bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of a frequently mutated transcriptional repressor in prostate cancer, in particular its role in modulating androgen signaling and its effects on TMPRSS2-ERG dependent tumor maintenance.
Authors: Bose Rohit , Abida Wassim , Iaquinta Phillip , Karthaus Wouter , Armenia Joshua , Wongvipat John , Doran Michael , Hieronymus Haley , Philip Watson , Liang Yupu , Schultz Nikolaus , Sawyers Charles L.
Published: February 2017

274

Background: Recent genomic profiling of primary and metastatic prostate cancers revealed up to 27% of tumors contain putative loss-of-function point mutations or copy number deletions within the gene ERF, an ETS transcriptional repressor with a remarkably similar DNA-binding domain to the TMPRSS2-ERG gene product. Methods: Bioinformatic analysis of 450 patient tumors was obtained from the TCGA and SU2C datasets. Transcriptomic and cistromic analysis was achieved by RNA-seq and ChIP-seq on VCaP cells, as well as patient-derived organoid cultures of both normal and neoplastic prostates. Gene expression was inhibited by CRISPR or shRNA technology. Results: ERF copy number deletions are associated with Gleason 8+ primary disease (p = 0.0369), and ERF mRNA level inversely correlates with androgen-driven transcription (p < 0.0001) in the absence of androgen receptor amplification. Transient inhibition of ERG expression in TMPRSS2-ERG+ cancer models leads to a contraction of the androgen transcriptome. On the other hand, inhibition of ERF leads to an expansion of the androgen transcriptome, and moreover, supersedes the opposing effects of ERG. ERF and the TMPRSS2-ERG gene product have overlapping ETS cistromes that are associated with androgen-receptor binding sites; inhibition of one leads to occupancy at the vacated sites by the other. CRISPR-mediated inhibition of ERG in TMPRSS2-ERG+ models leads to a complete halt of growth, but concomitant loss of ERF partially restores cellular proliferation. Conclusions: ERF is a tumor suppressor with genomic loss-of-function mutations in up to 27% of prostate cancers, thereby expanding the concept of an ETS positive subtype. ERF occupies ETS sites of androgen-regulated genes and is an endogenous dampener of their transcription. Moreover, even in tumors lacking ERF mutations, upregulated ERG now occupies many of these same ETS sites, unmasking their transcriptional control by androgen. Thus, a key oncogenic activity of TMPRSS2-ERG is to antagonize endogenous ERF.
Clinical impact of 11C-Choline PET/CT in selection and outcome of salvage cryoablation in patients with recurrent prostate cancer after radiotherapy.
Authors: Vallinga Marleen Suzanne , Breeuwsma Anthonius , Rybalov Maxim , Pruim Jan , De Jong Igle J.
Published: February 2017

276

Background: Salvage cryoablation is an effective but toxic treatment for local recurrent prostate cancer after primary radiotherapy. To assess the location of recurrent prostate cancer, an 11C-choline PET/CT can be used. We studied the clinical impact of 11C-choline PET/CT on the choice for and the results of salvage cryoablation. Methods: A total of 141 patients with a biochemical recurrence (BCR according to ASTRO-Phoenix criteria) after radiotherapy, and thus candidates for salvage cryoablation, were included. Patients were re-staged with an 11C-choline PET/CT, complementary prostate biopsies, when indicated a pelvic lymph node dissection and/or additional imaging. Change in choice of therapy was defined as major (no salvage cryoablation because of metastases or lack of local recurrence on PET/CT), minor (local salvage treatment was performed, but different technique of after additional diagnostics) or none (salvage cryoablation was performed). The impact of selection of patients for cryoablation with PET/CT on outcome was measured by time from cryoablation to BCR (according to Astro-Phoenix), first distant metastasis and start of hormonal therapy. Results: In 71 of 141 patients (51%) a change in therapy was implemented because of the result of 11C-choline PET/CT. A major impact was observed in 48 (34%) patients. In 83 patients, a salvage cryoablation was performed (59%). 18% of this group showed no PSA response. Of the remaining patients with PSA response, 37% developed a BCR after mean 25.7 months. 47% of patients are still in remission after a mean follow-up of 43 months. In 16 of 83 patients (19%) metastases were proven after mean 55.4 months (SD 26.3). 15 patients started with hormonal therapy, mean 29.5 months (SD 20.1) after cryoablation. Conclusions: 11C-choline PET/CT showed a significant impact on selection for salvage cryoablation. The choice for local salvage therapy was abandoned in 34% of patients. Of the men who underwent a salvage cryoablation, 47% stayed free of biochemical recurrence during mean 43 months follow-up.
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.
A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone (AP) for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on abiraterone.
Authors: Lin Jianqing , Sama Ashwin Reddy , Hoffman-Censits Jean H. , Kennedy Brooke , Kilpatrick Deborah , Ye Zhong , Yang Hushan , Mu Zhaomei , Leiby Benjamin E , Lewis Nancy , Cristofanilli Massimo , Kelly William Kevin
Published: February 2017

311

Background: Aurora A kinase (AK) phosphorylates and interacts with androgen receptor (AR) and enhances AR DNA binding activity. We hypothesized that AK contributes to castration resistance in PCa, and targeting AK can inhibit AR function and re-sensitize PCa cells to AR signaling inhibitors such as abiraterone. Methods: Aphase I/II, open label, single institution trial to determine the safety and efficacy of AK inhibitor alisertib when given in combination with abiraterone plus prednisone (AP) was planned. Eligible subjects had mCRPC with disease progression on abiraterone. Androgen deprivation plus abiraterone and prednisone were maintained through the trial. Subjects were treated with dose escalation per standard 3+3 design. Planned 3 dose cohorts of alisertib were 30, 40, 50 mg PO BID D 1-7 every 21 D. Correlative studies included kinetics of neuroendocrine tumor markers, enumeration and AK gene amplification of CTCs. Results: Nine of 43 planned subjects were enrolled, 3 in cohort 1 without DLT. Two DLTs developed in cohort 2, thus 3 more patients were enrolled into cohort 1, and 2 developed DLT (total 2/6) in this cohort. The grade 3/4 toxicities (4/9) include neutropenic fever (1/9), neutropenia (1/9), fatigue with memory impairment (1/9), and mucositis (diarrhea and mouth sores, 1/9). Pharmacodynamically, adding alisertib did not affect circulating total testosterone and DHEA levels. Only one patient had decreased Chromogranin A level lasted for 4 months when compared to baseline. Four (4/9) patients had ≥ 5 CTCs at baseline but no conversion ( to < 5) was observed. No PSA decrease was observed during the study. Mean duration of study was 2.5 months. The toxicity / efficacy ratio did not warrant further dose expansion and the trial was terminated early after discussion with sponsor. Conclusions: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. Clinical trial information: NCT01848067.
The association of JAK2 polymorphisms with prognosis in castration-resistant prostate cancer (CRPC).
Authors: Zhang Ben Yiming , Riska Shaun M. , Mahoney Douglas W. , Cerhan James Robert , Costello Brian Addis , Dronca Roxana Stefania , Quevedo Fernando , Pitot Henry C. , Kohli Manish
Published: February 2017

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Background: We evaluated variation in candidate genes implicated in either initiation or progression of prostate cancer with survival in CRPC stage. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of > 5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model using Cox regression adjusted for age at CRCP and Gleason score (GS) were used. Results: Two hundred and forty five CRPC patients who met the criteria of having adequate DNA were genotyped (14 genes, 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS = 7 and 13% with GS < 7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level JAK2 was detected to be associated with OS. Six of 18 JAK2 SNPs were associated with OS after adjustment for age and GS as well as pruning of SNPs in high linkage disequilibrium with each other (see table). In our multivariate model including age, GS, rs2149556, and rs4372063, the adjusted HRs for rs2149556 and rs4372063 were 0.67 (95% CI 0.38-1.18) and 2.17 (95% CI 1.25-3.76), respectively. The protective effect of rs2149556 appears after adjusting for the presence of minor alleles for rs4372063 in this dataset. Conclusions: Germline variation in the JAK2gene is associated with survival in CRPC stage and warrants further validation as a potential prognostic biomarker. [Table: see text]
Urologists’ experiences with treatment of castration-resistant prostate cancer.
Authors: Geynisman Daniel M. , Doyle Jaime , Kutikov Alexander , Uzzo Robert G. , Wong Yu-Ning , Smaldone Marc C.
Published: February 2017

315

Background: Urologists are at the forefront of treating prostate cancer. Since 2010 four non-chemotherapy drugs have been approved for castration-resistant prostate cancer (CRPC). We aimed to ascertain Society of Urologic Oncology (SUO) members’ practices, training, and barriers as they relate to the treatment of CRPC. Methods: An IRB approved nine item REDCap survey was emailed to 697 SUO members (440 US urologists) without a financial incentive. Urologists were asked whether they should and/or have treated men with CRPC, what barriers they experience and how these barriers may be overcome. Results: Eighty-four surveys were completed. 86% definitely or somewhat agreed that it was within the purview of urologists to prescribe therapy for CRPC. Abiraterone, enzalutamide, sipuleucel-T, or Radium-223 were prescribed by 51% and out of those, 44% personally prescribed them to > 50% of their CRPC patients; 52% were aware of other urologists who prescribed these drugs. Education on the use of these drugs was most commonly via self-study (19%), national meetings (19%), pharmaceutical representatives (17%), and informal discussions with colleagues (16%). Although some did not see barriers (27%), side-effects management (23%), the time it takes to counsel patients on these therapies (14%), and their practice’s time and energy costs (14%) were the greatest obstacles to using these medications. 34% felt that more educational sessions at national meetings or greater support by professional organizations would help them increase drug administration. 53% see the recent changes in the management of CRPC as increasing the collaboration between urologists and medical oncologists and 30% believe there are increasing opportunities for urologists to strengthen their relationship with their CRPC patients. Conclusions: The majority of SUO respondents agreed that it is within the scope and practice of urologists to prescribe therapy for CRPC. Half have prescribed these therapies themselves and/or were aware of other urologists who had done the same. Some would be encouraged to increase their use of therapies for CRPC via greater support by professional organizations and education at national meetings.
Identification of a predictive factor of metastatic castration-resistant prostate cancer patients’ response to alternative antiandrogen therapy with flutamide.
Authors: Yasui Masato , Yoneyama Shuko , Uemura Koichi , Kawahara Takashi , Hattori Yusuke , Teranishi Jun-ichi , Ohta Jun-ichi , Yokomizo Yumiko , Yao Masahiro , Taguri Masataka , Uemura Hiroji , Miyoshi Yasuhide
Published: February 2017

321

Background: Recently, new androgen pathway inhibitors, abiraterone and enzalutamide, are demonstrated to improve overall survival for metastatic castration-resistant prostate cancer (mCRPC). In Japan, alternative antiandrogen (AA) as second-line hormonal therapy for mCRPC that relapses after initial hormone therapy have been commonly used before new androgen pathway inhibitors. In this study, we attempted to identify the predictive factors for efficacy of AA as second-line hormone therapy. Methods: We identified consecutive 65 mCRPC patients treated with AA as second-line hormonal therapy. All patients were treated with maximum androgen blockade (MAB) initially and evaluated antiandrogen withdrawal syndrome after relapse. We analyzed the correlations between progression-free survival (PFS) of AA and clinicopathological characteristics, including patients’ age, initial PSA levels, PSA levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease (EOD) classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB. Results: The median duration of prostate cancer sensitivity to MAB was 11.3 months (range: 1.5-53.0 months). In multivariate analysis, four significant risk factors for poor PFS were identified; initial PSA levels ( > 263 ng/mL vs ≤ 263; HR 0.53, p = 0.038), N stage (1 vs 0; HR 3.00, p = 0.001), EOD classifications (3-4 vs 1-2; HR 2.50, p = 0.007), and the previous duration of prostate cancer sensitivity to MAB ( < 12 months vs ≥ 12; HR 2.16, p = 0.026). We stratified the patients into two cohorts with low risk (0-2 risk factor present) and high risk (3-4 risk factors present). We found a significant difference in PFS among risk groups (median PFS 7.3 months vs 1.5, p < 0.000). Conclusions: Initial PSA, N stage, EOD classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB were the significant predictive factors for efficacy of AA as second-line hormone therapy in patients with mCRPC. These findings might support that decision-making of when to start the new AR pathway inhibitors.
Is metronomic cyclophosphamide (mCTX) a therapeutic option for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) in the era of new agents (NAs)? A retrospective multicenter Italian study.
Authors: Caffo Orazio , De Giorgi Ugo , Ferraú Francesco , Donini Maddalena , Facchini Gaetano , Maruzzo Marco , Tucci Marcello , Conteduca Vincenza , Maines Francesca , Rossi Lorena , Veccia Antonello , Galligioni Enzo
Published: February 2017

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Background: Several NAs, such as abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ), are able to significantly prolong mCRPC pts survival after docetaxel (DOC) failure. Nevertheless, all pts eventually show progressive disease with NAs and several pts may require further treatment. mCTX was considered as a feasible and tolerable therapeutic option after DOC failure before the introduction of NAs in the clinical practice. The present retrospective study describes the clinical outcomes of mCTX, used in mCRPC pts after the failure of both DOC and at least one NA. Methods: We retrospectively reviewed the clinical records of all mCRPC pts treated in 8 Italian hospitals after the introduction of NAs in the clinical practice. We considered as eligible for the present analysis all pts who received mCTX after DOC and at least one NA. All pts were treated with CTX 50 mg po daily until disease progression. Results: From December 2011 to June 2015, a consecutive series of 48 mCRPC pts, median age 72 yrs (56-90), with bone (94%), nodal (67%) or visceral (25%) mets, was treated with mCTX. All pts have previously received a DOC-based chemotherapy followed by only one NA in 21 cases, two NAs in 20, and all three NAs in 7. The median duration of the treatment was 10.4 wks (range 3.6-61.1). Recorded grade 3-4 toxicities were: anemia (5 pts), leucopenia (1), thrombocytopenia (2), fatigue (2), and anorexia (1). Seven pts (14%) achieved a PSA reduction ≥ 50% and 2 (4%) an objective response. The median progression free survival (PFS) was 3.5 mos with 7 pts (14%) showing a PFS ≥ 9 mos. The median overall survival was 6.9 mos. Conclusions: In our experience, mCTX was a feasible and well tolerated therapeutic option in heavily pre-treated pts with very advanced mCRPC. Despite its activity was limited, the clinical outcomes of this cheap treatment are similar to those observed with NAs administered in third/fourth line with a quote of pts experiencing a prolonged disease control. Prospective studies are needed to define the therapeutic role of mCTX after NAs in mCRPC pts.
Prospective evaluation of the response to prednisone-dexamethasone switch in castration-resistant prostate cancer patients treated with abiraterone pre- and post-docetaxel.
Authors: Romero-Laorden Nuria , Castro Elena , Lozano Rebeca , Sáez M Isabel , Valero Jeannette , Van de Poll Floortje , Nombela M Paz , Rodriguez-Moreno Juan Francisco , Montesa A. , Grau Gala , Rivera Leticia , Olmos David
Published: February 2017

327

Background: Abiraterone acetate (AA) administered with prednisone (P) to reduce mineralocorticoid-related adverse events improves survival in CRPC with a favourable tolerance profile. However, in the phase I/II of AA without steroids, dexamethasone 0,5mg/day was added after biochemical progression reaching a 25% of PSA decline. Lorente et al (BJC, 2014) showed durable biochemical responses in 40% of cases treated with AA and steroid switch in the post-docetaxel setting. We hypothesize that P to D switch in patients with biochemical progression to AA+P would lead to secondary responses also in the pre-docetaxel setting. Methods: Change of P 5mg/12h to D 0.5mg/24h was prospectively tested in clinically stable CRPC with biochemical progression ( > 25% PSA rise over nadir, confirmed in a second determination) and/or limited radiological progression ( < 3 new bone/lymphatic metastasis, non-bulky), after ³12 weeks of AA+P. PSA was monitored q4wks. CT- & bone-scans were performed every 12-16 weeks. Biochemical and radiological responses were evaluated by PSAWG2 and RECIST criteria. Survival outcomes were calculated using Kaplan-Meier method. Results: 18 patients were included (11 pre- & 7 post-docetaxel). Median age 72 (60-85); visceral, bone and/or lymph metastasis were present in 17%, 83% and 50% of patients. Median PSA at AA+P and AA+D commencement was 81 ng/ml and 100ng/ml, respectively. Biochemical response was observed in 83% of patients: 56% with a PSA decrease ≥ 30%, and 28% with PSA decrease ≥ 50%. Median biochemical progression-free survival (bPFS) with AA+P was 5.7 months (CI95% 2.9-9.1) and 3.8m (CI95% 1.4-6.5) in the pre- and post-docetaxel setting, respectively. Median bPFS with AA+D was 5.4m (1.2-8.8) and 2.5 (CI95% 1.1-2.9) in the pre- and post-docetaxel settings. Two radiological partial responses were observed with AA+D. Conclusions: Clinically stable patients with limited disease progression after AA+P may benefit from steroid switch in both the pre- and post-docetaxel settings.
Characteristics of Chinese patients with advanced prostate cancer: A muliticentre, non-interventional, observational, prospective, registry study of docetaxel.
Authors: He Dalin , Sun Zhongquan , Guo Jianming , Zhang Zhigen , Shan Yuxi , Ma Lulin , Li Hanzhong , Jin Jie , Huang Yiran , Xiao Jiaquan , Wei Qiang , Ye Dingwei
Published: February 2017

328

Background: Prostate cancer (PC) is the second most frequently diagnosed malignancy in males worldwide, and stands in 7th place among malignancies in Chinese males. This study investigated the real-world treatment patterns of docetaxel as chemotherapy in patients with advanced PC in China. Methods: This was a multi-center, prospective, observational, non-interventional, product registry study. All patients with advanced PC who failed with previous endocrine therapies, were receiving docetaxel containing chemotherapy, and consented to participate in the study were eligible to be enrolled. Patients were followed-up 2 years, for the collection and analysis of data on docetaxel treatment mode, prostate specific antigen (PSA) remission rate, survival time, etc. Results: A total of 407 patients were enrolled from Aug 2011 through Jun 2014, with a mean Gleason score of 8.0 (SD: 1.11), and median PSA of 61.0 (range: 0.0 to 5000.0) ng/ml. 302 (74.2%) patients were classified as clinical stage IV. For Eastern Cooperative Oncology Group (ECOG) score, 145 (35.6%), 205 (50.4%), 48 (11.8%), patients had scores of 0, 1, 2, respectively. Metastasis to bone was present in 340 (83.5%) patients; metastasis to other organs (liver, lungs, adrenal glands, brain, etc.) was present in 57 (14.0%) patients. Last disease progression prior to enrolment was evidenced by tumor progression in 132 (32.4%) patients and by PSA elevation in 379 (93.1%) patients. 173 (43.0%) and 120 (29.9%) patients started docetaxel therapy after failure of the first line and second line endocrine therapies, respectively; 51 (12.7%) patients after failure of the third line or more endocrine therapies. Conclusions: This abstract presented characteristics of Chinese patients with advanced PC revealed by a Chinese PC study, which indicated Chinese patients were in later stage and higher risk compared with their western counterparts. The majority of patients started docetaxel therapy after failure of first line and second line endocrine therapies. PSA elevation and tumor progression were the 2 main causes that Urologists determined for disease progression. Clinical trial information: no registration number.
Analytical challenges in quantitative analysis (LC/MS/MS) of abiraterone: A validated assay to determine abiraterone in human plasma.
Authors: Benoist Mette , van der Meulen Eric , Van Oort Inge , Gerritsen Winald , Schalken Jack , Burger David , van Erp Nielka P
Published: February 2017

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Background: Abiraterone acetate is rapidly hydrolyzed to the active abiraterone in vivo. In order to study the relation between drug exposure and therapeutic effect an assay to determine plasma concentrations of abiraterone is required. A quantitative bioanalytical liquid chromatography tandem mass spectrometric (LC-MS/MS) assay with a BEH C18(2.1 × 50 mm, 1.7 µm) column was developed. Several analytical challenges were encountered. Methods: Protein precipitation with acetonitrile was used to pretreat the EDTA plasma samples. A stable isotope (D4-abiraterone) was used as the internal standard. During validation five quality controls were used (LLOQ, LQ, MQ, HQ, ULOQ). The method was validated according to EMA guidelines. Results: The LC-MS/MS method was validated over a concentration range from 1-500 ng/mL. Within – and between day precisions and accuracies were < 5%. The LLOQ was 1 ng/ml and the ULOQ was 499 ng/mL. Abiraterone is stable in plasma for at least 7 days at ambient temperature and at 2-8°C. Stability at -40°C was demonstrated for at least 6 months. Abiraterone is only stable for 3 hours in whole blood at ambient temperature. Stock solution stability was demonstrated for at least 1 year. The concentration levels of the LQ, MQ and HQ were 5, 300 and 400 ng/mL, respectively. During method development several analytical challenges were encountered and solved: abiraterone adsorption on glass containers, limited stability in citrate plasma and whole blood, carry-over issues, very limited stability of abiraterone acetate in whole blood was demonstrated, curiously with proven stability in plasma. Throughout the method polypropylene vials and utilities were used. EDTA plasma was used for development and validation. The needle wash was adjusted and the runtime was prolonged with a longer time at 100% acetonitrile to address the carry over issues. Whole blood samples were treated on ice. The quantification of abiraterone acetate was abandoned. Conclusions: After different hurdles the method is successfully validated and applied to determine plasma concentrations of abiraterone in clinical studies and in regular patient care in patients with prostate cancer.