bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistence of CD30 expression by embryonal carcinoma (EC) in the treatment time course: A retrospective series of multirelapsing germ cell tumors (GCT).
Authors: Giannatempo Patrizia , Necchi Andrea , Colecchia Maurizio , Paolini Biagio , Nicolai Nicola , Raggi Daniele , Catanzaro Mario , Biasoni Davide , Torelli Tullio , Stagni Silvia , Piva Luigi , Salvioni Roberto , Gianni Alessandro M.
Published: February 2017

329

Background: CD30 is invariably expressed by untreated EC thus lending support to a rationale for a targeted approach. However, preliminary reports claimed an effect of chemotherapy (CT)-induced downmodulation of CD30 that might affect the potential use in relapsing disease. We aimed at evaluating the persistence of CD30-positivity in post-CT residuals. Methods: We retrieved paraffin-embedded post-CT samples yielding non-teratoma viable cells after ≥ 1 CDDP-based CT from the institutional surgical series. EC component was required and assessed by morphology and Oct-3/4 staining. The entire set was re-stained for CD30 and assessed by 2 pathologists blinded to study purpose. CD30-positivity was defined as a >80% membranous staining with a diffuse moderate-to-strong intensity. Clinical data included site of tumor primary, histology, CT regimen, and type of surgery. Results: From 12/1990 to 09/2012, a total of 246 cases with pure EC or mixed GCT residuals were treated. 49 (EC: 16; mixed GCT: 33) had both complete data and suitable tissue for study purposes. 40 pts had retroperitoneal or mediastinal nodes, 12 pts had lung metastases, 4 had either liver, bone or brain mets. 35/49 cases (70%) preserved CD30 positivity. 20/35 (57%) pts had residual disease after 1stline CT, 15/35 (43%) after multiple CTs (median 3.5, range 2-5). 2 pts (6%) had undergone high-dose CT and 4/35 (11%) were late relapses. 32/35 pts (91%) had gonadal primary, 1 had a retroperitoneal and another a mediastinal primary. The median survival of 35 CD30-positive patients was 16 mos (IQR 3.3-22.9) while it was 48.5 mos (IQR 21.7-72.6) for the 14 CD30-negative patients (p=0.0297 at Gehan-Breslow-Wilcoxon test). 5-year overall survival of CD30-positive and negative patients was 35.7% (95% CI: 18.2-53.6) and 49.7% (95% CI: 19.7-74.0), respectively. Conclusions: Our results on selected relapsing pts suggest that EC retained CD30 even in the far salvage setting, thus confirming to be a reliable target for treatment. A trend towards a poorer prognosis and shorter survival characterized CD30+ cases. A phase 2 study with the antibody-drug conjugate Brentuximab vedotin is currently in plan for GCT.
Characterization of patients who present with de novo metastatic prostate cancer: Single-institution database analysis.
Authors: Strock Jessica , Gray Kathryn P. , Nakabayashi Mari , Evan Carolyn , O'Donnell Elizabeth , Pomerantz Mark , Kantoff Philip W. , Sweeney Christopher
Published: February 2017

33

Background: Less than 5% of men in a PSA screened population present with denovo metastatic prostate cancer. We sought to characterize the clinical characteristics and survival of this unique group of men. Methods: Retrospective analysis of an institutional data-base – Dana Farber Cancer Institute - Prostate Clinical Research Information Systems (CRIS). All men with metastatic disease as their first presentation of prostate cancer were identified. Patient and disease characteristics were summarized descriptively. The distributions of the study endpoints were estimated using the Kaplan-Meier method with median and 95%CI reported. Results: The analytic cohort has 185 patients with a median follow-up of 7.8 years (95% CI:7.5,11.1) and 94% diagnosed after 1998. Median age at diagnosis is 62 years (Range: 42-86); PSA at diagnosis: Median (Q1-Q3) - 100.2 (23.0, 346.0). Metastases: 97% bone, 2% liver, 2% lung, 8% lymph node. The median time from metastasis diagnosis to start of androgen deprivation therapy (ADT) was 26 days, 139 of those who started ADT had subsequently started treatment for castration resistant prostate cancer (CRPC) - 2nd line hormonal therapy and/or chemotherapy. The median time from ADT to subsequent therapy for CRPC is 14 months with 95% (CI:12,16). 128 patients have died and the median overall survival is 48 months (95% CI:40, 51). Conclusions: This unique cohort of patients at a referral institution tend to be younger and have an overall survival comparable to outcomes in modern day randomized hormone sensitive prostate cancer studies. Assessment of similar group in a multivariate analysis of a prospective trial is needed to confirm this observation. If confirmed, the data would suggest the responsiveness to therapy drives outcome rather than development of metastasis with or without a previously treated primary.
The development of a validated data linked tissue microarray of bladder cancer patients undergoing cystectomy.
Authors: Robinson Richard , Anderson Sarah , Ashton Gary , Womack Chris , Brown Mick D. , Clarke Noel W
Published: February 2017

330

Background: Over the last 25-30 years there has been little or no advancement in the prognosis or treatment of high grade and muscle invasive bladder cancer, with 5 years survival rates following radical treatment of 40-50%. The aim of this project was to develop a validated, data linked tissue microarray (TMA) of cystectomy patients for the assessment putative biomarkers the provision of a developmental drug pre-screening tool. Methods: All cystectomy derived FFPE tissue blocks from The Christie tertiary cancer centre (1969-2006) were retrieved and independently reviewed. Representative 1mm tissue cores were extracted for TMA construction and associated DNA/RNA bank. The TMA quality was validated using standard H&E histopathological assessment and immunohistochemistry for pan-cytokeratin and phospho-tyrosine. Results: Of 889 cases identified between 1969-2006, tissue of sufficient quality for inclusion was available from 605 patients, comprising 535 bladder cancer cases (85% TCC) and a normal cohort of 70 cases where cystectomy was performed for a non-bladder malignancy. All cases have been linked to a clinical database complete with follow up data up to 10 years post treatment or death. TMA construction has been validated by immunohistochemistry. General immuno-reactivity across the TMA was confirmed by pan-cytokeratin staining (100%). Preservation of phosphorylation, demonstrated by phosph-tyrosine staining, was confirmed in 80%. Notably there was no correlation between sample age and staining. Conclusions: We have successfully created a validated bladder cancer TMA linked to long term follow up data, which provides a powerful research tool for collaborative research into putative biomarkers and novel drug targets.
Defining early-onset kidney cancer: Implications for genetic counseling.
Authors: Shuch Brian , Vourganti Srinivas , Middleton Lindsay , Linehan W. Marston
Published: February 2017

342

Background: Approximately 1-4% of renal cell carcinoma (RCC) is hereditary. No guidelines exist for patient selection for RCC genetic counseling. We evaluate how age of onset could guide referral for genetic testing. Methods: We analyzed the age distribution of RCC cases in the Surveillance and Epidemiology and End Results (SEER-17) program and from our institutional hereditary kidney cancer population. The age distributions were compared by sex, race, histology, and hereditary syndrome. Models were established to evaluate the specific age thresholds for genetic counseling. Results: The median age of RCC in SEER-17 was 64 years old with the distribution closely approaching normalcy. Statistical differences were observed by race, sex, and subtype (p < 0.05). The bottom decile overall was 46 years of age and slightly differed by sex, race, and histology. The mean and median age of 608 cases of hereditary kidney cancer was 39.3 and 37 years old. While age varied by specific syndrome, 70% of the hereditary cases lied below the bottom age decile. Modeling demonstrated that age alone could limit the number of patients for counseling and that the 10th percentile maximized sensitivity and specificity. Conclusions: Besides associated clinical manifestations and personal/family history, early age of onset in RCC could be a sign of a hereditary kidney cancer. In the absence of clinical signs, an age of onset ≤46 should trigger referral for genetic counseling and may serve as a useful cutoff when establishing genetic testing guidelines.
Outcomes, complications, and costs of care of Bosniak IIF, III, and IV cystic renal lesions/malignancies: Data from the largest multi-institutional study to date.
Authors: Smith Andrew D. , Allen Brian , Sanyal Rupan , Zhang Haowei , Carson Daniel , Zhang Xu
Published: February 2017

344

Background: To evaluate outcomes, complications and costs associated with management of Bosniak IIF, III, and IV cystic renal lesions/malignancies. Methods: An IRB-approved HIPAA-compliant multi-institutional retrospective data registry of prospectively classified Bosniak IIF (N=143), III (N=114), and IV (N=29) cystic renal lesions diagnosed in adults between January 2000 and October 2011 at UMMC, UAB, or WFUBMC was performed. Included patients were managed by surgical excision (N=86), ablation (N=19), or imaging-surveillance >1yr (N=181). De-identified coded data was entered into a web-based REDCap database containing 168 fields/patient. Complication severity was assessed using the Clavien classification system. Inpatient/outpatient technical/professional charges from 6 months prior to 6 months after surgery or ablation were gathered. Results: Patient level malignancy on surgical pathology was 38% (3/8) for BIIF, 40% (26/65) for BIII, and 89% (17/19) for BIV lesions. No metastatic BIIF lesions (0/143). One metastatic BIII lesion (1/114) developed after thermal ablation in a patient with a prior history of papillary RCC. One metastatic BIV (1/29) at the time of initial diagnosis (necrotic papillary RCC). Moderate/severe complications in 19%(16/86) of surgical and 5%(1/19) of ablative patients (p = 0.299). 0%(0/181) complications in patients managed by imaging surveillance >1yr. 0%(0/286) deaths for any management strategy. Median charges of $51,902 for partial nephrectomy (N=50), $42,411 for complete nephrectomy (N=36), and $22,442 for ablation (N=19) were significantly different (p < 0.001). Median charges in surgical patients with moderate/severe complications was $80,393 (N=16), significantly higher than $45,024 (N=70) for no/mild complications (p = 0.002). Conclusions: No deaths from Bosniak IIF or III lesions, irrespective of management approach. Imaging surveillance appears to be a safe primary management strategy for Bosniak III lesions. Moderate/severe complications occurred in 19% of surgery and 5% of ablation patients and nearly doubled the charges for surgery.
Overall survival results from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma.
Authors: Motzer Robert John , Eisen Timothy , Hutson Thomas E. , Szczylik Cezary , Krygowski Mizue , Strahs Andrew Louis , Esteves Brooke , Krivoshik Andrew P. , Berkenblit Anna , Nosov Dmitry
Published: February 2017

350

Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor targeting all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib has shown tolerability and superior progression-free survival and overall response rate versus sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma. Final overall survival (OS) data (August 27, 2012) from TIVO-1 and its open-label, multicenter extension study are reported. Methods: A total of 517 patients were randomized 1:1 to tivozanib 1.5 mg/d (3 weeks on, 1 week off) or sorafenib 400 mg/d (twice a day, continuously) (J Clin Oncol2012;30[suppl]:Abstract 4501). In the extension study, patients who progressed (PD) on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients with PD on tivozanib received subsequent treatment according to regional standards of care. Final OS analysis was planned to be conducted after all patients had died or were lost to follow-up, or when all patients in follow-up had been on study for at least 2 years, whichever occurred first. OS was compared using the stratified log-rank test. OS distribution was estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazard regression model. Results: At the time of final OS analysis (2 years after last patient was enrolled), 219 deaths had occurred (tivozanib, n=118 [45.4%]; sorafenib, n=101 [39.3%]) (stratified HR=1.245; 95% confidence interval [CI] 0.954–1.624; p=0.105), trending in favor of the sorafenib arm. Median OS (95% CI) was 28.8 months (22.5–NA) for tivozanib and 29.3 months (29.3–NA) for sorafenib. Of the 257 patients on sorafenib, 155 (60.3%) had started next-line tivozanib at the time of the analysis. Conclusions: There was no significant difference in OS between the two treatment arms. The high rate of utilization of second-line tivozanib in patients following PD on sorafenib may have affected the OS outcome. Clinical trial information: NCT01030783.
Relationship between biomarkers and everolimus efficacy in the phase III RECORD-1 trial of patients with metastatic renal cell carcinoma (mRCC).
Authors: Oudard Stephane , Escudier Bernard J. , Thompson John A. , Grünwald Viktor , Masini Cristina , Bracarda Sergio , Panneerselvam Ashok , Gogov Sven , Chen David , Motzer Robert John
Published: February 2017

352

Background: Compared with placebo, everolimus provided significant improvement in median PFS in the RECORD-1 study of VEGFr-TKI-refractory mRCC. To investigate the role of angiogenesis pathway molecules as potential biomarkers of everolimus efficacy in RECORD-1, plasma levels of sVEGFR-2, VEGF-A, and bFGF were estimated. Methods: In addition to best supportive care, patients received everolimus 10 mg/day (n = 277) or placebo (n = 139). Placebo patients who progressed were offered everolimus. Predose blood samples were collected on day 1 of the first four 28-day treatment cycles. Plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed by ELISA. Effect of treatment over time on each biomarker was assessed by a mixed effects model. Hazard ratios (HR) for prognostic effects were obtained using log baseline biomarker values as continuous variables in a stratified Cox proportional hazards model. Results: Plasma levels of sVEGFR-2, VEGF-A, and bFGF were available for 45%, 45%, and 39% of everolimus patients and 50%, 50%, and 45% of placebo patients. Patients with biomarker data had baseline characteristics similar to those of the overall population. Mean baseline levels (pg/mL) of sVEGFR-2, VEGF-A, and bFGF were similar for everolimus (8945, 245, and 8, respectively) and placebo (8985, 253, and 13, respectively). Everolimus significantly improved median PFS over placebo irrespective of baseline levels of the analyzed biomarkers (p < 0.001), indicating they are not predictive of everolimus efficacy. Prolonged PFS in the biomarker population was associated with lower VEGF-A baseline level (HR, 1.27; 95% CI, 1.03-1.57; p = 0.028), suggesting VEGF-A may be prognostic for mRCC. Compared with placebo, everolimus significantly reduced bFGF (p = 0.0095) and sVEGFR-2 (p< 0.001) levels over the time course of the study; no effect on VEGF-A levels was observed. Conclusions: Everolimus significantly improved PFS compared with placebo, regardless of baseline biomarker levels. Lower VEGF-A levels may be a potential prognostic factor for longer PFS. Everolimus treatment significantly downregulated plasma levels of bFGF and sVEGFR-2 from baseline. Clinical trial information: NCT00410124.
Relationship of hypoxia signature with variant subgroup of clear cell renal cell carcinoma (ccRCC) and its association with clinical activity on tivozanib hydrochloride.
Authors: Robinson Murray Owen , Feng Bin , Nicoletti Richard , Berkenblit Anna , Strahs Andrew Louis , Esteves Brooke , Eisen Timothy , Motzer Robert John
Published: February 2017

361

Background: TIVO-1, a randomized Phase III trial in first-line targeted therapy for patients (pts) with ccRCC, demonstrated significant improvement in progression-free survival (PFS) in pts receiving tivozanib hydrochloride (T) vs. sorafenib (S) (11.9 vs. 9.1 months [12.7 vs. 9.1 in treatment-naïve pts]). To further characterize molecular ccRCC subtypes and assess relationships between subtypes and vascular endothelial growth factor tyrosine kinase inhibitor activity, we characterized available molecularly annotated datasets from TIVO-1. Methods: Tumor subtypes were established using hierarchical clustering and evaluated in two microarray ccRCC datasets using gene set enrichment analysis with 51 signatures representing a set of molecular phenotypes. A 9-gene signature comprising genes associated with hypoxia-inducible factor (HIF) transcription was quantified by RT-PCR on all available (69/517) formalin-fixed, paraffin-embedded material from patients using a predefined classifier score and cutoff. Results: Hierachical clustering generated 3 distinct tumor classes. Molecular clusters defining HIF gene expression (low), endothelial cell content (low), extracellular matrix (low), proliferation (high) epithelial cell phenotype (high), and metabolism (high) were differentially expressed in cluster 3 tumors, which represented approximately 15% of the populations. Based on predefined analysis, the hypoxia signature was significantly associated with better PFS on T using a previously established classifier (Table). The hypoxia signature was not significantly associated with PFS on S. There was no significant correlation to single largest diameter for either agent. Conclusions: A novel molecular subtype of ccRCC is characterized by a distinct molecular profile and can be classified by a low hypoxia signature. This hypoxia gene signature may help identify T responders. This signature is seen in subsets of other solid tumors supporting the broad exploration of this candidate T response biomarker. Clinical trial information: NCT01030783. [Table: see text]
Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): Updated results.
Authors: Matrana Marc Ryan , Duran Cihan , Shetty Aditya , Xiao Lianchun , Atkinson Bradley J. , Corn Paul G. , Charnsangavej Chusilp , Jonasch Eric , Tannir Nizar M.
Published: February 2017

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Background: Pazopanib is an multi-tyrosine kinase inhibitor shown to prolong progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety on its use after TT are limited. Methods: We retrospectively reviewed records of consecutive pts with mRCC who were treated with pazopanib between November 2009-November 2011 after having progressive disease (PD) with other TT. Radiographic response was assessed by a blinded radiologist using RECIST v1.1 criteria. PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Hazard ratios (HR) were estimated by fitting univariable and multivariable Cox proportional hazards models to evaluate the association of PFS with patient co-variates. Results: 112 pts (median age 63 years, 67% male, 83% clear cell) met inclusion criteria. Median number of previous TT was 2 (range 1-5). 85 events (PD or death) occurred. 14 pts (12.5%) had a partial response. Median PFS was 5.7 months (95% CI: 4.3-8.9 months). PFS was significantly associated with male gender (HR=0.55; 95% CI: 0.34-0.87; p=0.011), clear-cell histology (HR=0.42; 95% CI: 0.24-0.74; p=0.0031), number of metastatic sites (HR= 1.26; 95% CI: 1.05-1.52; p=0.0123), pancreatic metastases (HR=0.40; 95% CI: 0.18-0.85;p=0.0185), Karnofsky PS< 80 (HR=2.07; 95% CI: 1.22-3.48; p=0.0062), and elevated LDH (HR=1.63; 95% CI: 1.03-2.573; p=0.035). Median OS was 16.9 months (95% CI: 10.3–21.9). 26% of pts were still receiving pazopanib at the time of analysis. 51% discontinued pazopanib due to PD and 12% died of PD on treatment. 11% discontinued pazopanib due to adverse events (AEs). There were no treatment related deaths. Common AEs included fatigue (43%), increase LFTs (34%), diarrhea (28%), nausea/vomiting (14%), anorexia (14%), hypertension exacerbation (12%), and hypothyroidism (11%). 89% of AEs were grade 1/2. Conclusions: Pazopanib demonstrated meaningful clinical activity in heavily pretreated pts with mRCC following PD with other TT. AEs were mild/moderate and manageable.
Using presurgical sunitinib to select patients with newly diagnosed metastatic clear cell renal cell carcinoma for cytoreductive nephrectomy: A phase II study.
Authors: Jonasch Eric , Wood Christopher G. , Corn Paul G. , Sharma Padmanee , Pagliaro Lance C. , Aparicio Ana , Do Kim-Anh , Wang Xuemei , Marcott Valerie D. , Matin Surena F. , Tannir Nizar M.
Published: February 2017

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Background: Timing of cytoreductive nephrectomy (CN) is still a matter of debate in mRCC. This study was designed to test the hypothesis that lead-in treatment with sunitinib (Su) selects patients (pts) most likely to benefit from nephrectomy, and can aid in assessing determinants of response and resistance. Methods: Pts with biopsy proven, newly diagnosed clear cell mRCC with measurable disease, performance status of 0/1, and resectable primary tumor were eligible. Pts received one cycle of sunitinib 50mg PO QD on a 28 day on/14 day off cycle, were restaged, and if stable/responding underwent nephrectomy between day 7 and 21 of second cycle of Su. If disease remained stable on postop scans, pts continued Su. Mutations in a 200 gene cancer gene panel as well as copy number variation were used to correlate molecular changes with clinical outcome. Results: 50 pts were enrolled: 36 (72%) were male and 38 (76%) Caucasian, Median age 61 years (range: 43–84). 44 had intermediate MSKCC score and 6 were poor risk. 45 pts (90%) were evaluable. No drug-related perioperative complications were noted. A total of 9 (18%) pts did not have nephrectomy: 6 because of progression, 2 because of drug related toxicity, and one who required emergency surgery during the first cycle for bowel obstruction. Median primary tumor shrinkage after 1 cycle was 4 percent (range -18 to +11%). 4 (8%) pts were found to have nonclear cell pathology at nephrectomy (2 sarcomatoid, 1 papillary, 1 unclassified). Among the 45 evaluable pts, the median PFS was 8.7 months (95% CI: 5.8 – 37.3 months). 24 (53%) pts came off for progressive disease, and five (11%) pts came off for toxicity. With a median follow-up time of 27.3 months, median OS was 32.2 months (95% CI: 17.2 – Not estimable). To date, 20 (40%) pts have died. Copy number and genomic data analysis are underway, and will be presented and correlated with clinical outcome. Conclusions: Pretreatment with Su safely triaged mRCC pts into nephrectomy versus nonnephrectomy groups, with acceptable efficacy and OS. Ongoing studies will define molecular characteristics defining subgroups most likely to benefit from Su. Clinical trial information: NCT00715442.
Significance of zoledronic acid on survival in patients with bone metastases from renal cell carcinoma.
Authors: Yasuda Yosuke , Fujii Yasuhisa , Yuasa Takeshi , Kitsukawa Shinichi , Urakami Shinji , Yamamoto Shinya , Yonese Junji , Takahashi Shunji , Fukui Iwao
Published: February 2017

374

Background: It remains unclear whether zoledronic acid (ZOL) improves overall survival (OS) for renal cell carcinoma (RCC) patients with bone metastases. We retrospectively investigated the clinical benefit of ZOL for OS in RCC patients with bone metastases. Methods: Between 1978 and 2010, 77 patients who had RCC metastatic to bone were treated in our hospital. Of them, 36 were treated with ZOL and their OS was significantly better than that of the other 41 patients (1- and 3-year survival, 84% and 73% vs. 49% and 27%, respectively, p < 0.001). OS rates were clearly discriminated according to MSKCC model stratification: 3-year survival rates in the favorable, intermediate and poor risk groups were 83% (n = 12), 49% (n = 45), and 19% (n = 20), respectively (p=0.0033). To match characteristics in our retrospective study, we selected 45 patients conforming to MSKCC intermediate risk group criterion. In this cohort, 23 patients received ZOL (ZOL-treated group) whereas the other 22 did not (non-ZOL-treated group). The primary endpoint was OS and the secondary endpoint was the skeletal-related event (SRE) rate defined as the total number of SREs divided by the total years on study. Results: For the cohort of 45 patients, the median OS from diagnosis of bone metastases was 27.2 months. Multivariate analysis showed that low serum calcium (hazard ratio [HR]: 2.58, 95% confidence interval [CI]: 1.31 to 4.69; p = 0.0083) and ZOL treatment (HR: 1.89, 95% CI: 1.27 to 2.96; p = 0.0013) were independent factors predicting longer survival. The ZOL-treated group had significantly longer OS (1-year survival: 80.8%) than the non-ZOL-treated group (1-year survival: 59.1%, p = 0.0034). A difference in OS between the two groups still was present (p = 0.012) when the duration of molecular-targeted therapy was excluded from the OS period. Patients in the ZOL-treated group experienced a lower SRE rate (0.87/year) than patients in the non-ZOL-treated group (1.82/year, p = 0.0453). In particular, none of the patients in the ZOL-treated group developed spinal compression whereas 6 (28%) in the non-ZOL-treated group did (p = 0.0479). Conclusions: The current study indicates that ZOL not only reduces SREs but possibly improves OS in these patients.
Multiplexed tissue protein assay to predict patient response to targeted therapy in advanced renal cell carcinoma.
Authors: Vaishampayan Ulka N. , Sethi Seema , Chen Wei , Derrien-Colemyn Alexandrine , Gillespie John Williams , Dickow Brenda , Smith Daryn W. , Rait Vladimir , Tunon Peter
Published: February 2017

382

Background: Although a number of prognostic biomarkers have been explored in advanced renal cancer, to date none have been useful in therapeutic outcome prediction. Methods: Following regulatory approval, formalin-fixed paraffin embedded pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The samples were analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Two panels of 9 protein biomarkers each were used to probe tissue sections for proteins along the mTOR and/or the VEGFR/PDGFR signaling pathways. Biomarker expression in regions of cancer were scored and levels correlated with the patient’s clinical outcome status. Results: Tissue samples of 30 pts treated with sunitinib were analyzed and scored in a blinded fashion using 4 biomarkers. If the sum of the scores assigned to VEGFA, VEGF2 and HIF2alpha was above 19, pt was predicted to be a responder. If initial score < 19 and the sum of VEGFR2 and VEGFB was 2 or more, the pt was predicted to have an objective response (OR)/stable disease (SD). If score < 2 the pt was predicted to have no benefit from sunitinib. 14 of 15 OR/SD pts and 11 of 15 with progressive disease (PD) were accurately predicted. 35 cases treated with mTOR inhibitor were analyzed. 6 biomarkers in the mTOR pathway were used to create a composite score. 11/14 OR/SD pts (sensitivity 79%) and 18/21 PD pts (specificity 86%) were accurately predicted using a score cutoff of 10. Median time to treatment failure (TTF) was 2 months in the PD pts, as compared to 11 months in the OR/SD group. A subgroup analysis of patients followed for 18 months or less showed linear correlation between the biomarkers and the TTF (Spearman correlation coefficient 0.43 with p value 0.04). Statistical modeling, results of ongoing validation testing, and score correlation with TTF will be presented. Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information, to help guide therapy. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by 20/20 gene systems.
Increase in blood pressure with sorafenib exposure in renal cell carcinoma versus other solid tumors.
Authors: Shah Amishi , Motiwala Shweta , O'Dwyer Peter J. , Flaherty Keith T. , Keefe Stephen Michael
Published: February 2017

384

Background: Tyrosine kinase inhibitors (TKIs) such as sorafenib are widely used in the treatment of solid tumor malignancies. Incident hypertension with angiogenesis inhibitors has been well-documented in the population of patients with renal cell carcinoma (RCC) where incident hypertension on treatment is associated with improved clinical outcome. Little has been reported about increases in blood pressure with TKIs in other solid tumor malignancies. Methods: We performed a retrospective cohort study examining changes in blood pressure with sorafenib among the 101 patients treated at the University of Pennsylvania on a randomized discontinuation trial examining sorafenib in patients with advanced solid tumor malignancies. Solid tumor diagnoses were established on the basis of tumor histology. Treatment of patients on study with sorafenib was initiated at 400 mg BID. Patients were treated for at least 12 weeks and were evaluated at least every three weeks in the clinic. Blood pressure was recorded at each visit. Sorafenib exposure was recorded by patients in a pill diary. The primary endpoint for this study was a maximal change in blood pressure defined as the difference between baseline blood pressure and highest subsequent recorded systolic and diastolic blood pressures on treatment. Results: 72% of RCC patients developed an increase in systolic blood pressure (SBP) of at least 20 mmHg as compared to 32% of non-RCC patients. The mean increase in SBP on study for RCC patients was 30 mmHg versus 19 mmHg in non-mRCC patients. RCC patients in the top quartile of increased SBP showed a mean increase of 54 mmHg as compared to 35 mmHg for non-mRCC patients. A chi-squared test of proportions and t-tests were used to compare rates and means, respectively. Each of the aforementioned differences were found to be statistically significant with p-values <0.003. These relationships also held true for diastolic blood pressure. There was no difference in SBP between groups in terms of age or sorafenib exposure. Conclusions: In these patients treated with sorafenib the proportion of patients with increased blood pressure and the mean amplitude of change in blood pressure both were significantly greater in the RCC population than in the non-RCC group.
Supression of tumor progression and metastasis in renal cell carcinoma by miR-192, miR-194, and miR-215.
Authors: Khella Heba W. Z. , Bakhet Marize , Allo Ghassan , Jewett Michael A. S. , Girgis Andrew , Bjarnason Georg A. , Yousef George M.
Published: February 2017

385

Background: miRNAs play a crucial rule in tumor progression and metastasis. We previously identified miR-192, miR-194 and miR-215 to be down-regulated in metastatic compared to primary clear cell renal cell carcinoma (ccRCC). In this work, we examine the role of miR-192, miR-194, and miR-215 in RCC progression and aggressiveness. Methods: We examined the role of these three miRNAs on tumor cell migration and invasion abilities using RCC cell line models. We performed target prediction analysis and experimentally validated the targets using independent approaches. In addition, we examined the clinical utility of miR-215 as a potential prognostic marker in RCC by measuring miR-215 expression using qRT-PCR in 61 formalin-fixed paraffin-embedded tissues from primary ccRCC and correlated the expression levels with clinical outcome. Results: Restoration of miR-192, miR-194, and miR-215 expression decreased cell migration and invasion in RCC cell lines. Target prediction analysis identified three potential targets of these miRNAs; MDM2, TYMS, and SIP1/ZEB2. We validated the miRNA-target interaction experimentally using three approaches. First by measuring the effect of miRNA overexpression on mRNA and protein levels of the predicted target, then by measuring the effect of miRNA overexpression on a luciferase signal of a vector containing the 3’UTR of the predicted target, and finally, by validating these interactions in vivoby examining the presence of an inverse correlation between miRNA changes and the expression levels of their targets on clinical specimens. In 61 patients with resected ccRCC tumors, we found that low miR-215 expression in the primary was associated with a significantly reduced recurrence-free survival. (26.4 vs. 49.2 months, respectively, p = 0.0320). Conclusions: Our analysis showed that miR-192, miR-194, and miR-215 are involved in RCC metastasis and that miR-215 predicts for recurrence in patients with resected RCC. Our findings pave the way to the clinical use of miRNAs as prognostic markers and potential therapeutic targets.
The role of FGF signaling in VEGF-pathway targeted therapy resistance: Data from patients and model systems.
Authors: Ho Thai Huu , Warneke Carla L. , Hoang Anh , Tamboli Pheroze , Wang Fen , Jonasch Eric
Published: February 2017

386

Background: Angiogenesis plays a role in tumor growth and is partly mediated by factors in both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) pathways. Brivanib inhibits both VEGF receptor 2 and FGF receptors (FGFR)-1/2. Methods: Nephrectomy material from 40 patients with metastatic renal cell carcinoma (RCC) receiving sorafenib ± interferon was assessed by immunohistochemical (IHC) staining. The Ariol imaging platform was used to stratify the specimens based on intensity of staining for FGF biomarkers: FGFR-1 and fibroblast growth factor receptor substrate 2 (pFRS2). The relationship between fibroblast growth factor pathway marker levels and progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox proportional hazards regression methods. To assess the efficacy of dual targeting of VEGF and FGF receptor signaling by brivanib, we treated a xenograft RCC mouse model with sunitinib, brivanib, or sunitinib followed by brivanib. Results: Our analysis indicated that more intense FGFR-1 staining was associated with shorter PFS (p = 0.0452), and that pFRS2 staining were not significantly associated with PFS (p = 0.2610). FGF pathway activation was associated with decreased PFS in patients with metastatic RCC treated with sorafenib. Xenograft mice were treated with 20 mg/kg sunitinib and after an initial stabilization phase, resistance developed by day 20. A switch to 30 mg/kg brivanib prolonged the stabilization phase after progression on sunitinib (p = 0.0033). Conclusions: The PFS of patients treated with sorafenib is associated with FGF pathway activation. In a xenograft RCC mouse model, brivanib overcame the tumor escape after initial treatment with sunitinib. Switching from sunitinib to brivanib at the time of tumor escape prolonged the stabilization phase and overcame a sunitinib-induced resistance phenotype. The results suggest that FGF pathway activation mediates both innate and acquired tumor resistance to VEGF receptor inhibition. The efficacy of dual inhibition of FGF and VEGF in the subset of patients with increased FGF activation prior to treatment requires further study.
Changing trends in pelvic lymphadenectomy in radical prostatectomy with the advent of robotic surgery.
Authors: Sohn William , Paciorek Alan , Carroll Peter , Penson David F. , Dash Atreya
Published: February 2017

39

Background: It is important to determine whether changes in technology have impacted surgical practice. With the adoption of robotic surgery, it is our hypothesis that rates of pelvic lymphadenectomy (LND) have decreased, even when controlling for cancer risk and comorbidities. To assess whether adoption of surgical technology versus practice patterns in the extent of surgery over time changed, we propose to compare the rates of pelvic LND at the time of radical prostatectomy during the time period when robotic surgery was adopted. Methods: Data was extracted from CaPSURE, a multi-institutional, longitudinal observational database of men with prostate cancer. A total of 3,938 men diagnosed with localized prostate cancer between 2000 and 2011 were included in the analysis if they underwent surgical extirpation. The inclusion of LND was calculated for both groups. Other information included site type, age at diagnosis, comorbidities, and CAPRA risk assessment score. Results: A total of 3,616 open retropubic prostatectomies and 322 robotic prostatectomies were included for analysis. Among the open prostatectomies, 78.9% underwent pelvic LND. During the same time period, among robotic prostatectomies, 45.3% underwent pelvic LND. There was a statistically significant correlation between method of radical prostatectomy and the performance of LND (p < 0.001). There were no statistically significant differences between the two groups in CAPRA score, age, or comorbidities (p= 0.06, 0.29, and 0.60; respectively). The adjusted odds ratio of LND for the open group compared to the robotic group is 5.90 (95% CI [4.48,7.78]) while adjusting for clinical stage, grade, and PSA. Conclusions: Controlling for other factors, the difference in rates of LND between the open and robotic groups were statistically significant. These data suggest changes in surgical practice may have been altered by the adoption of a new technique to perform surgery (rather than new scientific data supporting omission of LND).
Real-world treatment patterns in third-line patients with metastatic renal cell carcinoma (mRCC): The changing landscape in the United States.
Authors: Pal Sumanta Kumar , Malangone Elisabetta , Bhurke Sharvari , Gorritz Magdaliz , Stern Lee , Coombs John , Turnbull James D. , Wang Xufang , Liu Zhimei
Published: February 2017

390

Background: Several targeted therapies (TTs) have become available in mRCC in recent years for first- and second-line use, including sorafenib (So), sunitinib (Su), bevacizumab (Be), temsirolimus (Te), everolimus (Ev), pazopanib (Pa), and most recently, axitinib (Ax). This study aimed to examine the current treatment patterns in mRCC patients who fail second-line therapy. Methods: Data were obtained from a large national U.S. claims database for patients with an RCC diagnosis and at least 3 lines of TT between January 1, 2004, and June 30, 2011. Patients were age 18 or older at diagnosis with at least 3 months of follow-up prior to initiation of third-line therapy. Patient characteristics and treatment patterns were examined for the final population. Results: A total of 812 mRCC patients initiated third-line therapy with So, Su, Be, Te, Ev, or Pa. The sample was majority male (70%) with a mean age of 60 years (SD=10.7). A large proportion of patients were from the South (42%), and the majority of the sample (72%) had commercial insurance. The most common sites of metastases at any time were lung (71%) and bone (52%). The most common first-line agent was Su (52%) and the most common second-line single agents were Te (25%) and Ev (17%). The most frequently used single-agents in third-line were Te (21%) and Ev (19%). Third-line treatment choice differed by year; Te (51%) was most common in 2007 while Ev and Pa were most common between 2009 and 2011. Additionally, the most frequently prescribed sequences of single agents were VEGF→mTOR→VEGF (25%), VEGF→mTOR→mTOR (25%), and VEGF→VEGF→mTOR (22%). Conclusions: The results demonstrate a rapidly changing therapeutic scenario for mRCC in the United States. The number of targeted therapies prescribed in third-line increased from 1 in 2006 to 4 in 2007 and 6 in 2011. This evolution of third-line therapies is possibly due to physicians adapting their practice with the advent of novel mRCC treatment options. These results are in line with the NCCN guidelines, with VEGF and mTOR being the most commonly prescribed first- and second-line single agents, respectively.
Treatment outcome with mTOR inhibitors for 65 cases of non-clear cell renal cell carcinoma: Association of long-term responses and oncogenomic events.
Authors: Voss Martin Henner , Bastos Diogo Assed , Karlo Christoph , Patil Sujata , Ajeti Albulena , Hakimi A. Ari , Feldman Darren Richard , Molina Ana M. , Berger Michael F. , Hsieh James , Motzer Robert John
Published: February 2017

391

Background: Temsirolimus and everolimus are standard agents in the management of advanced renal cell carcinoma, but the registration trials primarily enrolled patients with clear cell histology. We assessed outcome in patients with non-clear cell RCC (ncRCC) treated with mTOR inhibitors at our center. Methods: Clinical features and histologic subtypes were characterized for ncRCC patients treated with single-agent temsirolimus or everolimus. Outcome was analyzed using the Kaplan-Meier method to determine progression free survival (PFS) and overall survival (OS). Genomic analysis of outliers with either durable or poor response was done by next-generation sequence analysis of tumor tissue and germline DNA. Results: 65 patients received temsirolimus (n = 46) or everolimus (n = 19). Histologic subtypes included papillary (n = 16), chromophobe (n = 9), collecting duct (n = 6), translocation-associated (n = 3), and unclassified (n = 31) RCC. Median follow-up for survivors is 29 mos. Median treatment duration for 52 patients, who continue therapy or stopped due to progression or death, is 2 mos. 8 patients (12.3%) were treated for ≥ 1 year (max. 37 mos), including papillary (n = 3), chromophobe (n = 2) and unclassified (n = 3) RCC. Tumor analysis identified genomic determinants of long term response in 2 unclassified RCC (complete functional loss of TSC1 and TSC2, respectively). No such changes were seen in 2 patients with chromophobe RCC and rapid progression on therapy. Conclusions: A subset of ncRCC patients derives benefit from mTOR inhibitors, but most have poor outcome. Durable responses can be linked to oncogenomic alterations within the mTOR pathway, and future goals should include the identification and characterization of such predictive tissue biomarkers. [Table: see text]
Updated phase I results of a phase I/II trial of BNC105P with everolimus in patients with metastatic renal cell carcinoma (mRCC).
Authors: Hutson Thomas E. , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Galsky Matt D. , Bylow Kathryn A. , Cowey Charles Lance , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Sonpavde Guru , Logan Theodore , Hahn Noah M. , Sweeney Christopher , Sarantopoulos John ,   Hoosier Oncology Group
Published: February 2017

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Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during cycle 1. Results: Updated results from the completed phase I component confirm the BNC105P/everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia, and oral mucositis were also observed. 8 of the 12 phase I subjects achieved disease stabilization (7 of these subjects had a minimum time on therapy of 18 weeks, 6 cycles). Across all subjects a median of 6 cycles (range: 1-21) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in a randomized phase II study. Clinical trial information: NCT01034631.
Could a biomarkers-based patients' selection help to plan a clinical trial with targeted agents (TA) for metastatic renal cell carcinoma (mRCC)? Interaction and power analysis of randomized trials (RCTs).
Authors: Massari Francesco , Maines Francesca , Pilotto Sara , Bonomi Maria , Giannarelli Diana , Brunelli Matteo , Martignoni Guido , Tortora Giampaolo , Bria Emilio
Published: February 2017

399

Background: To predict the clinical benefit of TA in mRCC, several studies have analyzed some angiogenesis-related biomarkers including soluble VEGF and VEGF-Receptors, VEGF polymorphisms, IL-8 polymorphisms, and VHL mutations. We performed a power analysis to assess how much a biomarker-based approach can affect the sample size of a trial in mRCC. Methods: Hazard ratios (HR) for survival with 95% confidence intervals (CI) for overall survival were extracted and cumulated according to a random-effect model from RCTs. A sensitivity analysis according to ‘biomarker-selection’ approach and to ‘unselected’ fashion was accomplished in order to test for interaction. Testing for heterogeneity was performed as well. Results: A correlation between a featured biomarker and treatment effect was reported in three RCTs (1987 patients). The attrition rate for the survival analysis according to the molecular analysis was 45% (range 20 to 60%). In spite of the extremely different bio-markers’ profiles, demonstrated by the significant observed heterogeneity (p = 0.002), we found an Hazard Ratio (HR) for overall survival of 0.60 (95% CI 0.40-0.89; p = 0.013) and a significant interaction according to strategy (‘biomarker-selected’ vs.‘unselected’) (p = 0.025), supporting a differential effect of these drugs when administered according to a predictive phenotype. In the ‘unselected’ sample, considering the intention to treat analysis (all randomized patients) the HR was 0.90 (95% 0.80-1.00; p = 0.06). From a clinical trial design perspective, if targeting these expected survival differences, with a power 80%, and a alpha-error 0.05, the required events are described in the table. Conclusions: With the aim to avoid the attrition of the heterogeneity of biomarkers’ selection and drugs, we speculate that the sample size of a planned clinical trial design in mRCC according to a biomolecular classifier may help to shorten the gap between clinical research and practice. [Table: see text]