bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overall and progression-free survival with everolimus, temsirolimus, or sorafenib as second targeted therapies for metastatic renal cell carcinoma: A retrospective U.S. chart review.
Authors: Yang Hongbo , Wong Michael K.K. , Signorovitch James E. , Wang Xufang , Liu Zhimei , Liu Nathan S. , Qi Zhengyun , George Daniel J. 
Published: March 2020

4612 Background: Tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib) and inhibitors of the mammalian target of rapamycin (mTORs) (everolimus, temsirolimus) are used for treating metastatic renal cell carcinoma (mRCC) following initial treatment with a TKI. This study’s objective was to establish the effectiveness of the most commonly used 2nd line treatments based on real-use data. Methods: mRCC patients who received a TKI as their 1st targeted therapy and everolimus, temsirolimus or sorafenib as their 2nd therapy were identified by oncologists (85% in community practice) throughout the US as part of an online chart review study. Baseline characteristics were assessed prior to 2nd targeted therapy, including type and duration of initial TKI, response, histological subtype, performance status, and sites of metastasis. Overall survival (OS) and progression free-survival (PFS) were assessed after initiating 2nd targeted therapy. OS and PFS were compared between treatment groups using Cox proportional hazards models adjusted for baseline characteristics. Results: Charts were reviewed for 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib after an initial TKI, respectively. Median age was 64 years and 70.4% were male. Prior to initiating a 2nd targeted therapy, 86.0% used sunitinib and 85.9% had disease progression. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS compared to temsirolimus (hazard ratio [HR] 0.56; CI 0.40-0.78; p<0.001) and sorafenib (HR 0.65; CI 0.42-0.99; p=0.047). Everolimus was associated with significantly longer PFS compared to temsirolimus (HR 0.73; CI 0.55-0.96; p=0.025), and non-statistically significant longer PFS compared to sorafenib (HR 0.75; CI 0.53-1.07; p=0.110). Results were similar in the subgroup with sunitinib as 1st targeted therapy and the subgroup with progression on 1st TKI. Conclusions: Among mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.
Xp11.2 translocations in adult renal cell carcinomas with clear cell and papillary features.
Authors: Chan Susanne M. , Sherman Christopher G. , Gabril Manal Y. , Zbieranowski Ingrid J. , Sugar Linda M. , Yousef George M. , Bjarnason Georg A. 
Published: March 2020

4613 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a rare tumor with unpredictable clinical course and prognosis in adults. Recognition of these tumors depends on the identification of a RCC with unique histology, particularly clear cell and papillary (CCP) features. Our objectives were to determine the incidence of Xp11.2 translocations in adult RCCs with clear cell and papillary features, and to characterize the clinicopathological features and prognosis of adult Xp11.2 RCCs. Methods: Slides for 1047 RCCs in adults (1999-2009) were retrieved from multiple institutions. Cases were reviewed histologically in order to detect any degree of clear cell and papillary change. Tissue microarrays were constructed from the clear cell and papillary RCCs as well as 40 non-papillary clear cell, 5 papillary, 3 chromophobe and 2 unclassified RCCs. Immunohistochemistry using TFE3, a marker highly sensitive (97.5%) and specific (99.6%) for Xp11.2 translocations was performed. Four pathologists independently reviewed the TFE3 results. Clinical and pathologic data were also retrieved. Results: Out of 1047 RCCs, 140 (13%) exhibited clear cell and papillary features. Four out of these 140 (3%) were positive for TFE3. All of the non-papillary clear cell, papillary, chromophobe and unclassified RCCs were negative for TFE3. Mean follow up for TFE3+ RCCs was 55 months. Conclusions: Xp11.2 translocation RCCs diagnosed by TFE3 immunohistochemistry were identified in 3% of adult RCCs that had clear cell and papillary changes. These tumors appear to present with smaller tumour size, lower stage and better prognosis in comparison to non-Xp11.2 CCPRCC and clear cell RCCs. In addition to Xp11.2 translocation carcinoma, coexistence of clear cell and papillary features may be present in other subsets of tumors that have yet to be characterized. [Table: see text]
A phase I study of pazopanib (P) combined with bevacizumab (B) in patients with metastatic renal cell carcinoma (mRCC) or other advanced refractory tumors.
Authors: Negrier Sylvie , Pérol David , Bahleda Rastilav , Hollebecque Antoine , Chatelut Etienne , Boyle Helen Jane , Cassier Philippe A , Ferlay Celine , Metzger Severine , Blanc Ellen , Soria Jean-Charles , Escudier Bernard J. 
Published: March 2020

4614 Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a new VEGFR inhibitor P with B, in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This bicentric trial is conducted with 3+3+3 escalation doses of P + B. The MTD is the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. The effect of B on steady-state pharmacokinetic (PK) of P is also investigated. Major inclusion criteria are: ECOG PS ≤1, ALT and AST <=2.5 x ULN, serum creatinine <=1.5 mg/dL or creatinine clearance <=50 mL/mn and absence of uncontrolled hypertension. Results: 15 pts were enrolled with mRCC (n=7), melanoma (n=2), adrenocortical carcinoma (n=1), mesothelioma (n=1), pancreatic cancer (n=1), oesophageal cancer (n=1), bladder cancer (n=1) and seminoma (n=1). Median age is 61 (43-78), 12 pts are male. No DLT were reported at DL1 (P 400 mg/d + B 7.5 mg/kg q2w) (n = 9), or at the first step of DL2 (P 600 mg/d + B 7.5 mg/kg q2) (n=3), but the 3 following nephrectomized pts experienced DLT: a grade 3 transaminitis, a grade 3 pulmonary embolism and a reversible microangiopathic hemolytic anemia. Inclusion of nephrectomized pts was completed, but enrolment of 3 additional non-nephrectomized pts at DL2 was approved by IDSMB in November 2011 and these treatments are ongoing. Preliminary results of PK analysis showed a significantly higher P AUC at steady-state in pts with DLT. Moreover, lower P apparent clearance was observed in nephrectomized pts. Conclusions: The MTD of the combination of P and B is 400 mg/d and 7.5mg/kg respectively, in nephrectomized patients, but is not yet reached in other patients. Unexpected effect of nephrectomy status was observed on P pharmacokinetics.
Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): A single-institution experience.
Authors: Matrana Marc Ryan , Shetty Aditya V. , Atkinson Bradley J. , Xiao Lianchun , Corn Paul G. , Millikan Randall E. , Jonasch Eric , Tannir Nizar M. 
Published: March 2020

4615 Background: Pazopanib is an approved multi-tyrosine kinase inhibitor that prolongs progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety data on its use after TT are limited. Methods: We retrospectively reviewed pts with mRCC who received salvage pazopanib between 11/09-11/11. Kaplan-Meier method was used to estimate survival outcomes. PFS was calculated from start of pazopanib until progressive disease (PD) or death. Univariable and multivariable Cox proportional hazards models were fitted to evaluate associations of PFS with covariables. Results: 114 consecutive pts met inclusion criteria (median age 62.6 years, 66% males, 83% clear cell). All pts had PD after other TT (median # of prior TT 2, range 1-5; median time on prior TT 23.3 mos). 79% of pts had PD on sunitinib, 39% on sorafenib, 19% on temsirolimus, 59% on everolimus, and 23% on bevacizumab. 25% received prior chemotherapy and 16% received prior cytokines in addition to TT. 87% had prior nephrectomy. 11% had favorable-risk, 68% intermediate-risk, and 21% poor-risk per MSKCC criteria. 85 events (PD or death) occurred. Median OS was 17 mos (95% CI: 10.3-NA). Median PFS was 6.4 mos (95% CI: 4.5-9.5). By multivariable analysis, PFS was associated with male gender (HR=0.433, 95%CI: 0.269-0.696; p=0.0006), # of metastatic sites (HR=1.252; 95%CI: 1.04-1.503; p=0.016), hypertension exacerbation (HR=0.378; CI: 0.175-0.813; p=0.0128) and PS 2+ vs.0-1 (HR=2.067; CI: 1.243-3.437; p=0.0052). 58% discontinued pazopanib due to PD, 12% died of PD on treatment, and 11% discontinued pazopanib due to adverse events (AEs), mostly GI complaints or fatigue. There were no treatment related deaths. Common AEs included: fatigue (44%), diarrhea (29%), nausea/vomiting (15%), anorexia (14%), hypertension exacerbation (11%), hypothyroidism (11%), hand-foot skin reaction (9%), and increase LFTs (4%). 86% of AEs were grade 1/2. Conclusions: In this retrospective study, pazopanib demonstrated efficacy in mRCC following PD with other TT. AEs were mild/moderate and manageable.
Natural history of malignant bone disease in renal cancer: Final results of an Italian bone metastases survey.
Authors: Santini Daniele , Procopio Giuseppe , Porta Camillo , Mazzara Calogero , Barni Sandro , Fontana Andrea , Berruti Alfredo , Berardi Rossana , Vincenzi Bruno , Ortega Cinzia , Ibrahim Toni , Ottaviani Davide , Carteni Giacomo , Lanzetta Gaetano , Virzì Vladimir , Silvestris Nicola , Tanca Francesca Maria , Adamo Vincenzo , Tonini Giuseppe , Bracarda Sergio 
Published: March 2020

4627 Background: bone metastases (mts) are an emerging clinical problem in renal cancer patients related to survival increase. We report the final data of largest survey never published in literature. Methods: 398 renal cancer patients (pts) with evidence of bone mts, all died at the moment of study inclusion, have been included. Clinico-pathological data, data on survival and Skeletal Related Events (SRE) data and skeletal related therapies have been collected and statistically analyzed. Results: 286 males/112 females; median age: 63 (16-87); pts with bone mts at the moment of renal cancer diagnosis: 31.4%; pts with single bone mts: 31.1%. Type: lytic 77%, mixed: 14.6%, blastic: 7.6 %. Sites: spine (65.8%), pelvis (38.4%), long bones (31.6%), other (18.8%). Median time to bone mts: 8 months (0-288) (all patients); 24 months (1-288) (pts without bone mts at diagnosis). Pts with at least 1 SRE: 71.1%. Types of SREs: pathologic fracture (12.6%), radiotherapy (61.8%), spinal compression (7.6%), bone surgery (14.8%), hypercalcaemia (3.2%). Median number of SRE for patient: 1 (0-4). Median time to first SRE: 2 (0-72), to second SRE: 4 (0-113), to third SRE: 11 (1-108). Median survival after bone mts diagnosis: 12 (1-178). Median survival after first SRE: 10 (0-144). Median survival in pts with at least one SRE: 14 (1-178); median survival in pts without SREs: 9 (0-62). In according with MKSCC criteria median time to skeletal disease was in patients with good prognosis was 24 (0-288), intermediate was 5 (0-180) and poor prognosis was 0 (0-77). A total of 168 pts received zoledronic acid until performance status worsening or death. 162 pts have been analysed as control group. The median time to first SRE in the zoledronic treated pts was 3 mths (0-101) compared with 1 mth (0 - 25) in the control group (p< 0.05). 5 cases of ONJ have been diagnosed. Conclusions: The present survey is the largest descriptive study concerning the natural history of bone disease in renal cancer patients. The effects of biological therpies on bone met will be presented during the meeting.
Hypoxia-inducible factor (HIF) 1α and 2α as predictive markers of outcome to VEGFR tyrosine kinase inhibitors (TKI) in renal cell carcinoma (RCC).
Authors: Saez M.I. , Trigo Perez Jose Manuel , Perez-Rivas L.G. , Perez-Villa L. , Villatoro R. , Montesa A. , Cid J.I. , Leon M. , de Luque V. , Fernandez C. , Quero C. , Pajares B. , Alba E. 
Published: March 2020

4630 Background: Relevant biomarkers in RCC are needed to identify appropriate candidates for selected targeted therapies. Mutations in the von Hippel-Lindau (VHL) gene result in the accumulation of HIF and increased expression of proangiogenic factors, including VEGF. Methods: Metastatic clear RCC patients with available baseline tumor samples who received first-line oral VEGFR-TKI were included in this analysis. VHL mutation/hypermethylation status and HIF1α and HIF2α immunohistochemical staining were analyzed from paraffin-embedded tumors. Additionally, a panel of candidate VEGF and VEGFR2 genetic SNPs was determined from peripheral blood samples. HIF was scored as negative or positive based on staining intensity (0-10% and > 10%, respectively). Results were evaluated for associations with clinical outcome. Results: 80 patients were included: 71 evaluable for HIF expression, 63 for VHL status and 52 for SNPs. 73% received treatment with sunitinib and median follow-up was 21.5 months. Unlike VHL status, HIF1 and HIF2 positive expression showed a significant correlation with PFS and OS. HIF1α was also predictive for response rate (RR). On multivariate analysis adjusting for other prognostic factors, HIF1α and HIF2α remained the most significant independent predictive factors for survival (adjusted HR 0.09, 95% CI 0.03-0.28, p < 0.0001 and HR 0.13, 95% CI 0.04-0.37, p < 0.0001; respectively). We did not find any statistically significant differences based on the VEGF and VEGFR2 SNPs analyzed. Conclusions: HIF1α and HIF2α levels represent the most important independent predictive factors of outcome for VEGFR-TKI therapy in metastatic RCC. These findings may contribute to optimize treatment with targeted agents. [Table: see text]
Activity of insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic refractory adrenocortical carcinoma.
Authors: Naing Aung , LoRusso Patricia , Fu Siqing , Hong David S. , Chen Helen , Doyle L. Austin , Phan Alexandria , Habra Mouhammed Amir , Kurzrock Razelle 
Published: March 2020

4639 Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancywithout an available effective systemic chemotherapy. IGF-R2 overexpression leading to the activation of the IGF1R/mTOR pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), was combined with temsirolimus on the basis of preclinical data. Methods: Patientsreceived cixutumumab, 3-6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Results: Twenty-six patients were enrolled (13 [50%] men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug-related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolemia (31%), hypertriglyceridemia (35%), and hyperglycemia (31%). Eleven of 26 patients (42%) achieved stable disease (SD) > 6 months (duration range = 6 to 21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. Conclusions: Cixutumumab combined with temsirolimus was well tolerated and more than 40% of patients achieved prolonged SD. This study was supported by R21CA13763301A1 (AN), U01CA62461 (RK), and U01CA62487 (PL).
Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone: A rationale for increasing drug exposure in castration-resistant prostate cancer.
Authors: Sharifi Nima , Li Rui , Evaul Kristen , Sharma Kamalesh , Auchus Richard J 
Published: March 2020

4645 Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1,000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.
Guideline-discordant androgen deprivation therapy (ADT) use in localized prostate cancer (CaP) and cost implications: A population-based study.
Authors: Kuykendal Adam Rea , Hendrix Laura H , Salloum Ramzi George , Godley Paul Alphonso , Chen Ronald C. 
Published: March 2020

4647 Background: ADT use in localized CaP has increased overall survival and is recommended by National Comprehensive Cancer Network (NCCN) guidelines in certain clinical situations. However, ADT may cause harm and is without benefit in other situations. Prior studies showed a decline in “inappropriate” ADT use coinciding with Medicare reimbursement changes in 2004-2005. This study examines recent trends in ADT use and quantifies the cost of guideline-discordant ADT. Methods: Patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed with non-metastatic CaP between 2004 and 2007, ages 66-80 were included for analysis. PSA, Gleason score and clinical stage were used to define D’Amico risk categories. Logistic regression was used to examine factors associated with guideline-discordant ADT use. Annual direct cost was estimated using the current Medicare reimbursement amount for ADT. Results: Of 24,280 men included, 13% received guideline-discordant ADT. Discordant use declined from 15% in 2004 to 11% in 2007. In low-risk patients, 15% received discordant ADT, mostly due to simultaneous ADT with radiation. Discordant use was seen in 7% of intermediate and 16% of high-risk patients, mostly from ADT monotherapy. African American (AA) (p<.001), older patients (p<.001) and those with more comorbidities (p<.001) were more likely to receive discordant ADT (Table). The estimated annual direct cost to Medicare from discordant ADT is $43,500,000. Conclusions: Approximately one in eight patients received ADT discordant with published guidelines, with AA and elderly patients disproportionately affected. Elimination of discordant use would result in substantial savings in healthcare costs. [Table: see text]
Targeted next-generation sequencing (NGS) of advanced prostate cancer (PCA) using formalin-fixed tissue.
Authors: Beltran Himisha , Yelensky Roman , Frampton Garrett , Park Kyung , Downing Sean , Macdonald Theresa , Lipson Doron , Tagawa Scott T. , Nanus David M. , Stephens Philip , Mosquera Juan Miguel , Cronin Maureen T. , Rubin Mark A. 
Published: March 2020

4649 Background: The genomic landscape of advanced PCA is not well characterized, partly due to limited availability of frozen metastatic tissue. This has created a gap in our knowledge of treatment related and potentially targetable genomic alterations. The purpose of this study was to demonstrate feasibility of performing NGS to molecularly characterize advanced PCA using formalin-fixed paraffin embedded (FFPE) tissue. Methods: 25 metastatic CRPC, 4 metastatic hormone naïve PCA, 3 primary localized PCA, and 18 benign matched prostates were evaluated (40mm FFPE tissue per case). High-density foci were captured and sequenced for 3230 exons of 182 cancer-related genes and 37 introns of 14 genes often rearranged in cancer to an average depth of >800x in a CLIA lab (Foundation Medicine). Recurrent mutations, copy number alterations, and fusions were validated using PCR and FISH. Results: In >90% of samples, there was sufficient DNA (≥50 ng) for analysis. Recurrent high confidence cancer alterations in CRPC included: TMPRSS2-ERG fusion (44%), PTEN loss (44%), TP53 mutation (40%), AR mutation (24%), AR gain (24%), RB mutation (28%), MYC gain (12%), and BRCA2 loss (12%). Overall 48% of CRPC harbored AR gene alterations. Additionally, there were mutations in CTNNB1 (12%), ATM (8%) and PIK3CA (4%). Copy number alterations not previously described in PCA included CCND1, CDK4/6 gains and CDKN2A/CDKN2B deletions. Hormone naïve metastatic and high risk localized PCA demonstrated similar frequency of TMPRSS2-ERG gene fusion, BRCA2 deletion, and TP53 mutations as CRPC, but AR alterations and MYC gain were not seen. Conclusions: This study demonstrates feasibility of in-depth, NGS based DNA analysis using FFPE tissue, even biopsy material. Frequent AR alterations in CRPC, mutations associated with disease progression, and potential drug targets were identified. Focused NGS has clinical potential to identify actionable genomic alterations in advanced PCA that can impact patient participation in trials as well as treatment and outcome. Treatment options include PARP inhibitors for patients with BRCA2 and ATM alterations (20% of cases) and PI3K/AKT inhibitors for PIK3CA mutations.