bluuebunny/crossref_metadata_2025_split huggingface dataset:
Docetaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC): Cost of care for Medicare and commercially insured men.
Authors: Armstrong Andrew J. , Bui Cat N , Fitch Kate , Sawhney Tia , Brown Bruce , Flanders Scott C , Francis Peter St. John , Balk Mark A. , Deangelis Julie , Chambers James 
Published: February 2017

262 Background: Docetaxel (DTX) is commonly used to treat metastatic prostate cancer, yet little data is available about the cost of a DTX chemotherapy episode of care (DEC) for treating mCRPC. This study analyzes DEC cost and health service utilization for men with mCRPC. Methods: We performed a claims-based analysis using Truven MarketScan and Medicare 5% sample data sets. Eligibility was required in all months of 2010 and ≥ 1 month of 2011, along with ≥ 1 2011 claim coded with prostate cancer and ≥ 1 DTX claim. Initial 2011 DECs required no DTX claim in the prior 12 months while subsequent DECs required a 60-day gap between DTX claims. DEC costs included all paid claims, except prescription drugs, from the 1st DTX claim to 30 days after the last DTX claim with early termination for death, insurance disenrollment or the end of a 24-month look-forward period. DTX drug costs were adjusted for 2011 generic DTX introduction while all other DEC costs were adjusted to 2015 using national average unit cost increase. Results: 155 commercially insured patients (COMM) and 281 Medicare patients (MDCR) were identified with 172 and 325 DECs, respectively. The average number of DTX cycles per DEC was 6.3 for COMM and 6.9 for MDCR, with 105 and 102 average days between the 1st and last infusion, respectively. The average DEC cost was $63,788 for COMM and $28,742 for MDCR with DTX drug costs contributing $13,169 (21%) and $2,588 (9%) per DEC, respectively. The average cost per DEC contributed by DTX-infusion days was $27,900 (44%) for COMM and $8,577 (30%) for MDCR. Non-DTX-infusion day costs per DEC included $10,838 (17%) for infused/injectable drugs for COMM and $7,074 (25%) for MDCR, along with $9,324 (15%) and $6,875 (24%) for inpatient admissions, respectively. 29% of COMM-DECs and 40% of MDCR-DECs had ≥ 1 inpatient admissions while 22% and 25% had ≥ 1 emergency room (ER) visit, respectively. 22% of COMM and 28% of MDCR inpatient costs and 15% of COMM and 33% of MDCR ER costs were chemotherapy related. Conclusions: Non-DTX drug costs including infusion day services, infused/injectable drugs administered on non-DTX days and inpatient admissions contributed the majority of DEC costs in COMM and MDCR mCRPC populations.
ARV-330: Androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi K , Jin Meizhong , Crew Andrew P , Rossi AnnMarie K , Willard Ryan R , Dong Hanqing , Siu Kam , Wang Jing , Gordon Deborah A , Chen Xin , Ferraro Caterina , Crews Craig M , Coleman Kevin , Winkler James D. 
Published: February 2017

267 Background: The transition from localized prostate cancer to metastatic disease often involves modulation of the Androgen Receptor (AR). During the disease progression, patients progressing on enzalutamide or abiraterone therapy exhibit amplified AR, increased intra-tumoral androgen production or AR mutations leading to promiscuity to other ligands. Therefore, AR is still the principal driver of the disease. Methods: A novel approach to block AR signaling is to specifically target AR for degradation. To this end, we have developed the PROteolysis TArgeting Chimera (PROTAC) technology that employs hetero-bifunctional small molecules that simultaneously bind VHL E3 ubiquitin ligase and a target of interest (e.g. AR). Due to induced proximity between VHL and AR, an AR PROTAC leads to ubiquitination and subsequent degradation of AR. Results: Our lead AR PROTAC, ARV-330, degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentrations (DC50) < 1nM. AR degradation suppresses the AR-target gene PSA expression, inhibits proliferation, and induces potent apoptosis in VCaP cells with maximal apoptosis observed at 20 nM. While enzalutamide loses its activity in the presence of > 0.5 nM R1881, ARV-330 maintains its activity. In cells containing the ARF876L mutation, enzalutamide is an agonist; however, ARV-330 remains effective. In fact, ARV-330 is able to degrade all clinically relevant AR mutations. ARV-330 exhibits good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of > 80% after sc injection. Treatment of mice with ARV-330, at doses ranging from 0.3 to 10 mg/kg, results in reduction of AR protein levels. The in vitro potency translates into in vivo efficacy, as ARV-330 demonstrates prostate involution in intact mice. In castrated mice implanted with VCaP tumors, ARV-330 shows robust reduction of plasma PSA and blockade of tumor growth. Conclusions: In summary, the AR PROTAC ARV-330 removes AR from prostate cancer cells in a potent manner and produces therapeutic effects as a result. This cellular efficacy has translated into biomarker activity and efficacy in animal models, and ARV-330 is now in preclinical development.
Taxane sensitivity markers in prostate cancer.
Authors: Feldman Rebecca , Castro Michael , Reddy Sandeep K. , Myers Charles E. 
Published: February 2017

285 Background: The results from the CHAARTED and STAMPEDE trials that docetaxel plus androgen-deprivation therapy (ADT) significantly improves survival over ADT alone among men with metastatic, hormone-sensitive and hormone-naïve prostate cancers, represents a potential practice-changing movement. Clinical data exist to support the role of various predictive markers for taxane response, including low or negative class III beta tubulin (TUBB3), positive transducin-like enhancer of split 3 (TLE3) and low or negative p-glycoprotein (PGP/ABCB1). We examined a database of molecularly-profiled prostate cancer patients for taxane sensitivity markers for insight into the mechanism behind the clinical effect of docetaxel. Methods: 348 patients with prostate cancer were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: In all prostate cases tested, protein levels for taxane markers are: TLE3+ 58.6% (174/297), TUBB3 - 76.8% (228/297) and PGP – 89.9% (267/297). Combined rate of expression (TLE3+/TUBB3-/PGP-) is 41% (121/297), representing a subgroup of patients that may have best responses to taxane therapy. Taxane sensitivity markers by stage and AR status are shown in the table below. Conclusions: Taxane sensitivity markers are observed at a statistically significant higher frequency in AR-positive prostate cancer patients, providing a potential molecular hypothesis for the increased effectiveness of chemo-hormonal therapy observed in hormone-sensitive prostate cancers. A substantial number of both AR positive and negative patients have sub-optimal biomarker profile for taxane responsiveness highlighting an unmet need for on-going drug development in this disease. [Table: see text]
Somatic mutation detection from liquid biopsy-derived cellular aggregates formed by magnetic 3D bioprinting.
Authors: Tseng Hubert , Ionescu-Zanetti Cristian , Jensen Jeff , Gage Jacob A , Haisler William L , Desai Pujan K , Liao Angela , Brobey Reynolds , Dehghani Mehdi , Souza Glauco R , Amato Robert J. 
Published: February 2017

291 Background: A challenge in the analysis of circulating tumor cells (CTC) is their scarcity, and the inability to expand them for further analysis. To overcome this obstacle, we used magnetic 3D bioprinting to form CTC spheroids that could grow. The principle of magnetic 3D bioprinting is the magnetization of cells with nanoparticles and their subsequent printing into spheroids. For this project, CTCs can be aggregated into close contact to interact and grow in culture. In this study, we demonstrated the ability to aggregate CTCs and perform next generation sequencing (NGS) to detect somatic mutations from renal and prostate cancers. Methods: Blood samples from prostate and kidney cancer patients were enriched for CTCs (Isoflux, Fluxion), from a starting blood volume of 7.5-14 mL. CTCs were isolated immunomagnetically for EpCAM+ EGFR+ cells, then enumerated for CK+ CD45-. The cells were then removed of microbeads, then magnetized by incubation with NanoShuttle (NS, Nano3D), a magnetic nanoparticle assembly, and printed into spheroids in 384-well plates. After 4 d of growth, the cells were lysed and DNA was amplified by whole genome amplificaiton (WGA) with the NGS kit (Fluxion) and quantified via qPCR. Targeted libraries were sequenced using the PGM (ThermoFisher) sequencing instrument; data was analyzed using a customized variant calling/filtering pipeline based on standard Ion Reporter alignment tools and VarSeq for variant filtering and functional interpretation. Results: CTCs were successfully aggregated using magnetic 3D bioprinting, and grew over 4 d. We then demonstrated the detection of somatic variants within a majority of the samples, for both prostate and renal cancers. Using the commercial Oncomine, we found a median of 5 COSMIC variants (32 total) per sample using cell cultures. Conclusions: We successfully developed methods to aggregate CTCs with magnetic 3D bioprinting, expanded them, and then detected somatic mutations using NGS.
Effect of androgen signaling in stromal cells on growth of prostate cancer.
Authors: Liao Chun-Peng , Chen Leng-Ying , Luethy Andrea , Kim Youngsoo , MacLeod A. Robert , Gross Mitchell E. 
Published: February 2017

297 Background: Interactions between epithelial and stroma cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Methods: Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model (Liao, et al Cancer Res, 2010. 70(18):7294). A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. RT-PCR was used to investigate changes in gene expression. Results: Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorigenicity in epithelial cells were investigated. Markers associated with epithelial-mesenchymal transition (EMT, N-Cad) and “stemness” (OCT4, Sox2, Nanog) were increased in human prostate cancer cells grown with low-AR CAFs. Conclusions: Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorigenicity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer.
Study of PSMA-targeted 18F-DCFPyL PET/CT in the evaluation of men with an elevated PSA following radical prostatectomy.
Authors: Gorin Michael A. , Rowe Steven P. , Mana-ay Margarita , Szabo Zsolt , Schaeffer Edward M. , Tran Phuoc T. , Allaf Mohamad E. , Deville Curtiland , Cho Steve Y. , Pienta Kenneth J. , Pomper Martin G. , Ross Ashley 
Published: February 2017

299 Background: Positron emission tomography/x−ray computed tomography (PET/CT) utilizing radiotracers targeting prostate membrane specific antigen (PSMA) offer the promise of improved sensitivity for visualizing low volume sites of prostate cancer. In this study we evaluated the sensitivity of PET/CT using 18F-DCFPyL, a novel small molecule ligand of PSMA, for imaging sites of disease in men with an elevated PSA following radical prostatectomy. Methods: Patients with an elevated PSA following radical prostatectomy (defined as ≥ 0.2 ng/mL) were imaged with CT or magnetic resonance imaging (MRI) of the abdomen and pelvis, 99mTc-methylene diphosphonate bone scan and 18F-DCFPyL PET/CT. Conventional imaging studies (CT, MRI and boen scan) were clinically reviewed by readers blinded to the PET/CT scan results. Similarly, PET/CT scans were blindly reviewed and then the sensitivity of this novel imaging test was compared to that of conventional imaging. Results: In total, 12 men with a median PSA of 0.34 ng/mL (range 0.2 to 11) were imaged as part of this study. 2 (16.7%) patients had persistently elevated PSA values after surgery and 10 (83.3%) had values which were initially undetectable but then rose to ≥ 0.2 ng/mL. On conventional imaging, only 4 (25.0%) patients had at least 1 detectable site of disease. This included 1 patient with a local recurrence detected on MRI and 3 patients with bony lesions detected on bone scan. In contrast, 9 (75.0%) patients had areas of detectable disease on PET/CT. This included 3 (25.0%) patients with a local recurrence, 3 (25.0%) with lymph node metastases, 2 (16.7%) with bony lesions and 1 (8.3%) with both lymph node and bone findings. All lesions detected on conventional imaging had corresponding areas of radiotracer uptake on PET/CT. Conclusions: 18F-DCFPyL PET/CT appears to be more sensitive for detecting areas of prostate cancer recurrence in patients with an elevated PSA following radical prostatectomy. Future work aims to more precisely define the sensitivity of this imaging test in a larger patient cohort. Clinical trial information: NCT02523924.
NRG Oncology/RTOG 9601, a phase III trial in prostate cancer patients: Anti-androgen therapy (AAT) with bicalutamide during and after salvage radiation therapy (RT) following radical prostatectomy (RP) and an elevated PSA.
Authors: Shipley William U. , Pugh Stephanie L. , Lukka Himu R. , Major Pierre , Heney Niall M. , Grignon David A. , Sartor Oliver , Patel Malti , Bahary Jean-Paul , Zietman Anthony L. , Pisansky Thomas Michael , Zeitzer Kenneth Lee , Lawton Colleen Anne , Feng Felix Yi-Chung , Lovett Richard Dana , Balogh Alexander G. , Souhami Luis , Rosenthal Seth A. , Kerlin Kevin , Sandler Howard M. 
Published: February 2017

3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of < 0.5 ng/ml. 649 (85%) had an entry PSA value of <1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median follow up was 12.6 years. Actuarial overall survival at 10 years was 82% for RT plus AAT and 78% for RT + placebo and a hazard ratio of 0.75 (95% CI: 0.58-0.98) with a 1-sided p value of 0.018 (2-sided p = 0.036). The 12-year incidence of PC central-reviewed deaths were 2.3% for RT + AAT and 7.5% for RT + placebo ( p< 0.001).The cumulative incidence of metastatic PC at 12 years was less in the RT + AAT arm, 14% (51 patients), vs. 23% (83 patients) in the RT + placebo arm (p < 0.001). Subgroup analyses of the relative benefits of the addition of AAT to RT are planned and will be presented. Late grade III and IV toxicity were similar in the AAT and placebo arms. The combined grade III and IV toxicities for RT + AAT and RT + placebo were: bladder 7.0% vs. 6.7%, bowel 2.7% vs. 1.6%. Gynecomastia differed significantly by treatment arm, 70% vs. 11%. Conclusions: 24 months of AAT using 150mg bicalutamide daily during and after salvage RT significantly improved long term overall survival and reduced the incidence of metastatic PC and PC death. Support: NCI grants U10CA21661, U10CA180868, U10CA180822, and U10CA37422 and AstraZeneca. Clinical trial information: NCT00002874.
A randomized controlled trial to determine the effect of triptorelin on reduction of prostate volume preradiotherapy compared with standard therapy (goserelin).
Authors: Bahl Amit , Challapalli Amarnath , Masson Susan , Hilman Serena , Hurley Katrina , Persad Rajendra 
Published: February 2017

30 Background: Hormone therapy in combination with radiotherapy is a curative treatment option for prostate cancer (CaP). Neoadjuvant goserelin is known to reduce prostate gland volume by about 26%, such that radiotherapy treatment volumes are smaller, reducing the risk of damage to bladder and rectum. Triptorelin is 100 times more potent than native LHRH and has a longer half life than both native LHRH and goserelin. This study evaluated the equivalence of cytoreductive efficacy of neoadjuvant triptorelin and goserelin. Methods: Seventy-onepatients with localized CaP who have chosen radical radiotherapy had been randomized by stratified block design, toreceive either triptorelin (n=37) or goserelin (n=34) with bicalutamide cover. Prostate volume was measured at baseline and 14 weeks after start of therapy on transrectal ultrasound (TRUS). PSA, testosterone levels, and EQ5D, QLQ-PR25, QLQ-C30 questionnaires were completed at baseline, 6, 10, and 14 weeks after start of therapy. All the patients had subsequent radical radiotherapy and followed up as per departmental protocol. Changes in TRUS volume and time to castrate levels of testosterone were evaluated. Results: The mean (±S.D) baseline prostate volume in the goserelin and triptorelin groups was 38.1(±12.8) cc and 39.4(±17.5) cc, respectively. The mean (±S.D) reduction in the prostate volume after 14 weeks of goserelin and triptorelin was 36.8(±18.4)% and 32.5(±20.9)%, respectively (p=0.36: Analysis of Covariance). Twenty-nine out of 34 in the goserelin group and 33 out of 37 patients in the triptorelin group achieved castrate levels of testosterone (£0.5nmol/L). The median time to castration was 6.1 (95% CI: 5.8-6.5) and 6.4 (95% CI: 5.9-10.0) weeks for goserelin and triptorelin, respectively (p=0.72: log rank). Conclusions: Goserelin and triptorelin both caused a reduction inprostate volume and achieved castrate levels of testosterone. The cytoreductive efficacy of neoadjuvant triptorelin was equivalent (non-inferior) to that of goserelin. To our knowledge, this is the first reported prospective randomized data demonstrating the equivalence of goserelin and triptorelin in the neoadjuvant setting. Clinical trial information: 2008-007028-25.
The use of whole genome copy number variation (CNV) to measure genomic instability in mCRPC CTCs.
Authors: Wang Yipeng , Greene Stephanie , Rodriguez Angel , Lee Jerry , Landers Mark , Dittamore Ryan Vance , Marrinucci Dena C. 
Published: February 2017

307 Background: AR targeted therapies in combination with PARP inhibitors have recently shown efficacy in mCRPC patients with specific DNA repair gene mutations in metastatic tissue biopsies. Homologous recombination DNA repair deficiencies (HRD), associated with response to PARP inhibitors, can also be assessed by genomic instability/scarring. Accurate genomic scarring measurement in tumors can be confounded by intra-tumor heterogeneity and/or non-tumor genome contamination. To better identify PARPi sensitivity in mCRPC patients, we developed a genomic instability and scarring assay starting from single CTCs. Methods: VCaP, LnCaP or PC3 cell lines were spiked into healthy donor blood. Individual spiked cells were identified and recovered for genomic analysis using the standard Epic CTC assay. Post recovery, cells were lysed, whole genome amplified, constructed into shotgun libraries and sequenced to ~2M 2x150bp PE reads. Following alignment, whole genome copy number and instability analysis was performed to identify large scale transitions (LST, n of chromosomal breaks between adjacent regions of at least 10 Mb), % of genome altered (percentage of 1Mbp bins with copy number alterations), as well as specific tumor suppressor/oncogene copy number alterations. The association of PTEN loss with increases in genomic instability and scaring was performed. Results: Loss of PTEN function was previously shown to be associated with genomic instability. Our assessment of PTEN deletion was confirmed in PC3, while at least one genomic copy was observed in LnCaP and VCaP. The number of LSTs and % of genome altered was higher in PC3 (n = 19 +/- 3; 9.3% +/- 2.6%) than both VCaP and LnCap (n = 8 +/- 2; 6.1% +/- 0.4%). Conclusions: The association of higher genomic instability in a PTEN null cell line (PC3) vs. those with either heterozygous (LnCaP) or wild type (VCaP) PTEN status, matches published reports associating PTEN loss with increased genomic instability. Although, PC3 only demonstrates mild PARPi sensitivity in vitro, the detection of increased genomic scarring vs. cells with at least 1 functional PTEN allele confirms the assays ability to quantify genome instability at the single cell level from CTCs in a liquid biopsy.