mathieu Romain , Kaplan Jeremy B , Susani Martin , Rioux-Leclercq Nathalie , Shariat Shahrokh F. , Tomlins Scott A. , Palapattu Ganesh S. 
Published: September 2018

5061 Background: Current tissue-based prognostic biomarker assays claim that assessment of a single biopsy focus is sufficient to predict disease behavior. We analyzed and compared the genetic profiles of multifocal prostate cancer (PCa) with concordant lymph node metastasis (LNM) to determine if expression-based prognostic tests are robust to multifocality. Methods: This IRB-approved study comprised patients who underwent radical prostatectomy and lymph node dissection that revealed N1 or discordant multifocal (low- and high-grade foci) disease. DNA and RNA were co-isolated from each tumor focus pre-identified on formalin fixed paraffin embedded specimens. High depth, targeted DNA and RNA next generation sequencing was performed to characterize the molecular profile of each sample, using the Oncomine Comprehensive (11 patients) or Comprehensive Cancer (DNA, 3 patients) Panels and a custom targeted RNAseq panel comprising genes for deriving prognostic signatures. Results: A total of 67 primary tumor and 17 LNM foci from 14 patients were analyzed. We observed significant intra- and inter-patient molecular heterogeneity. For example, in patient #1, while all 4 regions of high-grade primary tumor showed TP53 somatic mutations and some copy number alterations (CNAs) with two samples from the LNM, tumor areas near the positive margin showed more complete concordance than intraprostatic regions. Critically, a low-grade primary tumor focus in this case showed no somatic mutation or CNA overlap with the high-grade or LNM samples. In patient #4, all tumor and LNM foci shared a large number of somatic mutations, including a frameshift mutation in PTEN, with no high level CNA, consistent with a hypermutated genotype. By targeted RNAseq, low- and high-grade tumors from the same patient showed distinct expression profiles using genes included in prognostic signatures. Conclusions: Our results challenge the claim that expression-based prognostic tests are robust to multifocality. Further studies are needed to better characterize the biologically dominant lesion in multifocal PCa and hold promise for the development of improved prognostic biomarkers.