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1.  The Safety and Efficacy of Single-Agent Pemetrexed in Platinum-Resistant Advanced Urothelial Carcinoma: A Large Single-Institution Experience 
The Oncologist  2015;20(5):508-515.
This study presents the largest reported series of patients treated with pemetrexed. The results show that although well-tolerated, pemetrexed had limited efficacy. They also suggest a role for neutrophil-lymphocyte in the prognostication of advanced urothelial cancer, which may be relevant when constructing prognostic models in future studies. There is an urgent need to develop novel therapies for this lethal disease.
Background.
Pemetrexed is a commonly used treatment for platinum-resistant advanced urothelial carcinoma (UC) based on objective response rates of 8% and 28% in two small phase II studies. To address the discrepancy in reported response rates and to assess efficacy and toxicity outside of a clinical trial setting, we performed a large retrospective analysis of pemetrexed use at Memorial Sloan Kettering Cancer Center. We also investigated candidate prognostic factors for overall survival in this setting to explore whether the neutrophil-lymphocyte ratio (NLR) had independent prognostic significance.
Patients and Methods.
Patients receiving pemetrexed for platinum-resistant advanced UC between 2008 and 2013 were identified. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to determine response rate. Kaplan-Meier and Cox regression analyses were used to examine the association of various factors with efficacy and survival outcomes. Hematologic toxicity and laboratory abnormalities were recorded.
Results.
One hundred and twenty-nine patients were treated with pemetrexed. The objective response rate was 5% (95% confidence interval: 1%–9%), and the median duration of response was 8 months. Median progression-free survival (PFS) was 2.4 months, and the 6-month PFS rate was 14%. There was no significant difference in response rate by age, Eastern Cooperative Oncology Group (ECOG) performance status, or number of prior therapies. On multivariable analysis, ECOG performance status (p < .01), liver metastases (p = .02), and NLR (p < .01) had independent prognostic significance for overall survival.
Conclusion.
This 129-patient series is the largest reported data set describing pemetrexed use in advanced UC. Activity was modest, although discovery of molecular biomarkers predictive of response would be valuable to identify the small subset of patients who do gain significant benefit. Overall, the data highlight the urgent need to develop novel therapies for these patients.
doi:10.1634/theoncologist.2014-0354
PMCID: PMC4425381  PMID: 25845990
Pemetrexed; Bladder cancer; Urothelial carcinoma
2.  Genomic Characterization of Upper Tract Urothelial Carcinoma 
European urology  2015;68(6):970-977.
Background
Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.
Objective
To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.
Design, setting, and participants
Tumor and germline DNA from patients with UTUC (n = 83) and UCB (n = 102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy-number alterations in 300 cancer-associated genes.
Outcome measurements and statistical analysis
We described co-mutation patterns and copy-number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n = 59) and high-grade UCB (n = 102).
Results and limitations
Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Alterations more common in high-grade UTUC included fibroblast growth factor receptor 3 (FGFR3; 35.6% vs 21.6%; p = 0.065), Harvey rat sarcoma viral oncogene homolog (HRAS; 13.6% vs 1.0%; p = 0.001), and cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B; 15.3% vs 3.9%; p = 0.016). Genes less frequently mutated in high-grade UTUC included tumor protein p53 (TP53; 25.4% vs 57.8%; p < 0.001), retinoblastoma 1 (RB1; 0.0% vs 18.6%; p < 0.001), and AT rich interactive domain 1A (SWI-like) (ARID1A; 13.6% vs 27.5%; p = 0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.
Conclusions
High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.
Patient summary
Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.
doi:10.1016/j.eururo.2015.07.039
PMCID: PMC4675454  PMID: 26278805
Upper tract urothelial carcinoma; Genomics; Bladder cancer; Targeted therapy
3.  Somatic ERCC2 Mutations Are Associated with a Distinct Genomic Signature in Urothelial Tumors 
Nature genetics  2016;48(6):600-606.
Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide excision repair (NER) pathway has not yet been identified. Here, we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts reveals a strong association between somatic ERCC2 mutations and activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify the first NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping the tumor mutational landscape.
doi:10.1038/ng.3557
PMCID: PMC4936490  PMID: 27111033
4.  Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma 
The Journal of urology  2016;195(6):1684-1689.
Purpose
Genomic characterization of radical nephroureterectomy (RNU) specimens in patients with upper tract urothelial carcinoma (UTUC) may allow for thoughtful integration of systemic and targeted therapies. We sought to determine if genomic alterations in UTUC are associated with adverse pathologic and clinical outcomes.
Materials and Methods
Next-generation exon capture sequencing of 300 cancer-associated genes was performed in 83 patients with UTUC. Genomic alterations were assessed individually and also grouped into core signal transduction pathways or canonical cell functions for association with clinicopathologic outcomes. Binary outcomes, including grade (high vs. low), T stage (pTa/T1/T2 vs. pT3/T4), and organ-confined status (≤pT2 and N0/Nx vs. >pT2 or N+) were assessed with Kruskal-Wallis test and Fisher's exact test as appropriate. Associations between alterations and survival were estimated using the Kaplan-Meier method and Cox regression.
Results
Of the 24 most commonly altered genes within 9 pathways, TP53/MDM2 alterations and FGFR3 mutations were the only two alterations uniformly associated with high-grade, advanced stage, non-organ-confined disease, recurrence-free survival, and cancer-specific survival. TP53/MDM2 alterations were associated with adverse clinicopathologic outcomes whereas FGFR3 mutations were associated with favorable outcomes. We created a risk score using TP53/MDM2 and FGFR3 status that was able to discriminate between adverse pathologic and clinical outcomes, including in the subset of patients with high-grade disease. The study is limited by small numbers and lack of validation.
Conclusions
Our data indicate that specific genomic alterations in RNU specimens correlate with tumor grade, stage, and cancer-specific survival outcomes.
doi:10.1016/j.juro.2016.01.006
PMCID: PMC4871772  PMID: 26778714
upper tract urothelial carcinoma; genomics; prediction; biomarkers; TCC
5.  Elevating the Horizon: Emerging Molecular and Genomic Targets in the Treatment of Advanced Urothelial Carcinoma 
Clinical genitourinary cancer  2015;13(5):410-420.
Despite recent advances in the identification of genomic alterations that lead to urothelial oncogenesis in vitro, advanced urothelial carcinomas continue to have poor clinical outcomes. In this review, we focus on targeted therapies that have yielded the most promising results alone or in combination with traditional chemotherapy, including the antiangiogenesis agent bevacizumab, the human epidermal growth factor receptor 2 antibody trastuzumab, and the tyrosine kinase inhibitor cabozantinib. We also describe ongoing and developing clinical trials that utilize innovative approaches, including dose-dense scheduling of singular chemotherapy combinations, prospective screening of tumor tissues for mutational targets and biomarkers to predict chemosensitivity prior to determination of therapeutic regimen, as well as novel agents that target proteins in the immune checkpoint regulation pathway (PD-1 and anti-PD-L1) which have shown significant potential in preclinical models and early clinical trials. New agents and targeted therapies, alone or in combination with traditional chemotherapy, will only be validated through accrual to developing clinical trials that aim to translate these therapies into individualized treatments and improved survival rates in urothelial carcinoma.
doi:10.1016/j.clgc.2015.02.009
PMCID: PMC4561017  PMID: 25862322
bladder cancer; urothelial cancer; metastatic; targeted therapy; drug resistance; novel agents; immune checkpoints; clinical trials
6.  Frequent somatic CDH1 loss-of-function mutations in plasmacytoid-variant bladder cancer 
Nature genetics  2016;48(4):356-358.
Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole exome and targeted sequencing, we find that truncating somatic alterations in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.
doi:10.1038/ng.3503
PMCID: PMC4827439  PMID: 26901067
E cadherin; plasmacytoid; bladder cancer; CDH1
7.  Molecular Signature of Response to Pazopanib Salvage Therapy for Urothelial Carcinoma 
Clinical genitourinary cancer  2015;14(1):e81-e90.
doi:10.1016/j.clgc.2015.07.017
PMCID: PMC5003615  PMID: 26371421
Advanced disease; Angiogenesis; Clinical benefit; Next-generation sequencing; Pazopanib
8.  A phase II trial of the nucleolin-targeted DNA aptamer AS1411 in metastatic refractory renal cell carcinoma 
Investigational new drugs  2013;32(1):178-187.
Background
DNA aptamers represent a novel strategy in anti-cancer medicine. These compounds are short sequences of DNA that have protein binding effects via shape specific recognition of a target protein in an interaction which is analogous to antibody-antigen binding. AS1411, a DNA aptamer that targets nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, predominantly clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 previous tyrosine kinase inhibitor. We present the first manuscript reporting the use of this novel anti-cancer agent in humans.
Methods
In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1–4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints.
Results
35 patients were enrolled and treated; 33 completed two treatment cycles. Median number of prior therapies was 2 (range 1–7). One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in the sum of longest diameters of selected target tumor lesions) and durable (the patient remains free of progression 2 years after completing therapy). No responses were seen in the other patients. Median PFS was 4 months. Only 34% of patients had an AS1411-related adverse event, all of which were mild or moderate.
Conclusions
AS1411 appears to have limited activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. Further studies with nucleolin targeted compounds may benefit from efforts to discover predictive biomarkers of response. Currently, promising pre-clinical studies are ongoing using AS1411 conjugated to traditional cytotoxic agents to selectively deliver these treatments to tumor cells. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.
doi:10.1007/s10637-013-0045-6
PMCID: PMC4560460  PMID: 24242861
renal cell carcinoma; novel therapeutics; DNA aptamer; nucleotide aptamer; Bcl2
9.  Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206 
Journal of Clinical Oncology  2008;26(33):5422-5428.
Purpose
Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted.
Patients and Methods
Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety.
Results
Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%).
Conclusion
Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.
doi:10.1200/JCO.2008.16.9847
PMCID: PMC2651074  PMID: 18936475
10.  Novel molecular targets for urothelial carcinoma 
doi:10.1517/14728222.2014.987662
PMCID: PMC4406627  PMID: 25633079
Urothelial carcinoma; Genomics; Targeted therapy; Molecular targets
11.  Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma 
Cancer discovery  2014;4(10):1140-1153.
Cisplatin-based chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole exome sequencing on pre-treatment tumor and germline DNA from 50 patients with muscle invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders”, 25 pT2+ “non-responders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with non-responders (q < 0.01). Expression of representative ERCC2 mutations in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. Lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle invasive urothelial carcinoma.
doi:10.1158/2159-8290.CD-14-0623
PMCID: PMC4238969  PMID: 25096233
ERCC2; cisplatin sensitivity; urothelial carcinoma; exceptional responders; nucleotide excision repair defect
12.  Genomic Predictors of Survival in Patients with High-Grade Urothelial Carcinoma of the Bladder 
European urology  2014;67(2):198-201.
Urothelial carcinoma of the bladder (UCB) is genomically heterogeneous, with frequent alterations in genes regulating chromatin state, cell cycle control, and receptor kinase signaling. To identify prognostic genomic markers in high-grade UCB, we utilized capture-based massively-parallel sequencing to analyze 109 tumors.
Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases. The presence of a recurrent PIK3CA mutation was associated with improved recurrence-free survival (RFS; HR=0.35, p=0.014) and cancer-specific survival (CSS; HR=0.35, p=0.040) in patients treated with radical cystectomy. In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR=0.39, p=0.032). The most frequent alteration, TP53 mutation (57%), was more common in extravesical (69% vs. 32%, p=0.005) and lymph node-positive (77% vs. 56%, p=0.025) disease. Patients with CDKN2A altered tumors experienced worse RFS (HR=5.76, p<0.001) and CSS (HR=2.94, p=0.029) in multivariable analyses. Mutations in chromatin modifying genes were highly prevalent but not associated with outcomes.
In UCB patients treated with radical cystectomy, PIK3CA mutations are associated with favorable outcomes whereas TP53 and CDKN2A alterations are associated with poor outcomes. Genomic profiling may aid in the identification of UCB patients at highest risk following radical cystectomy.
doi:10.1016/j.eururo.2014.06.050
PMCID: PMC4312739  PMID: 25092538
bladder cancer; genomics; clinical outcomes; PIK3CA; mutation
13.  Update in Urothelial Carcinoma: Novel Agents and Targeted Therapy 
Urothelial carcinoma (UC) is a chemosensitive disease with high response rates to platinum-based combination chemotherapy in locally advanced or advanced disease. However, de novo or emergence of cisplatin-resistance limits the duration of response, patients are frequently ineligible for cisplatin, and therapies tested thus far have minimal activity as second-line therapy. The first wave of clinical trials of novel agents and targeted therapy have modestly advanced the field and laid the foundations for future studies. These trials include the deployment of monoclonal antibodies and tyrosine kinase inhibitors that target mediators of angiogenesis and growth receptors. Novel cytotoxic agents have also been tested as single-agents in the second-line setting and together with the first-line combination of gemcitabine with cisplatin. To date, these novel agents have yet to demonstrate the ability to substantially improve the overall survival of patients with bladder cancer. Comparative trials of chemotherapy with or without a novel agent are ongoing and have the potential to improve upon current standard therapy. Moreover, state-of-the-art technologies have been developed that will likely identify the molecular alterations which drive both UC and platinum-resistance and in turn provide opportunities for drug development. The latter includes an interrogation of microRNAs and the integrated study of genetic mutations in extreme phenotypes of the disease. In essence, this ongoing work paired with physician and patient commitments to clinical trial participation will ultimately lead to advances in the care of patients with urothelial cancer.
PMCID: PMC4587660  PMID: 26430392
14.  Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma 
Journal of Clinical Oncology  2012;31(2):181-186.
Purpose
Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.
Patients and Methods
Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).
Results
Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.
Conclusion
Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.
doi:10.1200/JCO.2012.43.3383
PMCID: PMC3532390  PMID: 23213094
15.  Docetaxel, bevacizumab, and androgen deprivation therapy for biochemical relapse after definitive local therapy for prostate cancer 
Cancer  2015;121(15):2603-2611.
Background
Patients with biochemical recurrence (BCR) following definitive treatment for prostate cancer (PC) comprise a heterogeneous population for which standard therapy options are lacking. The purpose of this trial is to evaluate the feasibility, toxicity, and efficacy of early multimodality systemic therapy in men with BCR.
Methods
Eligible patients had an increasing prostate-specific antigen (PSA), PSA doubling time ≤10 months and no evidence of metastases following radical prostatectomy (RP) and/or radiation therapy (RT) for localized disease. Treatment consisted of docetaxel 75 mg/m2 every 3 weeks for 4 cycles, bevacizumab 15 mg/kg every 3 weeks for 8 cycles, and androgen deprivation therapy (ADT) for 18 months. The primary endpoint is the proportion of patients free from PSA progression one year following therapy completion.
Results
Forty-one patients are included in the analysis. At one year following completion of ADT, 45% (n=13/29) and 29% (n=5/17) of patients with a testosterone ≥100 ng/dL and testosterone ≥ 240 ng/dL had a PSA < 0.2 ng/mL. The median follow-up is 27.5 months (inter-quartile range: 21.8, 38.1). Eight (20%) patients are free from PSA progression, 19 (46%) did not restart ADT, and 34 (83%) are free from metastasis. Sixteen (39%) patients experienced grade 3 and five (12%) experienced grade 4 toxicities.
Conclusion
Multimodality systemic therapy with docetaxel, bevacizumab, and ADT is feasible and produces PSA responses in men with BCR. Long term follow-up is needed to determine the proportion of patients with a durable PSA response who are able to avoid restarting of prostate cancer therapy.
doi:10.1002/cncr.29398
PMCID: PMC4566852  PMID: 25903013
Androgen deprivation therapy; Bevacizumab; Biochemical recurrence; Docetaxel; Prostate cancer
16.  The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma 
Purpose
Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIFs) and overexpression of HIF target genes, such as vascular endothelial growth factor (VEGF) and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.
Patients and Methods
We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF1α and HIF2α immunohistochemistry staining, and HIF1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate and progression-free survival to pazopanib, a standard first-line VEGF-targeted agent.
Results
The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with overall response rate or progression-free survival. Similarly, HIF1α (65 samples) and HIF2α (66 samples) protein levels (high vs. low) did not correlate with overall response rate or progression-free survival to pazopanib. The HIF1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF1α levels. However, the HIF1α gene expression signature was not associated with clinical outcome to pazopanib.
Conclusion
In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF1α/HIF2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.
doi:10.1158/1078-0432.CCR-13-0491
PMCID: PMC4522695  PMID: 23881929
renal cell carcinoma; VEGF; HIF; VHL; biomarkers; pazopanib
17.  Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer 
Journal of Clinical Oncology  2011;30(5):507-512.
Purpose
Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.
Patients and Methods
The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.
Results
In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.
Conclusion
In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.
doi:10.1200/JCO.2011.37.7002
PMCID: PMC4104290  PMID: 22184381
18.  Advanced Urothelial Carcinoma: Overcoming Treatment Resistance through Novel Treatment Approaches 
The current standard of care for metastatic urothelial carcinoma is cisplatin-based chemotherapy but treatment is generally not curative. Mechanisms of resistance to conventional cytotoxic regimens include tumor cell drug efflux pumps, intracellular anti-oxidants, and enhanced anti-apoptotic signaling. Blockade of signaling pathways with small molecule tyrosine kinase inhibitors has produced dramatic responses in subsets of other cancers. Multiple potential signaling pathway targets are altered in Urothelial carcinoma (UC). Blockade of the PI3K/Akt/mTOR pathway may prove efficacious because 21% have activating PI3K mutations and another 30% have PTEN inactivation (which leads to activation of this pathway). The fibroblast growth factor receptor 3 protein may be overactive in 50–60% and agents which block this pathway are under development. Blockade of multiple other pathways including HER2 and aurora kinase also have potential efficacy. Anti-angiogenic and immunotherapy strategies are also under development in UC and are discussed in this review. Novel therapeutic approaches are needed in UC. We review the various strategies under investigation and discuss how best to evaluate and optimize their efficacy.
doi:10.3389/fphar.2013.00003
PMCID: PMC3565214  PMID: 23390417
urothelial cancer; bladder cancer; oncogenes; chemotherapy; resistance mechanisms
19.  DNA copy number analysis of metastatic urothelial carcinoma with comparison to primary tumors 
BMC Cancer  2015;15:242.
Background
To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease.
Methods
Using molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients.
Results
Based on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p < 0.001). In particular, there was a higher frequency of E2F3 amplification in metastases (30% vs 7%, p = 0.046). Paired primary and metastatic tissue was available for 11 patients and 3 of these had amplifications of potential clinical relevance in metastases that were not in the primary tumor including ERBB2, CDK4, CCND1, E2F3, and AKT1. The transcriptional activity of these amplifications was supported by RNA expression data.
Conclusions
The discordance in alterations between primary and metastatic tissue may be of clinical relevance in the era of genomically directed precision cancer medicine.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1192-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1192-2
PMCID: PMC4392457  PMID: 25886454
20.  Six-Month Progression-Free Survival as the Primary Endpoint to Evaluate the Activity of New Agents as Second-line Therapy for Advanced Urothelial Carcinoma 
Clinical genitourinary cancer  2013;12(2):130-137.
This study examined the association of progression-free survival at 6 months with overall survival in the context of second-line therapy of advanced urothelial carcinoma in pooled patient-level data from 10 phase II trials and then externally validated in a large phase III trial. Progression-free survival at 6 months was significantly correlated with overall survival and is an innovative primary endpoint to evaluate new agents in this setting.
Objective
Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents.
Methods
Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction.
Results
In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R2 = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R2 = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared
doi:10.1016/j.clgc.2013.09.002
PMCID: PMC4142680  PMID: 24220220
Advanced urothelial carcinoma; Intermediate endpoint; Overall survival; Progression-free survival at 6 months; Second-line treatment
21.  Synthetic lethality in ATM-deficient RAD50-mutant tumors underlie outlier response to cancer therapy 
Cancer discovery  2014;4(9):1014-1021.
Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small cell cancer to combined checkpoint kinase 1 (Chk1) inhibition and DNA damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of Chk1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy whereby checkpoint inhibition in combination with DNA damaging chemotherapy is synthetically lethal in tumor but not normal cells with somatic mutations that impair Mre11 complex function.
doi:10.1158/2159-8290.CD-14-0380
PMCID: PMC4155059  PMID: 24934408
DNA damage and repair; cancer genomics; exceptional responders; targeted and systemic therapy; RAD50
22.  Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium 
Journal of Clinical Oncology  2009;27(17):2772-2778.
Purpose
Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.
Patients and Methods
Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or ≥ grade 3 nonhematologic toxicity.
Results
Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced ≥ 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone ≥ 30 mg/m2, nine (43%) experienced ≥ 50% PSA declines (95% CI, 22% to 66%).
Conclusion
These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.
doi:10.1200/JCO.2008.19.8002
PMCID: PMC2698016  PMID: 19349545
23.  Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib 
Cancer discovery  2014;4(5):546-553.
Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole exome sequencing of a patient with a 14-month complete response on this trial revealed two simultaneous mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or “personalized”) medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.
doi:10.1158/2159-8290.CD-13-0353
PMCID: PMC4122326  PMID: 24625776
24.  Integrative analysis of 1q23.3 copy number gain in metastatic urothelial carcinoma 
Purpose
Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum-based chemotherapy.
Experimental Design
We obtained overall survival (OS) and array DNA copy number data from metastatic UC patients in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by Nanostring nCounter to identify transcripts from the region that are associated with copy number gain. In addition, expression data from an independent cohort was used to identify candidate genes.
Results
Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in the both cohorts (adjusted HR 2.96; 95% CI, 1.35 to 6.48; P = 0.01 and adjusted HR 5.03; 95% CI 1.43-17.73; P < 0.001). The F11R, PFDN2, PPOX, USP21 and DEDD genes, all located on 1q23.3, were closely associated with poor outcome.
Conclusions
1q23.3 copy number gain displayed association with poor survival in two cohorts of metastatic UC. The identification of the target of this copy number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of poor risk UC patients. Prospective validation of the survival association is necessary to demonstrate clinical relevance.
doi:10.1158/1078-0432.CCR-13-0759
PMCID: PMC3975677  PMID: 24486590
25.  Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials 
European urology  2012;63(4):717-723.
Background
Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM).
Objectives
The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352).
Outcome measurements and statistical analysis
Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures.
Results and limitations
ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable.
Conclusions
Shorter TFPC enhances prognostic classification independent of ECOG-PS>0, Hb<10 g/ dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
doi:10.1016/j.eururo.2012.11.042
PMCID: PMC4127896  PMID: 23206856
Urothelial carcinoma; Second line; Prognosis; Time from prior chemotherapy; Hemoglobin; Liver metastasis; Performance status

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