bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loco-regional treatment (LRT) for M1 at diagnosis prostate cancer (PCa) patients (pts) and impact on overall survival (OS): A retrospective analysis.
Authors: Bianchini Diletta , Lorente Estelles David , Rescigno Pasquale , 'O Sullivan Hazel , Kolinsky Michael Paul , Sumanasuriya Semini , Zafeiriou Zafeiris , Mehra Niven , Jayaram Anurhada , Mateo Joaquin , Perez Raquel , Tunariu Nina , Van As Nicholas John , Khoo Vincent , Tree Alison , Parker Chris C. , Eeles Rosalind , Dearnaley David P. , Attard Gerhardt , De Bono Johann S. 
Published: February 2017

280 Background: The optimal management of the primary tumour in pts with M1 at diagnosis PCa is not established. We aimed to evaluate the impact on OS of LRT (surgery or radiotherapy to the primary tumour) in de novo metastatic disease. Methods: PCa pts with M1 disease at diagnosis treated at the Royal Marsden between June 2003 and December 2011 were evaluated. LRT+ patients were defined as those that had received surgery or radiotherapy for the primary. Covariates analysed included age, diagnostic Gleason score, lines of CRPC treatment, PSA, burden of bone metastases ( ≥ 4 vs < 4 bone metastases) and ECOG PS. Kaplan-Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models. Results: Overall 234 pts with M1 at diagnosis were identified; 27 (11.53%) received LRT (25 XRT; 2 prostatectomy). Median time interval between diagnosis and LRT was 782 days (range 0-4130). Patients receiving LRT were younger (49 vs 61 yrs, p = 0.042), had lower baseline PSA values (68 vs 148; p < 0.001), and were more likely to have lymph node only disease (26% vs 10%; p = 0.029) and a lower burden of bone metastases with < 4 metastases (85% vs 34%;p < 0.001). Patients receiving LRT had a significantly longer survival (74.2 vs 55.1 months; HR 0.39; p < 0.001) in UV and MV cox-regression analysis (table). LRT+ remained highly prognostic, independently of disease volume at diagnosis and baseline PSA. Conclusions: LRT was associated with increased survival in patients with de novo metastatic disease, and in these analyses the prognostic utility of this LRT prognostic biomarker was independent of volume of metastatic disease at baseline and I'd baseline PSA. Other possible confounder factors may need to be taken into account when interpreting these results which require prospective validation from clinical trials such as STAMPEDE . [Table: see text]
Cost-benefit analysis of AR-V7 testing in patients (Pts) with metastatic castration resistant prostate cancer (mCRPC) eligible for abiraterone (Abi) or enzalutamide (Enza).
Authors: Markowski Mark Christopher , Frick Kevin D. , Eshleman James R. , Luo Jun , Antonarakis Emmanuel S. 
Published: February 2017

283 Background: The rising cost of oncology care in the US is an ongoing societal challenge, and identifying biomarkers that inform clinical decisions and reduce the use of ineffective therapies remains elusive. A splice variant of the androgen receptor, AR-V7, was found to confer resistance to Abi and Enza in men with mCRPC, but did not negatively affect responses to taxanes, suggesting that early use of chemotherapy may be a more effective option for AR-V7(+) pts. With the recent development of a CLIA-certified clinical assay for AR-V7 at Johns Hopkins, we hypothesized that AR-V7 testing in mCRPC pts may result in cost savings by avoiding futile treatment with Abi/Enza in men with AR-V7(+) disease. Methods: We calculated the cost savings of performing AR-V7 testing in mCRPC pts prior to starting Abi/Enza (and avoiding these drugs in AR-V7(+) men) versus treating all mCRPC pts with Abi/Enza (without use of the biomarker). We have set the cost of the AR-V7 assay at $1000. The cost of 3 months of Abi/Enza (the minimum time it would take to determine resistance, clinically) was approximated at $20,000. We estimated that 30,000 mCRPC pts per year are eligible for Abi/Enza in the US. Results: In our prior studies, about 30% of mCRPC pts previously treated with Abi/Enza had detectable AR-V7 in CTCs. Assuming an AR-V7 prevalence of 30%, about 9,000 AR-V7(+) mCRPC pts per year would receive ineffective treatment with Abi/Enza, at an estimated cost of $180 Million. The upfront cost of testing all mCRPC pts who are Abi/Enza-eligible for AR-V7 is $30 Million, resulting in a net cost savings of $150 Million. When performing a continuous cost-benefit analysis after assuming other prevalences of AR-V7 (ranging from 4% to 50%) and a range of costs for Abi/Enza ($2000 to $24,000 per 3 months), we determined that AR-V7 testing would result in a cost savings as long as the prevalence of AR-V7 is > 5% (if the cost of 3 months of Abi/Enza remains at $20,000). Conclusions: AR-V7 testing in mCRPC pts (at $1000/test) is cost-beneficial when considering the current price of Abi/Enza, and may reduce the ineffective use of Abi/Enza leading to a net cost savings to the healthcare system.
Persistence of androgen receptor (AR) expression in patients (pts) with small cell prostate cancer (SCPC): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: Aggarwal Rahul Raj , Youngren Jack , Sokolov Artem , Huang Jiaoti , Thomas George , Foye Adam , Alumkal Joshi J. , Ryan Charles J. , Beer Tomasz M. , Evans Christopher P. , Gleave Martin , Rettig Matthew , Small Eric Jay 
Published: February 2017

288 Background: Historically, SCPC has been regarded as an AR-null subtype observed in ~ 1% of pts. In castration-resistant metastatic biopsies, we have observed a higher frequency of SCPC (~ 15%), associated with shortened survival. We sought to contrast AR signaling between adenocarcinoma and SCPC. Methods: Pts underwent a metastatic tumor biopsy of bone or soft tissue. Formalin fixed, paraffin-embedded tissue underwent pathologic review, fluorescence in situ hybridization (FISH) for assessment of AR amplification, and assessment of AR expression by immunohistochemistry (IHC). A novel AR transcriptional signature was applied to RNA sequencing data from frozen tissue. AR-V7 transcripts in biopsy tissue were quantified and compared to AR-full length (AR-FL) expression. Results: Overall, 70 of 114 biopsies were AR amplified by FISH (61%). AR amplification was seen in similar proportions of adenocarcinoma (53%) and small cell tumors (54%) (p = ns). AR expression by IHC was observed in 27/32 (84%) and 5/6 (83%) of evaluable adenocarcinoma and SCPC biopsies, respectively (p = ns). AR was localized to nucleus in 85% of biopsies and did not differ by histology. AR-V7 splice variants were detected in all evaluable biopsies. Neither the absolute AR-FL expression level nor the ratio of AR-V7/AR-FL differed by histology. AR transcriptional signature scores were lower in SCPC versus adenocarcinoma (p = 0.029); scores were not correlated with AR-V7/AR-FL transcript ratio (r = 0.16). Of the 5 pts with SCPC identified on biopsy subsequently treated with abiraterone or enzalutamide, 3 achieved PSA declines > 50%. Conclusions: Contrary to the classical description of SCPC as an AR-null phenotype, the majority of metastatic SCPC biopsies were positive for AR amplification and expression, reflecting their likely clonal origin from adenocarcinoma. AR transcriptional activity was lower in SCPC, potentially related to epigenetic or post-translational modulation of AR activity upon transdifferentiation from adenocarcinoma to SCPC. As novel therapeutic targets are identified in SCPC, continued co-targeting of the AR may be warranted.
AR DNA binding domain inhibitors to treat AR splice variant-driven prostate cancer.
Authors: Jones Jeremy , otto-Duessel Maya , Zhou Ye , Pal Sumanta K. 
Published: February 2017

293 Background: Nearly all prostate cancer (PC) cells depend on androgen receptor (AR) signaling for growth. Resistance to novel PC drugs like abiraterone and enzalutamide appears to occur through ligand-independent AR signaling, often by expression of AR splice variants (ARv’s) that lack the ligand binding domain (LBD). Thus, drugs that inhibit AR activity via domains other than the LBD may provide a way to inhibit the growth of drug-resistant PC. We discovered the first non-competitive, ligand-independent AR inhibitor, pyrvinium pamoate (PP), which functions by interacting with the DNA-binding domain (DBD) and preventing the recruitment of RNA polymerase II to transcription start sites. PP inhibits AR activity with low nanomolar potency and functions synergistically with competitive antagonists. Here, we undertook experiments to learn more about PP’s mechanism of action and developed an orally available derivative for translation to human studies. Methods: AR immunoprecipitation (IP) followed by mass spec sequencing was used to identify proteins that differentially bind to AR in the presence of PP. Additionally, RNA-seq was used to identify pathways affected by PP treatment. Functional studies of hits were conducted using over-expression and knock down in relevant PC cell lines. PP derivatives were developed through a medicinal chemistry approach. Lead compounds were tested in a battery of assays to determine potency in cultured cells and in vivo, as well as their solubility and pharmicokinetics. Results: RNA-seq results suggest that AR and hormone pathways are the primary target of PP in PC cells but that the splicing machinery is also be affected. Mass spec results also demonstrate that PP affects the interaction between AR and splicing machinery, as well as many transcription and translation-related proteins. Medicinal chemistry efforts led to a molecule with superior aqueous solubility, oral availability, and a half-life > 6hrs. This compound inhibited the activity of AR and ARv’s in cultured cells and in xenograft models. Conclusions: PP was the first identified AR DBD inhibitor and the development of an orally available derivative holds great promise for the treatment of ARv-driven PCs.
Quantifying the potential of C-11 acetate PET scanning in avanced prostate cancer patients.
Authors: Gardner Thomas A. , Thygesen Jack , Cox John , Westphal Steven M , Green Mark A , Tann Mark , Fletcher James W. 
Published: February 2017

300 Background: Detection of advanced prostate cancer has historically relied on radionuclide bone scanning and cross-sectional imaging with varying degrees of sensitivity and specificity based on the clinical scenario. In the current era, use of NaF and Choline based whole body scans have led to increased detection, but access to these scan can be limited and expense can be prohibitive. Similar to choline based scanning, acetate is metabolically active in cancer, including prostate. Methods: Fifty-six men previously diagnosed with prostate cancer with PSA recurrences after some failed primary treatment, have undergone whole body C-11 Acetate PET scans at Indiana University since June of 2013. Patient demographics, prior treatments, PSA values, prior imaging, post-scan therapies, and therapeutic outcomes have been recorded prospectively and updated as follow-up information becomes available. Results: Analysis of these initial 56 men demonstrated 31/56 men had a C-11 Acetate PET scan that lead to further definitive loco-regional treatments, including salvage radiation therapy ( 12), salvage regional lymph node dissection (11) and salvage cryo-ablation (8), while 9/56 men had initiation of hormonal ablation, secondary to detection of systemic disease. The remainder of these men had negative scans and are currently under continued active surveillance without evidence of disease progression requiring either loco-regional or systemic therapy. Closer analysis of the 31 men who received loco-regional treatments revealed 10 men who benefited with clear PSA declines, 4 men who failed to demonstrate a benefit from the definitive loco-regional therapy and 17 of men are too early to determine at the time of analysis. Careful pathological analysis of the regional lymph dissections revealed the limit of detection of the C-11 Acetate PET scan of greater than or equal to 3mm. Correlations of SUV readings of detected prostate cancer lesions with PSA kinetics, suggest importance of both PSA doubling time and absolute PSA value cutoffs. Conclusions: The C-11 Acetate PET scan is a useful adjunct to current imagining techniques and provides additional clinical information to guide clinicians caring for prostate cancer patients.
Clinical validation of CTC subtype frequency to prognosis OS in mCRPC patients.
Authors: Dittamore Ryan Vance , Louw Jessica , Schreiber Nicole A. , Graf Ryon , Jendrisak Adam , Johnson Ann , Dugan Lyndsey , McLaughlin Brigit , Heller Glenn , Fleisher Martin , Wang Yipeng , Marrinucci Dena C. , Scher Howard I. 
Published: February 2017

302 Background: CellSearch is an FDA cleared assay that enumerates intact CK+, DAPI+, CD45- cells via EpCAM capture. CTC number is prognostic for survival pre- and post- systemic therapy. These cells are a subset of confirmed genomically altered CTC’s in blood. We report the prognostic significance for OS in mCRPC of CTC subtypes not enumerated by CellSearch including apoptotic CTCs, CK- CTCs, small CTCs, and CTC clusters. Methods: 221 blood samples from 179 unique patients were collected from pts about to begin AR directed (n = 150) or taxane (n = 71) therapy for progressive CRPC. Samples were analyzed utilizing the Epic Sciences platform to enumerate traditional (CK+, abnormal morph), apoptotic (CK+, fragmented nuclei), CK- (CK-/abnormal morph), small (CK+, normal morph), and CTC clusters. Patients were followed for up to 2.3 yrs. Paired CellSearch and Epic traditional CTC counts were collected on 173 patient samples. Results: In paired analysis, Epic traditional CTCs were identified in 86% of patients vs. 67% by CellSearch, and any Epic CTC subtype was found in 96% of the patient samples. Increased frequency of any CTC subtype was a univariate predictor of OS (see table). Conclusions: Epic identified CTC subtypes not identified by CellSearch or other technologies that select or sort based upon size or epithelial expression. Cells were detected in 96% of the patient samples and all 5 subtypes were found to be prognostic for survival. The biologic characterization of CTC subtypes as a biomarker of drug sensitivity is ongoing. The increased clinical sensitivity of subtypes and prevalence of CTCs identified on the Epic platform provides a greatly expanded array of clinically relevant biomarkers to develop predictive liquid biopsy signatures in the metastatic setting. [Table: see text]
Deciphering the genomic fingerprint of small cell prostate cancer with potential clinical utility.
Authors: Alshalalfa Mohammed , Tsai Harrison , Haddad Zaid , Ross Ashley , Karnes R. Jeffrey , Davicioni Elai , Schaeffer Edward M. , Lotan Tamara L. 
Published: February 2017

303 Background: Small cell (SC) neuroendocrine carcinoma of the prostate has very poor prognosis and does not respond well to androgen receptor (AR)-targeted therapies. Neuroendocrine prostate carcinomas are increasingly recognized to show a spectrum of morphologic changes, and may not always be distinguishable from adenocarcinoma (adeno) based on morphology alone. Here we hypothesize that SC carcinoma harbor a unique gene expression signature that, when measured in primary prostatic adenocarcinoma, may help guide subsequent management. Methods: In total, 617 whole genome expression profiles were retrieved from the Decipher GRID providing gene expression data for 1.4 million markers. 17 morphologically-diagnosed SC carcinoma samples were compared to 32 Gleason 8-10 and 77 Gleason 6 RP adeno samples with no prior treatment and no evidence of metastasis, and this comparison was used to define SC Genomic Fingerprint (SCGFt) through adjusted median fold difference and Wilcoxon test. An additional 493 RP adeno from Mayo Clinic and John Hopkins Hospital were used to evaluate the utility of the SCGFt for predicting outcome. Results: Based on genomic prognostic tests calculated using the Decipher assay including Decipher, Penney and microarray-derived Cell Cycle Progression, SC carcinomas have very poor prognosis compared to high grade adeno. A total of 356 genes defined the SCGFt with 258 gene upregulated in SC and 98 down-regulated. PEG10, HELLS and RB1-loss program are the most overexpressed genes in SC and AR-related genes the most down-regulated. As expected, SC lacked ERG and alternative ETS expression and showed relatively low SPINK1 expression. A median summarization of the 356 genes in SCGFt was used to build a small cell genomic score (SCGS). Evaluating SCGS in RP adeno cohorts showed that patients with high SCGS are at higher risk of developing metastasis after RP in a natural history cohort or after adjuvant hormonal therapy based on Kaplan Meier analysis (both p< 0.001). When restricted to patients with high Decipher scores, SCGS provided independent prognostic information. Conclusions: SC carcinoma has a distinct genomic profile that may be useful for treatment management of patients with adenocarcinoma.
The adverse effects of androgen-deprivation therapy: Comparison between gonadotropin-releasing hormone agonists and orchiectomy in the SEER-Medicare population.
Authors: Sun Maxine , Hamnvik Ole-Petter Riksfjord , de Velasco Guillermo , Jiang Wei , Loeb Stacy , Nguyen Paul L. , Trinh Quoc-Dien , Choueiri Toni K. 
Published: February 2017

304 Background: Androgen-deprivation therapy (ADT) through surgical castration is equally effective as medical castration in controlling prostate cancer (PCa). However, the adverse effect profiles of both ADT groups have never been compared. Our objective was to provide a comparative effectiveness analysis of the adverse effects of gonadotropin-releasing hormone agonists (GnRHa) vs. bilateral orchiectomy in a homogeneous population. Methods: A total of 3295 men with metastatic PCa aged ≥ 66 years old, treated with GnRHa or bilateral orchiectomy between 1995 and 2009 were identified. Multivariable competing-risks regression models were performed, with the adjustment of all-cause mortality and treatment propensity score. Secondary analyses examined the effect of increasing duration of GnRHa treatment, and expenditures. Our main examined measures were: [1] any fractures, [2] peripheral arterial disease, [3] venous thromboembolism, [4] cardiac-related complications, [5] diabetes mellitus, [6] cognitive disorders, and [7] total expenditures. Results: In adjusted analyses, orchiectomy was associated with significantly lower risks of any fracture (HR: 0.80, 95% CI: 0.65–0.97), peripheral arterial disease (HR: 0.70, 95% CI: 0.53–0.92), and cardiac-related complications (HR: 0.82, 95% CI: 0.69–0.97) compared to those treated with GnRHa. No statistically significant difference was noted between orchiectomy and GnRHa for diabetes and cognitive disorders. When compared to individuals treated for ≥ 35 months with GnRHa, the increased risk for GnRHa compared to orchiectomy was noted for fractures, peripheral arterial disease, venous thromboembolism, cardiac-related complications, and diabetes mellitus (HR: 1.69, 2.19, 1.60, 1.62, and 1.36, respectively, all P≤ 0.04). No difference with respect to total expenditures was observed between GnRHa and orchiectomy (odds ratio [OR]: 1.21, 95% CI: 0.92–1.58). Conclusions: GnRHa was associated with higher risks in 3/7 examined adverse effects: any fractures, peripheral arterial disease rates, and cardiac-related complications.
Tumor progression versus bone scan “flare” in new lesions detected on early bone scans in patients with chemo-naïve metastatic castration resistant prostate cancer (mCRPC) treated with placebo or enzalutamide.
Authors: Ning Yangmin M. , Chen Clara , Maher Virginia Ellen , Xu James Xunhai , Kim Geoffrey , Pazdur Richard 
Published: February 2017

305 Background: To differentiate between bone metastasis progression vs. Tc99m scan “flare” in new lesions on early bone scans ( ≤ 12 wks), ≥ 2 additional lesions on a confirmatory scan (6 wks later) are proposed. This reduces the risk of misreading scan “flare” as progression in responding patients (pts). Independent central review (ICR) of scans from placebo (PLC)-controlled trials can help evaluate the role of confirmatory scans as PLC should neither delay progression nor elicit scan “flare”. Methods: The ICR datasets from a randomized PLC-controlled trial of enzalutamide (ENZ) in pts with chemo-naïve mCRPC were examined. Pts with ≥ 2 new lesions on Week 9 bone scans who underwent confirmatory scans were analyzed. Scan “flare” was defined as unconfirmed progression associated with responses in PSA ( ≥ 50% decline). Results: Summarized in the table. Confirmed progression on Week 9 bone scans occurred more in pts on PLC than in pts on ENZ (57% vs. 14%). In pts with unconfirmed progression, scan “flare” occurred in 80% of pts on ENZ. Of the pts with unconfirmed progression who had PSA progression, nearly 60% progressed on follow-up scans. Conclusions: The findings from this large PLC-controlled trial provide strong evidence for performing confirmatory bone scans to verify tumor progression in new lesions on early bone scans in mCRPC. For pts with unconfirmed progression, early PSA progression appears associated with progression on follow-up scans. [Table: see text]
Evaluating PSA nadir drift in high-risk and metastatic prostate cancer.
Authors: Miller Eric Tyler , Kwan Lorna , Liu Sandy , Garraway Isla 
Published: February 2017

310 Background: Prostate cancer (PC) is a heterogeneous, clinically disparate, and often unpredictable disease whereby nearly 3% of patients present with bone metastatic PC (BMPC). Virtually all patients diagnosed with stage M1 disease fail to achieve complete remission and rapidly progress to castration-resistant PC (CRPC) and death (28% 5-year survival). Androgen deprivation therapy (ADT), the current standard of care for M1 disease, does not induce durable remissions. Improved understanding of tumor biology associated with lethal progression is desperately needed to guide clinical trials. Methods: We assembled a diverse, clinically annotated biorepository with diagnostic biopsy tissue from 428 patients with high-risk M0 and M1 disease. Retrospective analysis was performed on M0 (n = 157) and M1 (n = 112) patients stratified by treatment sequence. Clinical and pathological variables analyzed included age at diagnosis, race, primary Gleason sum, tumor burden, initial treatment received, PSA at time of biopsy, PSA velocity and length of follow-up. Primary endpoints included PSA nadir per treatment round, time from biopsy to CRPC, and death. Results: Compared to M0 cases, M1 patients were older, displayed significantly higher PSAs at the time of biopsy, and were more likely to display primary Gleason pattern 5. Patients with stage M1 disease had significantly worse survival, shorter time to CRPC, and median PSA nadir following each treatment round never fell below 2ng/ml. Median PSA nadirs associated with each treatment round demonstrated marked upward drift in the M1 cohort when compared to the M0 cohort. Conclusions: The presence of distant metastases is a major obstacle in achieving durable remissions for very high-risk PC. Our data confirms that ADT has limited effect on controlling cancer progression in M1 patients. PSA nadir drift in M1 compared to M0 patients may indicate intrinsic tumor resistance to currently available therapies. Multimodal profiling of M1 primary tumors may reveal actionable targets for initiation of combination treatment regimens at diagnosis.