bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic landscape of metastatic platin-resistant urothelial cancer patients.
Authors: Loriot Yohann , Massard Christophe , Lefebvre Celine , Dogan Semih , Ileanaecaterina Elena , Lacroix Ludovic , Job Bastien , Ngo-camus Maud , Fizazi Karim , Auger Nathalie , Richon Catherine , Koubi-Pick Valerie , Hollebecque Antoine , De Baere Thierry , Vielh Philippe , Ledeley Marie-cecile , Vassal Gilles , Eggermont Alexander M. , Soria Jean-Charles
Published: February 2017

316

Background: Although several studies have reported genomic characterisation of primary urothelial carcinoma (UC), little is known about the genomic alterations of the metastatic cisplatin-resistant UC. We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with metastatic cisplatin-resistant lethal UC. Methods: Patients with metastatic UC, who progressed after at least one line of standard therapy, were enrolled in a prospective molecular screening trial (MOSCATO 01) at Gustave Roussy. CT-Scan or ultrasound-guided biopsies were performed in metastases to carry out a comprehensive molecular characterization. DNA was extracted from fresh tumor samples and analyzed by comparative genomic hybridization (CGH) (≥ 30% tumor cells) and by Next Generation Sequencing (NGS) for up to 74 target genes (≥ 10% tumor cells). Whole-exome (WES) and RNA seq sequencing were performed retrospectively in selected cases. Results: From 12/2011 to 12/2013, 30 heavily pretreated patients with metastatic UC were included. Median age was 61 (37-73); all patients had been treated with platin-based chemotherapy with a median number of lines of 2.5 (1-5). A tumor biopsy could be performed in 26 patients (87%). CGH and targeted exome sequencing profiles were assessed in 19 (73%) and 23 (88%) of them, respectively. A total of 19 patients (73%) were profiled for both sequencing and CGH. WES and RNA seq was performed in 16 (62%) pairs of metastatic tissue and normal DNA (Integragen Inc, Hiseq platform). Our analyses identified potential therapeutic targets in 61 % of the tumours, including 31% with targets in the PI3K/AKT/mTOR pathway, 35% with targets in the FGF/FGFR pathway and 15% with targets in the RTK/MAPK pathway (including ERBB2). Others frequent aberrations were found in the chromatin regulatory genes (MLL gene family) and cell-cycle regulatory genes (E2F3, CDKN2A/B genes). FGFR gene fusions were found in 1 out of 16 screened patients (6%) Conclusions: Lethal platin-resistant UC exhibit high-level of genomic heterogeneity. The majority of these tumors harbour actionable genomic alterations that can be targeted with selective agents currently in clinical development (phase I trials) or registered.
Safety of cisplatin in patients with urothelial carcinoma (UC) and renal dysfunction.
Authors: Singh Parminder , Necchi Andrea , Giannatempo Patrizia , Niegisch Guenter , di Lorenzo Giuseppe , Hsu Chiu-Hsieh , Sonpavde Guru
Published: February 2017

321

Background: Patients (pts) with UC and creatinine clearance (CrCl) < 60 ml/min are considered cisplatin-ineligible. Since the safety of cisplatin use in patients with CrCl < 60 has not been comprehensively studied, we conducted a retrospective study in this population. Methods: Data were requested and retrospectively collected from 5 collaborating institutions. All patients had stage 2 or higher UC and CrCl < 60. Patient characteristics including age, sex, indication for chemotherapy (neoadjuvant, adjuvant or metastatic disease), schedule, total dose of cisplatin, adverse effects, renal function, blood cell counts and radiologic tumor response were collected. Descriptive statistics were employed with no baseline assumptions. Results: 104 patients were evaluable with a mean age of 63.7+ 8.1 yrs (range 41-77yrs) and 63.5% (n=66) were men. Mean CrCl by Cockroft-Gault formula was 50.8 + 8.0 ml/min (range 26-59 ml/min). Baseline ECOG performance status was 0 in 71.8% (n=74); 1 in 20.3% (n=21) and 2 in 7.8% (n=8) of patients. 40.4% (n=42) received chemotherapy for metastatic disease and the rest received perioperative chemotherapy. Of the patients with metastatic disease, 7.1% patient had complete response (CR), 40.5 % patients had partial response. Mean total dose of cisplatin used in all patients was 414.32±198.01 mg, with 81.7% (n=85) patients receiving ≥70mg/m2 dose per cycle. Percentage of patients with any toxicity with baseline CrCl <45 and >45 were 43.5% and 39.5%, respectively (p=0.81). Neutropenic infection occurred in 16.3% and thrombocytopenic bleed in 8.6%. Grade 3 renal toxicity was seen in only one patient (0.96%) and no toxic deaths were reported. Conclusions: This retrospective clinical experience in pts with UC with CrCl <60 ml/min and mostly ECOG-PS 0-1 suggests that cisplatin-based chemotherapy is feasible and warrants exploration given CRs induced in metastatic disease. Incorporation of prophylactic growth factors and modified schedules may mitigate myelosuppression.
Androgen deprivation therapy to prevent bladder cancer recurrence.
Authors: Uemura Hiroji , Izumi Koji , Taguri Masataka , Miyamoto Hiroshi , Morita Satoshi , Miyoshi Yasuhide , Hara Yoshinori , Kishida Takeshi , Chiba Kimio , Murai Tetsuo , Hirai Kotaro , Suzuki Kotaro , Fujinami Kiyoshi , Ueki Teiichiro , Udagawa Koichi , Kitami Kazuo , Moriyama Masatoshi , Tsuchiya Futoshi , Ikeda Ichiro , Kobayashi Kazuki
Published: February 2017

329

Background: Accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development and further suggests androgen deprivation therapy (ADT) as a new therapeutic option for BC. However, the clinical efficacy of ADT in BC recurrence remains unclear. We compared the rates of BC recurrence in prostate cancer (PC) patients between who did and did not receive ADT. Methods: We retrospectively reviewed 20,328 patients with PC diagnosed during1991-2013 and identified 239 (1.2%) men having primary BC. Among them, 162 patients met the inclusion criteria. Using Kaplan-Meier analyses and Cox proportional hazard models, we assessed the prognostic significance of ADT and other clinical variables for recurrence-free survival (RFS) and cumulative recurrence. Results: With a median follow-up of 62 months, 38 (50%) of 76 control patients experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT showed a significantly lower risk of BC recurrence (5-year actuarial RFS: 76% v 40%; P < 0.001) compared to the control group. ADT patients also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001) compared to control patients. A multivariate analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17-0.49) for BC recurrence. Conclusions: This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence. Randomized clinical trials are required to confirm these findings. Clinical trial information: 000012926.
Open versus robot-assisted radical prostatectomy: A contemporary analysis of an all-payer discharge database.
Authors: Leow Jeffrey J. , Trinh Quoc-Dien , Chung Benjamin I. , Chang Steven L.
Published: February 2017

33

Background: Robot-assisted radical prostatectomy (RARP) has been rapidly adopted in the US despite the lack of Level 1 evidence. There is no conclusive evidence regarding its morbidity profile compared to open RP (ORP). Our aim was to compare perioperative outcomes of RARP vs. ORP on a contemporary cohort of patients. Methods: Using the Premier Hospital Database, an all-payer discharge database representing over 600 hospitals in the US, we captured men diagnosed with prostate cancer (ICD-9 code 185) who underwent a radical prostatectomy (60.5) from 2003 to 2013.We classified procedures as RARP through a review of the charge description master by identifying supplies unique to robotic procedures. We evaluated 90-day postoperative complications (using Clavien classification), transfusion of blood products, operating room time, length of stay and direct hospital costs. We performed regression analyses, adjusting for potential confounders, accounting for clustering by hospitals and survey weighting to ensure nationally representative estimates. Results: Over the 11-year study period, there was a total of 345,313 ORP and 328,731 RARP. The use of RARP grew rapidly from 2% in 2003 to 85% in 2013 (p<0.001). On adjusted analyses, compared to ORP, RARP patients were less likely to suffer major complications (odds ratio [OR] 0.77, p=0.03), readmissions (OR 0.81, p=0.02), or receive blood products (OR 0.28, p<0.001). RARP patients had shorter LOS (-0.88 days, p<0.001). Mean operating room time for RARP was longer by 71 min (p<0.001); higher surgeon and hospital volume were significant predictors of shorter operating time. 90-day direct hospital costs were higher for RARP (+$4085, p<0.001), primarily attributed to operating room and supplies costs. Conclusions: Our contemporary analysis of men who underwent RP found that the robotic approach appears to confer a perioperative morbidity advantage at a higher cost. The widespread adoption of RARP in the management of localized prostate cancer implies a randomized trial will unlikely be conducted; therefore this large retrospective study may represent the best available evidence for the morbidity and cost profile of ORP vs. RARP.
Feasibility of plasma circulating free RNA (cfRNA) microarray profiling and gene-specific prognostic associations in metastatic urothelial carcinoma (mUC) patients receiving platinum-based chemotherapy.
Authors: Hahn Noah M. , Wang Zhiping , Liu Yunlong , Moore Marietta L. , Prasad Nagendra K
Published: February 2017

333

Background: The current study was undertaken to determine the feasibility of detection and expression profiling of cfRNA in mUC patients treated with platinum-based chemotherapy. Methods: Plasma samples were identified from consented mUC subjects treated with platinum-based therapy at the IU Simon Cancer Center (IUSCC) from 12/2008 – 8/5/2010. The primary feasibility measure was the detection of cfRNA at any quantitative level. An IUSCC urologic cancer 48-gene array was designed. After cfRNA extraction and cDNA preparation, cDNA were amplified in a specific target amplification step using gene-specific primers for the 48 genes in the array. Gene expression analysis was performed on amplified cDNA using 96.96 format DELTAgene microfluidic Dynamic Array platform (Fluidigm). CT values were calculated for each gene after normalization against expression of internal control gene, GAPDH. To identify associations between individual gene expression and OS, a Cox proportional hazards regression analysis was performed. Results: Plasma samples and OS data were available from 15 pts. Patient demographics included: median age – 70.8, M/F – 14/1, Cisplatin/Carboplatin regimen – 9/6, lymph node/visceral mets – 13/7. Median PFS/OS were 8.7 and 23.0 months respectively. cfRNA was detectable in all 15 patients (100%). Median quantitative cfRNA concentration was 2.68 ng/ml (range 1.9 – 6.3). 96.96 Dynamic Array was performed in all patients. All 48 gene probes passed QC testing and produced CT values suitable for analysis. On univariate analysis, overall survival was significantly associated with presence of visceral metastases and plasma cfRNA expression of AKT1, AKT2, BRCA1, CCND1, HPRT1, HSD3B1, PARP1, and RPA3 (all p < 0.05). Conclusions: Successful extraction of cfRNA suitable for microarray analysis from archived mUC patient plasma samples is feasible. Intriguing hypothesis generating associations between OS and cfRNA expression of genes mediating DNA repair, apoptosis, and cell-signaling pathways were observed. Demonstration of these findings in larger independent patient cohorts is warranted.
Clinical significance of SDF-1 isoforms in bladder cancer.
Authors: Hupe Marie C , Gosalbez Miguel , Lokeshwar Soum D , Shields John , Yates Travis J , Lokeshwar Vinata B
Published: February 2017

334

Background: Stroma-Derived Factor (SDF)-1 is a ligand for chemokine receptors CXCR4 and CXCR7. The six known SDF-1 isoforms are generated by alternative mRNA splicing. While SDF-1 expression has been detected in various malignancies, only a few studies have reported differential expression of SDF-1 isoforms and its clinical significance. In this study we evaluated the expression three SDF-1 isoforms (α,β,γ) in bladder cancer (BCa). Methods: Using quantitative PCR, mRNA levels of SDF-1α, SDF-1β and SDF-1γ were measured in bladder tissues (normal: 25; BCa: 44) and urine specimens (n=210; normal: 28; benign conditions: 74; BCa: 57, history of BCa (HxBCa): 35, Hx other Ca: 8; other Ca: 8) from consecutive patients. The transcript levels were normalized to β-actin. Correlation between SDF1-isoform transcript levels and clinical outcome (metastasis and disease specific mortality (DSM)) was evaluated in univariate and multivariate analyses. Results: Among SDF-1 isoforms, only SDF-1β mRNA was significantly overexpressed by 2.5-6-fold in BCa tissues when compared to normal bladder tissues. While SDF-1α was expressed in bladder tissues, SDF-1γ expression was undetectable. In univariate analysis, pathologic stage, lymph node positivity for tumor, SDF-1α and SDF-1β transcript levels significantly associated with metastasis and DSM. However, in multivariate analysis, stage (P=0.005) and SDF-1β levels (P=0.017) were independent predictors of metastasis and DSM. In exfoliated urothelial cells, only SDF-1β mRNA levels were differentially expressed and having 91.2% sensitivity and 73.8% specificity for detecting BCa. In patients with HxBCa, elevated SDF-1β levels indicated 4.3-fold increased risk (chi-square: 15.1; P=0.0001; relative risk = 4.3) for developing recurrence within 6-months. Conclusions: SDF-1 isoforms are differentially expressed in bladder tissues and exfoliated urothelial cells. SDF-1β mRNA levels in BCa tissues predict poor prognosis. Further, SDF-1β mRNA levels in exfoliated cells detect BCa with high sensitivity and are potential predictors of future recurrence. Support: Grant NCI/NIH R01 CA-72821-14; Women’s Cancer Association – University of Miami.
Impact of obesity in patients with metastatic urothelial carcinoma.
Authors: Leiter Amanda , Doucette John , Krege Susanne , Lin Chia-Chi , Hahn Noah M. , Ecke Thorsten , Sonpavde Guru , Bamias Aristotelis , Oh William K. , Galsky Matt D.
Published: February 2017

346

Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, the impact of obesity on outcomes of patients with metastatic disease has not previously been evaluated. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (<18.5 underweight (4.1 % of patients), 18.5-24.99 normal weight (42.8%), 25-29.99 overweight (41.0%), >30 obese (12.1%)). BSA was classified as either below (56.8% of patients) or greater than or equal to (43.2%) the European average (1.91 m2 for males and 1.71 m2 for females). There was no significant difference in number of chemotherapy cycles across BMI and BSA categories. Patients’ treatment regimens significantly differed across BMI (p=0.02) and BSA (p<0.01) categories, with patients with higher BMI category and average or above BSA more likely to receive gemcitabine-cisplatin-based therapy rather than MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)-based or other therapy regimens. There was no significant difference in adverse events across BMI categories, but the incidence of embolic events was significantly higher in patients with an average or higher BSA (6.6%) than those with a lower than average BSA (2.7%) (p=0.03). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates and survival outcomes to non-obese patients. Toleration of cisplatin-based therapy is similar across BMI and BSA categories, with the exception of a higher incidence of embolic events in patients with an above average BSA.
A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy (RT) in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).
Authors: Armstrong Andrew J. , Halabi Susan , Healy Patrick , Lee Robert , Koontz Bridget F. , Moul Judd W. , Mundy Kelly , Creel Patricia , Yenser Wood Sarah , Davis Kristen , Reimer Brooke , Nguyen Minh , Spitz Avery N. , Bratt Ellen , Kim Sung , Tran Phuoc T. , Stein Mark N. , Carducci Michael Anthony , George Daniel J.
Published: February 2017

35

Background: In men with high grade PC and rapid PSA progression after RP, failure rates are unacceptably high despite salvage RT. Androgen deprivation therapy (ADT) is not curative in this setting and we thus evaluated a novel multi-modality approach of systemic chemotherapy and anti-angiogenic therapy prior to prostate bed salvage RT in a multicenter trial. Methods: Eligible men had a rising PSA of 0.1-3.0 ng/ml within 4 years of RP, no metastatic disease except resected positive nodes, no prior ADT, and Gleason 7-10. Men received 4 cycles of docetaxel 70 mg/m2 q3w with prednisone 5 mg bid and sunitinib 37.5 mg qd for 14/21 days each cycle. Salvage RT (66Gy/33fx) to the prostate bed started at day 100. The primary endpoint was progression-free survival at 2 years (PFS2), defined as a confirmed PSA rise above the post-RT nadir or baseline if no nadir occurred, clinical/radiographic progression, or death from date of enrollment. Safety and dose-limiting toxicities were evaluated. This was a single arm prospective open-label phase 2 trial. Results: Thirty-four men accrued in this multisite Dept. of Defense Prostate Cancer Clinical Trials Consortium trial (median age 62, 85% Caucasian, 9% African American); 24% were node positive at surgery, 47% had Gleason 8-10. Median PSA at entry was 0.54 (range 0.2-2.8) and median time since RP was 11 months. The trial was terminated prematurely due to excess dose-limiting toxicity (9 DLT events) including grade 3 events of hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1), and vomiting with diarrhea (n=1). PFS at 2 years was 48.9% (95% CI: 32.8%, 67.2%) with a median PFS of 26.2 mo (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. Conclusions: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. However, efficacy data suggests that some men achieved durable long-term disease control with this aggressive approach. Longer-term follow-up and comparative data with salvage XRT and ADT is needed to fully understand the risks/benefits of this combined modality approach in high risk PSA-recurrent PC. Clinical trial information: NCT00734851.
A microdosing study to identify chemoresistance in bladder cancer.
Authors: Chow Helen , Wang Sisi , Zhang Hongyong , Zimmermann Maike , Lin Tzu-yin , Scharadin Tiffany , Malfatti Michael , Evans Christopher P. , Cimino George , Turteltaub Kenneth , de Vere White Ralph , Henderson Paul T. , Pan Chong-Xian
Published: February 2017

356

Background: DNA adduct formation and incorporation of gemcitabine into genomic DNA are critical steps in cancer cell response to platinum (Pt) and gemcitabine chemotherapy, respectively. We hypothesize that levels of Pt-DNA adducts and gemcitabine in genomic DNA below a threshold are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14C bound to DNA, AMS was used to quantify carboplatin-DNA damage and gemcitabine incorporation into DNA after mice or patients received nontoxic “microdoses” of 14C-labeled carboplatin or gemcitabine. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1% of the therapeutic dose) or therapeutic dose of [14C]carboplatin or [14C]gemcitabine. Carboplatin-DNA adducts and gemcitabine incorporation in DNA were correlated with cell/tumor response to chemotherapy. In the Phase 0 trial, patients with advanced bladder or non-small cell lung cancer were treated with one microdose of [14C]carboplatin followed by tumor sampling 24 hours later. Carboplatin-DNA adducts and other relevant parameters, such as pharmacokinetics and repair of DNA damage, were measured and correlated with cancer response to chemotherapy. Results: The levels of microdose-induced carboplatin-DNA damage were linearly proportional to that caused by the therapeutic dose (R2=0.92, p<0.001); and correlated with chemoresistance to carboplatin. Low gemcitabine incorporation into DNA correlated to gemcitabine resistance in patient-derived bladder cancer xenografts (p<0.001). In the Phase 0 trial, 18 patients have been enrolled. DNA damage induced by carboplatin was measured by AMS in peripheral blood mononuclear cells and, in some patients, in tumor tissues; and will be correlated with cancer response to chemotherapy. The pharmacokinetics and DNA adduct levels were linear between microdose and therapeutic doses. No microdose-related toxicity was observed. The radiation exposure was less than that of one chest X-ray per microdose. Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance. The current status of the Phase 0 trial will be presented. Clinical trial information: NCT01261299.
miR125 and miR200a as potential circulating miRNA biomarkers in metastatic urothelial carcinoma patients treated with docetaxel.
Authors: Mullane Stephanie A. , Zhou Chensheng Willa , Martin-Doyle William , Loda Massimo , Choueiri Toni K. , Bellmunt Joaquim , Bowden Michaela
Published: February 2017

364

Background: Docetaxel is frequently used as second-line therapy in advanced bladder cancer. The response rate is 10-15% with a median PFS of 2.5 months and without data showing improvement of QoL, however, some selected patients derive significant benefit. Understanding the mechanisms underlying the sensitivity of docetaxel in bladder cancer will help to customize treatment in second line. Circulating miRNAs have been shown to be predict outcome in GU malignancies (for example, prostate cancer). Using circulating miRNA can identify patients who will respond to therapy non-invasively. The main aim of our study was identify circulating miRNAs predicting docetaxel response in urothelial carcinoma (UC). Methods: We obtained pre- and post-treatment plasma samples from patients included in the zactima phase II clinical trial assigned to the placebo + docetaxel arm. RNA from plasma was extracted and RT-PCR was performed on both the pre- and post-treatment samples looking at miRNAs known to be important in docetaxel response1(miR125, miR27a, miR34a, miR429, miR141, miR200a, miR200c, miR 146a, and miR9). Samples were normalized by the mean global miRNA levels. We divided patients based on progression free survival (PFS) as good responders (>4 months PFS or 6 cycles) versus poor responders (<2 months PFS or progression at first evaluation). Differences in miRNA levels were assessed using the student t test (p<0.05). Results: miR125 and miR200a were shown to be significantly different between the poor and good responders (p=0.056 and p=0.028, respectfully) in the pre-docetaxel samples. Higher expression of both miRNAs correlated with a good response in our small patient cohort. Additional analysis comparing pre- and post-miRNA levels will be presented. Conclusions: miR125 and miR200a are potential extracellular biomarker to docetaxel treatment in metastatic UC.
Targeting the PI3K/AKT/mTOR pathway with MLN0128 (mTORC1/2 inh) and MLN1117 (PI3K alpha inh) in bladder cancer: Rational for its testing in clinical trials.
Authors: Martinez Alejandro , Hernandez Anna , Arpi Oriol , Menendez Silvia , Iarchouk Natalia , Gavilan Elena , Bellosillo Beatriz , Arumí Montserrat , Rojo Federico , Mullane Stephanie A. , Choueiri Toni K. , Rovira Ana , Albanell Joan , Brake Rachael , Bellmunt Joaquim
Published: February 2017

369

Background: PI3K/AKT/mTOR pathway is a promising target for cancer treatment being commonly deregulated in human bladder tumors and resulting in the promotion of tumor cell growth, survival, and resistance to chemotherapy. The aim of this study is to characterize the effects of MLN0128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, and MLN1117, an orally bioavailable inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha isoform that may be more efficacious and less toxic than pan-PI3K inhibitors as bladder cancer therapies. Methods: We evaluated the effects of MLN0128 and MLN1117 both as single agents and in combination with each other or with a SOC chemotherapy agent (paclitaxel). The effects of the agents alone or in combination were analysed in a panel of six bladder cancer cell lines and in tumor xenografts. These models were selected based on specific genomic alterations that could be considered as potential therapeutic targets (PIK3CA and TSC mutations). Molecular effects of both agents and the combinations on cell-cycle, apoptosis, autophagy and on cell viability were tested in the bladder cancer cell lines. The in vivo effects on tumor growth inhibition were also assessed. Results: Both MLN0128 and MLN1117 inhibit the PI3K/AKT/mTOR pathway and reduce cell proliferation in bladder cancer cell lines with diverse genetic backgrounds. Combination of MLN0128 + MLN1117 produced synergistic antiproliferative effects in cell lines and improved the effect of each drug alone in vitro and in vivo, with no signs of toxicity in these models. Similar effects were observed with the combination of paclitaxel + MLN0128. Conclusions: Our results show that MLN0128 and MLN1117 are promising investigational agents that might be of value for bladder cancer patients. Further investigation as novel anti-cancer agents alone or in combination with chemotherapy in clinical trials in humans is warranted.
Clinical features and outcomes of testicular choriocarcinoma: A single cancer center experience.
Authors: Wang Jue
Published: February 2017

401

Background: Pure choriocarcinoma (PC) is a very rare entity and the most aggressive subtype of nonseminomatous germ cell tumor. There is limited published data regarding treatment outcomes in this group of patients. In this series, we report our experience of sixteen patients treated at a single cancer center. Methods: The hospital tumor registry was utilized to retrospectively identify patients with the diagnosis of testicular cancer between 1997-2011. Clinical pathological, radiographic, treatment, and outcome data were retrospectively reviewed and descriptive statistical analysis was performed. Results: Sixteen patients were identified containing choriocarcinoma as component in 120 testicular cancer patients. Four patients (3.3%) had PC and twelve (10%) had mixed choriocarcinoma (MC). The median age of entire cohort was 25 years (range 21–41). Patients with PC was younger (p < 0.001); more advanced stage (IIIC stage 100% vs. 41.7%; p < 0.001), higher rate of lung metastasis (100% vs. 12%; p < 0.001), higher rate of brain metastasis (70% vs. 16.7%; p < 0.001), received more aggressive therapies: RPLND (50% vs. 33.3%; p < 0.001); >2 lines chemotherapy (75% vs. 16.7%; p < 0.001); high dose chemotherapy with stem cell transplant (HDCT) (50% vs. 8.3%; p < 0.001); in comparison with patients with MC. All four PC patients (100%) were classified as poor risk group at diagnosis according to the IGCCCG prognostic classification system. One PC patient died before receiving any therapy, three had standard first and second line chemotherapies (BEP and viep). Two PC patients underwent HDCT (one as third and another as fourth line). One PC patient had pulmonary resection of chemo-resistant disease after HDCT with long term survival. At a median follow-up of 40 months (range 0.2 - 189), three PC (75%) and two MC (16.7%) patients have died in last follow-up. Three-year survival was 25% and 80% in PC and MC, respectively. Conclusions: PC is associated with advanced disease and high rate of pulmonary and brain metastases. The prognoses of these patients remain poor despite of receiving more aggressive therapy, in comparison with patients with MC. Novel therapeutic strategies are urgently needed for patients with this rare cancer.
Preclinical development of a docetaxel nanocarrier to enhance prostate cancer radiosensitivity.
Authors: Crehange Gilles , Boudon Julien , Boidot Romain , Chevrier Sandy , Dalban Cecile , Loiseau Alexis , Collin Bertrand , Oudot Alexandra , Gauthier Thomas , Millot Nadine , Mirjolet Celine
Published: February 2017

41

Background: From 30% to 50% of high risk prostate cancer patients who undergo radiation therapy (RT) will have a biochemical failure. Combining chemotherapy, such as Docetaxel (DXL), with RT can enhance its efficiency. Multidrug resistance mechanisms often limit drug efficacy by decreasing tumor cell intracellular concentration of drugs. There is interest to develop nanocarrier of DXL to maintain drug inside cancer cells by improving its efficacy. The purpose of this study was to develop a titanate-nanotube (TiONt)-DXL nanocarrier (nanohybrid) and to evaluate its in vivobiodistribution as well as its radiosensitizing efficacy in association with RT on a hormone-independent prostate cancer model. Methods: DXL molecules were grafted on TiONts using PEG-3000 molecules to generate the nanohybrid. In vitrocytotoxic activity of the nanohybrid was evaluated on PC-3 cell line using MTS assay. After intratumoral injection, biodistribution analysis was performed by SPEC-CT imaging of mice bearing subcutaneous PC-3 human prostate tumors. To evaluate the benefit of nanohybrid and RT association, tumors were irradiated using 3 fractions of 4Gy administrated after the injection of nanohybrids. Nine groups of 7 mice were used to evaluate nanohybrid and RT association efficacy : untreated, control with buffer IT injection, +/- RT, free DXL, +/- RT, TiONt +/- RT and TiONt-DXL +/- RT. Mice behavior, health status and tumor volume were monitored twice a week until tumor growth recovery. Results: Biodistribution kinetics showed that more than 70% of nanohybrids were localized into the tumor 96 hours after injection. Mice receiving nanohybrid-RT exhibited a significant tumor growth delay to reach a volume of 1,000mm3compared to mice receiving free DXL-RT: 73.7 days (median, [58.9-89]) vs 56 days (median, [31.5-74]) (p=0.0127). Conclusions: TiONt-DXL improves RT efficacy compared to free DXL. These results suggest that local control might be enhanced by TiONt-DXL. TiONt-DXL can be injected as a radiosensitizer in men harboring high risk localized prostate cancer with needles during prostate brachytherapy procedure.
High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the targeted therapy era: Extension of OS benefits beyond complete response (CR) and partial response (PR).
Authors: Aung Sandra , Morse Michael A. , Wong Michael K.K. , Kaufman Howard , Daniels Gregory A. , McDermott David F.
Published: February 2017

423

Background: HD IL-2 has been reported to have a overall response rate (ORR) for mRCC of 15% and a median OS of 19 months (Fyfe, 1995), however, the studies that led to its regulatory approval are >15 years old and were performed in an era preceding targeted therapies. Methods: The PROCLAIM registry (www.proclaimregistry.com), a HD IL-2 observational database currently with over 30 participating sites, consists of a retrospective cohort (treated between 2007 and 2012) informing an ongoing prospective cohort (~600 patients). We report on the retrospective mRCC subjects (n=97, 13 sites) with survival status determined as of November 2013 and a median follow-up of 32 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least one dose of HD IL-2. Results: The ORR was 22% (8% CR and 14% PR). Of 97 subjects, 36 were confirmed deceased and 61 were known to be alive, none were lost to follow-up. The median OS was 51 months, compared to a median OS range of 5-35 months for FDA-approved targeted agents (Harrison, 2013). There was significant clinical benefit in patients with CR, PR, and stable disease (SD), none of which reached median OS compared to 37.9 months in patients with progressive disease (PD). There is a significant advantage in PROCLAIM for those patients treated 1st vs. 2nd line HD IL-2; the median OS was 61.8 months (n=82) vs. 15.3 months (n=15), respectively. The clinical benefit of HD IL-2 therapy as front line is consistent with published data (Birkhauser, 2013). No deaths due to IL-2 related toxicity were reported in the retrospective cohort. Conclusions: The PROCLAIM registry documents a vastly improved OS for HD IL-2 compared to historical results during a time interval marked by the advent of targeted therapy for advanced RCC. Response to IL-2 (CR or PR) is associated with prolonged survival, however, stable disease as well as front line use also appears to positively impact survival. Issues including patient selection characteristics and treatment sequencing are hypotheses currently being explored in the prospective database. Clinical trial information: NCT01415167.
Association of genome-wide copy number alterations with metastasis of clear cell renal cell carcinoma.
Authors: Gowrishankar Banumathy , Thodima Venkata Jaganmohan , Molina Ana M. , Ma Charles , Guttapalli Asha , Gold Theresa Margaret , Motzer Robert J. , Chaganti Raju S.K. , Houldsworth Jane
Published: February 2017

428

Background: About one-third of patients with clear cell renal cell carcinoma (ccRCC) exhibit metastasis at the time of diagnosis and show poor prognosis. The genetic and epigenetic alterations associated with metastasis in ccRCC have variably been studied, and their role in the metastatic process is unclear. The goals of the current study were to identify genomic copy number alterations (CNAs) associated with ccRCC metastasis and examine their clinical utility. Methods: In this IRB-approved study, genome-wide copy number profiling was performed on DNA from 144 ccRCC (81 primary and 63 metastatic lesions). Differential CNAs between primary and metastatic lesions and between different metastatic sites were identified using Fisher’s exact test. Associations between CNAs and overall survival (OS) were tested using the log rank statistic and Kaplan-Meier method. Genomic profiling data of 437 and 240 primary ccRCC (TCGA and PMID: 23797736, respecitively) were used for verification. Results: Between primary and metastatic lesions, 25 CNAs were significantly different (p<0.05). Of the 11 more frequent in metastatic lesions, nine retained significance when comparing stage IV and stage I TCGA ccRCC. For 368 TCGA locally-invasive tumors (stages I, II, and III), three CNAs (loss of 9p24.3-p13.3, 9p12-q11, and 9q21.12-q21.33) were associated with inferior survival (p=0.002). In the second dataset of 214 locally-invasive lesions, loss of 18q11.2-q23 correlated with shorter OS (p=0.025). Across metastatic lesions, nine CNAs were found to be significantly enriched in lung lesions and three in bone. In a subset of 127 ccRCC with known metastatic status at 5 years after diagnosis, two of these CNAs (gain of 7q36.1-36.3 in lung and loss of 22q13.2 in bone) were significantly enriched in the corresponding primary specimens. Conclusions: This study identified CNAs associated with ccRCC metastasis and common sites of metastasis that have the potential to serve as biomarkers to assist in better risk stratification of patients with this disease. Integrated analyses of genes mapping to the loci of genomic imbalance would further our understanding of the biology of metastasis in renal cancer.
Third-line therapy in metastatic renal cell carcinoma: Results from the International mRCC Database Consortium.
Authors: Heng Daniel Yick Chin , Wells Connor , Donskov Frede , Rini Brian I. , Lee Jae-Lyun , Bjarnason Georg A. , Beuselinck Benoit , Smoragiewicz Martin , Alva Ajjai Shivaram , Srinivas Sandy , Wood Lori , Yamamoto Haru , Ernst D. Scott , Pal Sumanta Kumar , Yuasa Takeshi , Broom Reuben James , Kanesvaran Ravindran , Bamias Aristotelis , Knox Jennifer J. , Choueiri Toni K.
Published: February 2017

430

Background: Third-line targeted therapy efficacy in metastatic renal cell carcinoma (mRCC) is not well characterized and many funding bodies do not provide reimbursement for it. Methods: The International mRCC Database Consortium (IMDC) consists of consecutive patient series from 25 cancer centers. It was queried for specific sequences of targeted therapy and third-line therapy. Kaplan Meier estimates were used for survival. Cox proportional hazards models were used to adjust hazard ratios for confounders. Patients that stopped second-line therapy were divided into two groups: those that went onto third-line therapy and those did not. Results: 4,050 patients were treated with first-line targeted therapy, of which 2,011 (49.6%) had second-line therapy and 879 (21.7%) had third-line targeted therapy. The most common third-line therapies were everolimus 25%, sorafenib 14%, sunitinib 13%, temsirolimus 11%, pazopanib 10%, and axitinib 6%. IMDC prognostic groups at third-line therapy initiation were 6% favorable risk, 67% intermediate risk, and 27% poor risk. Overall response rate for third-line therapy was 10.5% and 50.9% had stable disease in those patients that were evaluable. Median PFS was 5.1 months (95% CI, 4.5-5.7) and median OS from third-line therapy initiation was 12.0 months (95% CI, 10.7-12.9). Patients stopping second-line therapy that move on to third-line therapy vs. those that do not receive third line therapy have a median OS from stopping second-line therapy of 13.1 vs. 2.3 mons (p<0.0001). When adjusted for second-line IMDC prognostic criteria and KPS at second-line treatment cessation, patients who do receive third-line therapy have a HR of death of 0.41 (95% CI, 0.32-0.52; p<0.0001) compared to those that do not receive third-line therapy. This may be in part due to patient selection. To further limit bias, when excluding patients that live less than 3 months after second-line therapy cessation, the adjusted HR was similar. Conclusions: Third-line targeted therapy has demonstrated activity and is prevalent in use. Further studies are required to determine appropriate sequencing.
Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma.
Authors: Bourlon Maria Teresa , Gao Dexiang , Trigero Sara , Clemons Julia Elizabeth , Lam Elaine Tat , Flaig Thomas W.
Published: February 2017

453

Background: Increases in mean corpuscular volume (MCV) and hypothyroidism have been observed in patients on sunitinib treatment. We characterized tyrosine kinase-associated macrocytosis in metastatic renal cell carcinoma (mRCC) patients and its relationship, along with thyroid dysfunction, to progression-free survival (PFS). Methods: A retrospective chart review was performed on patients treated with sunitinib and/or sorafenib (01/2005-01/2011). Data pertaining to the development of macrocytosis was analyzed in association with our previous data on thyroid dysfunction in these patients. We assessed PFS, as clinically defined by the treating provider. Results: Seventy-four patients with 103 treatment periods for sorafenib (47) and sunitinib (56) were analyzed. Macrocytosis was found in 55% and 8% of sunitinib and sorafenib treatment periods, respectively (p<0.001). Focusing on the sunitinib-treated patients for all further analysis, the median PFS was 11 months (mo) (95% CI, 6-19). Median PFS was 21 mo (95% CI, 11-25) for patients who developed macrocytosis compared to 4 mo (95% CI, 3-8) in normocytic patients (p=0.0001). The time to development of macrocytosis did not affect the degree of macrocytosis observed (p=0.47). Macrocytosis and hypothyroidism were both significant predictors of prolonged PFS in our cohort. The greatest difference in PFS was noted between patients who developed both macrocytosis and hypothyroidism (25 mo) versus those who remained both normocytic and euthyroid (5 mo) (p<0.0001). Conclusions: Sunitinib-related macrocytosis is associated with a prolonged PFS in mRCC. The concurrent development of both hypothyroidism and macrocytosis in this setting was associated longer PFS compared to either alone. Increased MCV may be used as a biomarker for sunitinib response in this setting. [Table: see text]
Risk factors and a model to predict toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with VEGF-targeted therapy: Results from the International Metastatic RCC Database Consortium.
Authors: Kaymakcalan Marina Dusevic , Xie Wanling , Albiges Laurence , North Scott A. , Kollmannsberger Christian K. , Smoragiewicz Martin , Kroeger Nils , Wells Connor , Rha Sun Young , Lee Jae-Lyun , Fay Andre Poisl , Heng Daniel Yick Chin , Choueiri Toni K.
Published: February 2017

464

Background: VEGF targeted therapy (VEGF-TT) are standard in advanced metastatic renal cell carcinoma (mRCC), however, toxicities that can lead to drug discontinuation can have a significant impact on patient (pt) outcomes. We aimed to identify risk factors for toxicity and develop the first model to predict toxicity-related treatment discontinuation (TrRD) in mRCC pts treated with VEGF-TT. Methods: Baseline characteristics and treatment outcome data were collected on 936 mRCC pts on first-line VEGF-TT from 7 IMDC institutions. TrTD was analyzed using a competing risk regression model for treatment discontinuation. Results: Median follow up was 23 months. Treatment discontinuation occurred in 833 pts (89%), of which 198 (23.8%) were related to drug toxicity. Sunitinib was the most common VEGF-TT (77%) in our series followed by sorafenib (18.4%). Median time on therapy was 7.1 months in all pts and 4.4 months for pts with TrTD. Most common toxicities leading to TrTD included fatigue, diarrhea and mucositis. On multivariate analysis, significant adverse predictors for TrTD (p<0.05) were: age (≥60 years), baseline glomerular filtration rate (GFR) <30 cc/min, number of metastatic sites (>1), and baseline sodium level (<LLN). A model was developed using the number of patient risk factors to predict the risk of TrTD (Table). Conclusions: In the largest series reported to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors that predict toxicity-related treatment discontinuation in mRCC pts treated with VEGF-TT. Based on the number of risk factors present, we built the first model to predict treatment-related drug discontinuation. This model can be used for treatment and frequency of monitoring considerations in clinical practice. [Table: see text]
Bevacizumab monotherapy as salvage therapy for patients with advanced clear cell renal cell carcinoma pretreated with targeted drugs.
Authors: Lee Chung-Han , Hoetker Andreas M , Voss Martin Henner , Feldman Darren Richard , Woo Kaitlin , Patil Sujata , Coskey Devyn Taylor , Akin Oguz , Hsieh James , Motzer Robert J.
Published: February 2017

468

Background: Bevacizumab targets vascular endothelial growth factor (VEGF) and has showed benefit in first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α (Lancet 370: 2103). This retrospective analysis assessed the efficacy of bevacizumab monotherapy after progression on targeted drugs such as VEGFr tyrosine kinase inhibitors (TKI), and/or mTOR inhibitors. Methods: A retrospective analysis was performed on patients with metastatic ccRCC who received bevacizumab monotherapy at MSKCC after progression on prior targeted therapies. Primary end point is overall survival and secondary endpoints include progression free survival, time on therapy, and toxicity analysis. Results: 71 patients were treated with bevacizumab monotherapy in the salvage setting. Patients were heavily pretreated with 36 (51%) patients receiving bevacizumab as a fourth-line agent or later and 33 (46%) patients received at least 2 prior VEGF targeted agents. Seventeen (24%) patients had a KPS <80% and 20 (28%) patients were in the poor prognosis MSKCC risk group. Overall median OS was 11.5 months (95% CI, 6.4-17.4 months) and overall median PFS was 1.9 months (95% CI, 1.7-4.1). Nine (13%) patients had a prolonged time on therapy of >12 months. At last analysis, 8 (11%) patients remained on therapy. Therapy was discontinued for progression of disease (n=56, 89%), adverse events (n=4, 6%), or unknown/unrelated reasons (n=3, 5%). Univariate analysis showed KPS (<80% vs. ≥80%) and MSKCC Risk Factor Classification (poor vs. favorable) as prognostic for poor outcome with hazard ratios of 3.97 (95% CI, 2.09-7.52, p<0.001) and 2.84 (95% CI, 1.17-6.89, p=0.021), respectively. No significant differences in OS were seen when comparing number of lines of prior therapy or lines of prior VEGF targeted therapy. Conclusions: Bevacizumab monotherapy resulted in prolonged disease control in a subset of patients with few discontinuations for adverse events in patients after progression on other targeted therapies, including those who were heavily pretreated. The number of prior VEGF targeted TKI therapies did not correlate with response to bevacizumab, which may reflect a difference in targeting the receptor vs. ligand.
Preoperative renal parenchymal volumetrics and prediction of renal insufficiency following radical nephrectomy.
Authors: Pruthi Deepak Kumar , Oomah Sasha , Chhibba Ruchi , Kirkpatrick Ian , McGregor Thomas
Published: February 2017

471

Background: To identify predictors of post-operative renal insufficiency by analyzing pre-operative imaging volumetrics among patients undergoing radical nephrectomy (RN) for renal cell carcinoma (RCC). Methods: A retrospective review of all patients undergoing RN for RCC between January 2011 and August 2013 was performed. Estimated glomerular filtration rate (eGFR) was calculated employing the modified diet in renal disease (MDRD) formula using the pre-operative and one-year serum creatinine values. Pre-operative and 1-year post-operative CT/MRI scans were reviewed. AW Volume Share 5 workstations were utilized to calculate volumes. Statistical analysis using Chi-square and Fisher exact test were employed. Results: Of the 147 patients undergoing RN 65 patients met the inclusion criteria. Patients with smaller tumor volumes (<375 cm3) were more likely to have a greater decline in their post-operative eGFRs (>35%) when compared to patients with larger tumors (58 vs. 21%; p=0.0165). Patients with a pre-operative eGFR >60 ml/min/1.73m2 had a greater (>25%) drop in their 1-year eGFR (81 vs. 47%; p=0.0084). A smaller volume (<150 cm3) of parenchyma of the ipsilateral kidney was associated less compensatory (<25%) hypertrophy (100 vs. 69, p=0.0348). Smaller tumors (<300 cm3) were more likely to have a greater degree (>10%) of compensatory hypertrophy (78 vs. 43% p=0.0234) and less blood loss (<300 cc, 82 vs. 44%, p=0.0082). Older patients and patients with a combined history of diabetes (DM) and hypertension (HTN) were more likely to have compensatory (>25%) hypertrophy (age >65, 100% vs. 31%, p<0.001; DM+HTN, 100% vs. 75%, p=0.0084). The degree of compensatory hypertrophy (>25%) however, did not predict 1-year eGFR (35%) change (p=0.2203). New kidney disease (eGFR<60 ml/min/1.73m2) occurred in 71% patients. Conclusions: Volumetric imaging shows promising potential and may become a valuable tool in predicting post-operative renal insufficiency for patients undergoing nephrectomy and should be investigated further both in RN and partial nephrectomy cohorts.