bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging metastatic prostate cancer with 18F-DCFBC PET/CT (DCFBC) and 18F-NaF PET/CT (NaF).
Authors: Fakhrejahani Farhad , Lindenberg Maria Liza , Bargvall Ethan S. , Mena Esther , Turkbey Baris , Adler Stephen , Gulley James L. , Madan Ravi Amrit , Pomper Martin G. , Dahut William L. , Choyke Peter L.
Published: March 2017

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Background: Conventional imaging of advanced prostate cancer (computerized tomography and nuclear bone scintigraphy) is limited and indicates a need for a more specific molecular imaging probe. DCFBC is a radiolabeled PET agent that binds with high affinity to prostate specific membrane antigen (PSMA), which is overexpressed in almost all prostate cancers and through whole-body non-invasive functional imaging, may provide new information on the expression of PSMA. We compare the uptake of DCFBC in bone with respect to NaF PET/CT in metastatic prostate cancer patients. DCFBC has added capability to detect soft tissue metastasis whereas NaF is confined to secondary effects of bone disease. Methods: Subjects with known or suspected prostate cancer metastasis underwent DCFBC PET/CT imaging performed at 1 hour and 2 hours after IV bolus injection of 8 mCi of DCFBC. Patients also underwent a whole body NaF PET/CT scan within 3 weeks of DCFBC PET/CT to assess for bone metastases. Patients received 3 mCi of NaF IV bolus and then were imaged 1hour post injection. PSA levels and antiandrogen therapy status were obtained at the time of DCFBC imaging. Results: Fifteen patients have been preliminarily analyzed. PSA ranged from < .01 to 4379 ng/mL. NaF identified bone lesions in 10 patients but matching focal DCFBC uptake was only seen in 3 patients. DCFBC additionally showed lymph node metastasis in 1of these 3 patient. There were 5 patients without focal abnormal bone uptake on NaF or DCFBC. In this group, 4 of 5 patients had focal DCFBC uptake in lymph nodes or soft tissue lesions. Ten patients were on some form of androgen deprivation therapy (ADT). For those on ADT, 7 of 10 patients had positive findings on NaF, compared to 2 of 10 patients on DCFBC. Conclusions: DCFBC uptake in bone metastasis does not routinely correspond to focal NaF uptake which could be due to distinct mechanisms of tracer uptake and tumor biology. There is an inverse association in focal bone findings when comparing each tracer on antiandrogen therapy. Through whole-body non-invasive functional imaging and further study, DCFBC may prove useful in characterizing prostate cancer based on PSMA expression. Clinical trial information: NCT02190279.
Treatment sequencing of abiraterone and enzalutamide in patients with mCRPC.
Authors: Feibus Allison H. , Vasudevamurthy Ashwin , Guccione Jeffrey R. , Ledet Elisa M. , Cotogno Patrick , Manogue Charlotte , Ernst Emma M. , Lewis Brian E. , Silberstein Jonathan L. , Sartor Oliver
Published: March 2017

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Background: Abiraterone (Abi) and Enzalutamide (Enza) are among the treatment modalities available for treating metastatic castrate-resistant prostate cancer (mCRPC). This study aimed to analyze the efficacy of Abi and Enza as direct sequential treatments for patients with mCRPC. Methods: A single institution retrospective review was performed on 66 patients, in which 52 (79%) of the patients received Enza following Abi. The primary outcome measure was PSA response (50% PSA decline). Patients treated with taxanes between Abi and Enza were excluded from these analyses. Results: In patients treated first with Abi and second with Enza (n = 52), 35/52 (67%) responded initially to Abi. Following PSA progression or lack of initial response, all 52 patients were then treated with Enza, and 15/52 (29%) responded. Of the 17 patients that did not initially respond to Abi, 9 (53%) patients had a PSA response to Enza, in which 5/9 had a PSA decline ≥ 50%. 14 patients had a PSA decline ≥ 50% on initial Abi only (no PSA declines at all were noted post-Abi) and 3/14 responded to Enza. The median duration on the 1st drug was 294 days; median duration on the 2nd drug was 89 days. Conclusions: Additional investigation is needed for clinicians to understand better the cross resistance of Abi and Enza in mCRPC patients. [Table: see text]
Risk factors for metastatic prostate cancer: A sentinel event case series.
Authors: Paller Channing Judith , Cole Alexander , Partin Alan W. , Carducci Michael Anthony , Kanerak Norma
Published: March 2017

235

Background: After 25 years of declines in late stage prostate cancer (PCa), evidence is mounting that an increasing fraction of men may present with metastatic disease, well after they might have been treated with local therapy. Identification of modifiable risk factors may allow for systems-level interventions to reduce delayed diagnoses. Methods: We performed an in-depth case series analysis of 15 patients who presented with metastatic disease at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center using root cause analysis, a tool commonly employed to understand the root cause of dangerous adverse events. Results: Key factors in late diagnosis include lack of insurance, lack of routine PSA testing, comorbidities, reluctance of patients to follow up actionable PSA as well as aggressive disease. Three patients had aggressive disease that would likely not have been discovered at an early stage regardless screening. However, analysis of the remaining 12 patients illuminated how health system factors led to missing important diagnostic information might have led to diagnosis of PCa at an earlier stage. Conclusions: These cases emphasize the need for systems-based approaches to early diagnosis of prostate cancer, which may prevent men from missing the opportunity to cure prostate cancer at an early stage. These results show how one might target PCa screening recommendations to more fully reflect key risk factors such as race and family history.
A personalized medicine approach to identifying dysregulated epigenetic enzymes in the development of castrate-resistant prostate cancer.
Authors: Jarrard David Frazier , Lee Jin-Hee , Boersma Melissa , Yang Bing , Damaschke Nathan Alan , Corey Eva , Denu John M
Published: March 2017

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Background: Recent advances in proteomic and chromatin immunoprecipitation tools have been crucial in studying cancer epigenetics but the ability to measure directly the enzyme activities of dysregulated histone-modifiers is lacking. We utilize a novel approach to identify altered histone-modifying enzymes in the progression from hormone sensitive (HS) to castrate-resistant prostate cancer (CRPC) progression. Methods: We developed, validated and utilized a high-throughput peptide microarray assay to identify altered histone lysine (de)acetylation activity in tumor lysates. Functional assays, novel HS and CRPC human tumor arrays and xenografts were utilized to confirm these findings. Results: This microarray-based activity assay revealed up-regulated histone acetyltransferase (HAT) activity against specific histone H3 sites in a castrate-resistant CR cell line compared to its hormone-sensitive (HS) isogenic counterpart. NAD+-dependent deacetylation assays revealed down-regulated Sirtuin activity in validated CR lines. Levels of acetyltransferases GCN5, PCAF, CBP and p300 were unchanged between matched HS and CR cell lines. However, auto-acetylation of p300 at K1499, a modification known to enhance HAT activity and a target of deacetylation by SIRT2, was highly elevated in CR cells. Among all 7 Sirtuins, only SIRT2 and SIRT3 protein levels were reduced in CR lines. Interrogation of HS and matched CR xenograft lines reveals that H3K18 hyperacetylation, increased p300 activity, and decreased SIRT2 expression are associated with progression to CR in 8/12 (66%). Tissue microarray analysis revealed that hyperacetylation of H3K18 is a feature of CRPC. Inhibition of p300 results in lower H3K18ac levels and increased expression of androgen receptor. Conclusions: This novel microarray approach provides a method to identify commonly dysregulated chromatin enzymes during progression providing a personalized therapeutic strategy to direct available drugs to target enzymes. Reduced SIRT2 expression and increased p300 activity lead to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18)
Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Garcia Jorge A. , Dreicer Robert , Pantuck Allan J. , Haas Naomi B. , Vaishampayan Ulka N. , Rasco Drew W. , Tyler Allison Janine , Rao Niranjan Sathyanarayana , Bristow Penelope J. , Reddy Sanjeeva , Denis Louis J. , Tolcher Anthony W.
Published: March 2017

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Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase. It selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction supporting its use in future combination trials. Methods: This Phase 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While the Phase 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Phase 2. Endpoints included maximum dose (MTD) and dose limiting toxicities, recommended Phase 2 dose, pharmacokinetics, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 23 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, nausea and dizziness. At 400mg, two pts experienced asymptomatic, reversible Gr 3 elevation of ALT/AST, but no recurrence when retreated at a lower dose (300mg). Testosterone decreased to below quantifiable limits and DHEA decrease of up to 80% was observed in ABI/ENZA naïve patients. Systemic exposure was high (Cmax, AUC and T1/2 at 300 mg QD was 6.7 µm, 80 µm.h and 21.5h, respectively). RECIST defined Stable Disease up to 15+ months has been observed at the 100mg cohort despite prior ABI and ENZA exposure. PSA decline of > 50% (51%-70%) was observed in 3 of 3 ABI/ENZA naïve patients at doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated without need for prednisone co-administration. Encouraging preliminary evidence of efficacy is based on the PSA decline observed in evaluable mCRPC pts not pretreated with ABI or ENZA and based on durable disease stabilization after progression on ABI and ENZA. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.
The role of cytoreductive radical prostatectomy (cRP) in men with hormone-sensitive, metastatic prostate cancer (mPCA).
Authors: Heidenreich Axel , Fossati Nicola , Suardi Nazareno , Montorsi Francesco , Karnes Jeffrey , Shariat Shahrokh F. , Gandaglia Giorgio , Briganti Alberto
Published: March 2017

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Background: Androgen deprivation represents the standard treatment for PCA with osseous metastases. We explored the role of cRP in the largest cohort of contemporary patients with mPCA treated in 4 tertiary referral centres. Methods: A total of 114 patients with mPCA, lymph node, osseous or visceral metastases underwent cRP. Surgery related complications (Clavien-Dindo classification) and functional outcome were analysed. Oncologic outcome parameters such as cancer specific & overall survival as well as biochemical and clinical-free survival were evaluated using descriptive statistical analysis. Results: Mean patient age was 61 (42-69) years. Mean and median follow-up was 39.7 months (7-75) and 47 months (28-96), resp. 93 (81.6%) and 21 (18.4%) patients had low volume and high volume mets, resp.,. 80(70.2%) pts underwent neoadjuvant ADT with LHRH analogues. Surgical approach was open retropubic RP in 104 (92%) pts and 2 (1.8%), 10 (8.8%) and 101 (89.4%) pts underwent no, limited or extended pelvic LAD, resp. Adjuvant therapy was delivered in 99 (86.8%) pts. Pathohistology revealed significant vital PCA in 100% of cases: n = 16 (14.0%) exhibited pT4a, n = 21 (18.4%) had pT2 and the remainder had pT3a/b PCA. Positive lymph nodes or positive surgical margins were identified in 61.6% and 36.8%, resp.. 110 (96.5%) are alive and 66.7% are relapse-free. 74 (64.9%) pts did not experience any surgery related complications; 15 (13.1%) pts experienced Clavien Dindo grade IIIb/IV complications and underwent reintervention. Low versus high volume (32.2% vs 50%, p = 0.03), PSA at cRP < 1ng/ml vs PSA > 4 ng/ml, (18.9% vs 45.6%, p = 0.02) were associated with relapse. Low vs high volume disease (7.1% vs 32.1%), PSA < 4ng/ml vs PSA > 4 ng/ml (6.1% vs 47.8%) and neoadjuvant vs no neoadjuvant therapy (8.75% vs 24.2%) were associated with Clavien-Dindo IIIB complications (p < 0.05). Conclusions: cRP is feasible in men with mPCA independent on the extent of disease with a low rate of significant complications and good functional outcome. About two thirds of the patients remain relapse-free after a median follow-up of close to 4 years. cRP might be an individualized treatment option in the multimodality management of mPCA.
Telemedicine-enabled clinical trial of metformin in patients (pts) with biochemically-recurrent prostate cancer (PCa).
Authors: Galsky Matt D. , Shahin Mohamed , Olson Ashley , Shaffer David R. , Gimpel-Tetra Kiev , Tsao Che-Kai , Baker Charles , Leiter Amanda , Holland John , Sablinski Tomasz , Mehrazin Reza , Sfakianos John , Acon Patricia , Oh William K.
Published: March 2017

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Background: Clinical trials are critical to informing cancer care but are hampered by slow accrual and suboptimal generalizability, both contributed to by poor geographic accessibility. We previously reported that > 50% of the US population resides > 1 hour from the nearest PCa clinical trial site (Galsky, JAMA Int Med, 2015). We sought to test the feasibility of replacing on-site study visits with telemedicine visits in a prospective clinical trial. Methods: Castration-naïve non-metastatic pts with PCa and a rising PSA after local therapy were eligible. Pts required a single on-site visit for enrollment. Treatment consisted of metformin 850 mg QD x 1 month followed by 850 mg BID x 5 months. Telemedicine visits were conducted monthly using a HIPAA-compliant smartphone application. The primary objective was to determine feasibility defined as completion of all eligible telemedicine visits by > 2/3 enrolled pts; pts were ineligible for future telemedicine visits if treatment discontinued early for toxicity or disease progression. Secondary objectives included safety, % patients with ≤ 20% PSA rise at 6 months, quality of life, and patient satisfaction. Results: 15 pts were enrolled, median age 68 (range, 57, 83), one-way driving time 1.3 hours (range, 0.2-2.8), Gleason score 7 (range, 6, 9), and pre-study PSA 4.1 (range, 0.52, 31.7). The 6 month course of metformin was completed by 11/15 (73%) pts; 2 discontinued early due to rising PSA, 1 due to adverse event (AE), and 1 remains on study. Excluding 1 pt still on study, 14/14 (100%; 95% CI 76, 100) pts completed all 78 eligible telemedicine visits. The most common AEs were diarrhea (grade 1 = 60%) and fatigue (grade 1 = 20%); 1 pt experienced grade ≥ 3 AE (dehydration). The 6-month PSA was ≤ 20% baseline in 1 pt; median % PSA change at last televisit was +52.8% (range, -3.0, +318.8). Quality of life and pt satisfaction will be reported at the meeting. Conclusions: To our knowledge, this is the first ever interventional oncology clinical trial conducted via telemedicine. Telemedicine-enabled trials are feasible and may overcome barriers to trial participation. Metformin was generally well tolerated but associated with minimal anti-PCa activity as measured by PSA. Clinical trial information: NCT02376166.
A phase II study of muscadine grape skin extract in men with biochemically recurrent prostate cancer.
Authors: Paller Channing Judith , Heath Elisabeth I. , Taplin Mary-Ellen , Stein Mark N. , Bubley Glenn J. , Pili Roberto , Mayer Tina M. , Zhou Xian Chong , Hudson Tamaro , Abbas Muneer , Anders Nicole , Dowling Donna , KIng Serina , Drake Charles G. , Antonarakis Emmanuel S. , Eisenberger Mario A. , Denmeade Samuel R. , Rudek Michelle A. , Rosner Gary L. , Carducci Michael Anthony
Published: March 2017

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Background: Pulverized muscadine grape ( Vitis rotundifolia) skin (MPX) is a potential therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. MPX demonstrated antitumor effects in PCa through antioxidant activity of its principal polyphenol components, ellagic acid, quercetin, and resveratrol. A Phase I trial demonstrated safety of MPX in doses up to 4000 mg/day. Methods: This is a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX (manufactured by Muscadine Naturals Inc. in Warsaw, NC) in 125 men with BCR PCa. Participants were stratified by baseline PSADT and Gleason score, with no restrictions for PSADT and no upper limit PSA value. Patients were randomly assigned 2:2:1 to receive 4000 mg (8 capsules) of MPX, 500 mg (1 capsule) of MPX plus 7 capsules of placebo, or 8 capsules of placebo. PSA levels were obtained every 3 months The trial was powered to detect a statistically significant between-group difference of around 6 months (low dose) and 12 months (high dose) in PSADT relative to placebo. Results: The intention to treat (ITT) population included 116 patients, of which 97% were treated for up to 6 and 58% were treated for up to 12 months. This ITT population was 79% white, with median age 68 years, 47% with Gleason score ≤ 6 or 3+4, and 12% with ECOG status of 1. Median PSADT in the ITT population lengthened from 7.5 months at baseline (range 1.4 to 74.6) to 9.8 months after treatment (range 2.3 to 151.5) (p < 0.001). There was no significant treatment difference in PSADT between the control and the treatment groups (p = 0.84). Eighteen percent (21/116) of men had a post-baseline PSADT of more than 200% of baseline. No clinically significant toxicities were seen. Conclusions: These data suggest that both 500 and 4000 mg of MPX are safe. The lengthening PSADT in patients treated with MPX is not significantly greater than that provided by placebo. A subgroup analysis of patients more likely to benefit (those with the AA genotype of MnSOD) is ongoing. Clinical trial information: NCT01317199.
Patient NCCN risk classification based on combined clinical cell cycle risk (CCR) score.
Authors: Stone Steven , Reid Julia E. , Brawer Michael K.
Published: March 2017

249

Background: Improved prognostic tools for newly diagnosed prostate cancer are needed to more appropriately match treatment to a patient’s risk of progression. The cell cycle progression (CCP) score is a highly validated prognostic RNA expression signature which has been combined with CAPRA (CCR, combined clinical cell cycle risk score) to generate an estimate of prostate cancer mortality (PCM) within 10-years of diagnosis. Here, we evaluate how the prognostic information from CCR can reclassify patients compared to their initial assignment to an NCCN risk category based on clinicopathologic features alone. Methods: The CCR score was previously validated and is calculated as a linear combination of CAPRA and CCP score (0.39 x CAPRA + 0.57 x CCP). A risk reclassification scheme was applied to patients tested by the Myriad Genetics commercial laboratory (N = 16,442). First, PCM risk was assigned based on the patient’s CCR score. Next, patients whose PCM risks were outside the interquartile range (IQR) of their NCCN risk category were reclassified according to whether their PCM risks fell within the IQR of another NCCN risk category. Finally, patients whose PCM risks were below (or above) the IQR of the NCCN low (or high) category were reclassified as low (or high). Results: Based on clinicopathologic features alone the commercial cohort was classified according to NCCN Guidelines as low (N = 8,695), favorable intermediate (N = 3,347), intermediate (N = 3,086), or high risk (N = 1,224). After calculating patient risk of PCM based on CCR, 25% of the NCCN low risk men were reclassified to favorable intermediate or intermediate risk; 47% of the NCCN favorable intermediate risk men were reclassified (24% lower and 23% higher); 49% of the NCCN intermediate risk men were reclassified (24% lower and 25% higher); and 25% of the NCCN high risk were reclassified to favorable intermediate or intermediate risk. There is no outcome data associated with commercial samples. Conclusions: The prognostic information in the CCR score results in significant amounts of risk reclassification for all patients with localized disease when compared to stratification based only on NCCN risk categories.
Cost-effectiveness analysis of magnetic resonance imaging-ultrasound fusion biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer.
Authors: Ingham Matthew , Mossanen Matthew , Wang Ye , Chang Steven Lee
Published: March 2017

25

Background: We sought to determine if the reported improved performance of magnetic resonance imaging-ultrasound (MRI-US) fusion biopsy over systematic transrectal ultrasound-guided biopsy (TRUS) in the detection of prostate cancer justifies the added cost of the MR imaging. Methods: A decision-analytic Markov model with a lifetime horizon of 10 years was developed to evaluate diagnostic accuracy, long-term health outcomes, costs, and quality-of-life of two strategies (i.e., TRUS versus MRI-US fusion biopsy [prostate MRI followed potentially by MRI-US fusion biopsy]) as the initial diagnostic test in men with elevated prostate-specific antigen ( > 4 ng/ml) without prior evaluation. Probabilities of clinical events were obtained from published literature. Direct medical costs, including diagnostic and treatment-related costs, were derived from the Premier Hospital Database. Costs were inflated to 2015 US dollars and discounted at an annual rate of 3%. Health outcomes were measured in quality-adjusted life years (QALYs), which were determined based on published literature and expert opinion. We calculated the incremental cost-effectiveness ratio and performed sensitivity analyses to assess uncertainty. Results: The MRI-US fusion biopsy strategy yielded a lower average discounted cost ($5,358 versus $6,372) and higher total QALYs-gained (7.21 versus 7.19) than TRUS. The reduced expenditures associated with MRI-US fusion biopsy was primarily due to avoiding intervention for clinically insignificant prostate cancer. The results were robust with the sensitivity analyses. Conclusions: For men in the United States with an elevated PSA, the use of MRI-US fusion biopsy in the evaluation for prostate cancer represents a greater value than TRUS, the standard of care option. Widespread adoption of MRI-US fusion biopsy may serve to reduce the economic burden of prostate cancer.
Liver metastases in mCRPC patients post-therapy with abiraterone (Abi) and/or abiraterone/enzalutamide (Enza).
Authors: Ranasinghe Lahiru , Cotogno Patrick , Ledet Elisa M. , Steinberger Allie E. , Feibus Allison H. , Degeyter Kyle , Bordlee Bruce , Sartor Oliver
Published: March 2017

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Background: Liver metastases (mets) are a particularly poor prognostic group among mCRPC patients. The objective of this study is to characterize mCRPC patients who have had treatment with Abi or Enza to identify risk factors that may be associated with subsequent development of liver mets. Methods: A sample of 67 patients (n = 17 liver mets and 50 non-liver met patients matched by treatment history) seen at Tulane Cancer Center were selected for analysis. All patients had prior Abi and or Abi/Enza. Race, age at PCa diagnosis and Gleason Score at PCa diagnosis were assessed. For patients with liver mets, total liver metastatic volume was measured using CT scans and correlated against PSA, LDH and AST values at the time of the scan. Wilcoxon rank sum tests were run analyzing PSA, LDH and AST at the start of Abi treatment, end of Abi treatment as well the duration of Abi treatment, and the nadir PSA for these patients. Results: Patients were predominantly Caucasian, had a median Gleason Score of 8 at diagnosis and were at a median age of 57 for those with liver mets and 62 for non-liver met at PCa diagnosis. Pearson correlation analysis of the total liver lesion volume and lab values revealed a significant correlation for LDH (R = 0.491, < 0.01) and AST (R = 0.368, p < 0.05), but not for PSA. Further evaluation of PSA and AST values at the start and end of Abi treatment as well as at nadir PSA revealed no statistically significant differences between liver met patients and non-liver met patients. However, there was a significant difference (p = 0.015) between LDH levels at the end of Abi treatment with a median of 347 U/L for liver met and 238 U/L for non-liver met patients. Conclusions: LDH and AST levels correlate with extent of liver metastases. Additionally, elevated LDH at the end of Abi treatment is indicative of an increased risk for developing liver metastases. Larger sample sizes and molecular characterization of these tumors are required to gain more insights into this important patient population.
AR amplification eradication with high-dose testosterone (T) in patients with heavily pretreated mCRPC.
Authors: Cotogno Patrick , Ledet Elisa M. , Schiff Joshua , Manogue Charlotte , Lewis Brian E. , Sartor Oliver
Published: March 2017

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Background: Patients (Pts) with mCRPC resistant to novel hormones (abi/enza) and taxanes pose a challenge for clinicians. Typically, once these agents are exhausted, clinical trials represent the best therapeutic option; however, many pts are not appropriate for clinical trials due to marrow suppression and/or extensive pre-treatments. Herein we present limited experience with three pts treated with high dose T when therapeutic clinical trial options were not available. Methods: Data was retrospectively collected at Tulane Cancer Center for pt treatment history, laboratory parameters, and circulating free-DNA genomic testing. High dose testosterone was used at a dose of 87.5-100 mg given daily as a 1% testosterone gel applied to the skin. Results: All the mCRPC patients were pre-treated with abi, enza, taxanes, & radium-223. All pts had RBC transfusions due to marrow suppression. All patients were previously treated on clinical trials. After starting high dose T, pt 1 demonstrated a clinical improvement in energy and appetite with a PSA decline from 530 to 45.8 ng/ml (-91.4%) over 30 days. At baseline, cfDNA analyses measured 15.9X AR amplification and 3.7X MYC amplification. The cfDNA also contained 9.8% of P53R273H mutation. Post high-dose T (serum T from castrate to 1462 ng/dL), both of the cfDNA measured amplifications returned to normal and P53 mutation declined to 0.5%. The PSA nadir occurred 30 days after T start; T was stopped 96 days after starting because of PSA rise to 280 ng/ml. The pt then restarted abi, despite prior resistance, and PSA declined from 280 to 65 ng/ml (-76.6%). The 2 other patients had PSA increases and clinical deterioration and high dose T was stopped after 2-3 weeks. Conclusions: Response to high dose T has been reported in occasional case reports going back over 60 years ago (see Brendler H et al. Arch Surg 1950;61:433–40). The frequency of favorable responses is unknown. In one case, a reversal of AR and MYC amplification was observed. The responding patient then was re-sensitized to abi, a drug to which he was previously resistant. Further research, such as the TRANSFORMER trial, is needed to understand the molecular changes and treatment options for this population.
Validation of the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer (CRPC): Data from TRUMPET.
Authors: Flanders Scott , Wilson Samuel D. , Kim Janet , Greenfield Sheldon , Kaplan Sherrie H. , Billimek John , Barlev Arie , Wong Elaine , Lin Daniel W. , Karsh Lawrence Ivan , Quinn David I. , Shevrin Daniel H. , Shore Neal D. , Symanowski James Thomas , Penson David F.
Published: March 2017

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Background: The TRUMPET registry is a prospective, observational cohort study of patients (pts) with CRPC designed to evaluate treatment patterns and health-related quality of life (HRQoL) outcomes associated with CRPC and its management in a real-world setting. Comorbidities may influence how physicians approach CRPC treatment; therefore, evaluation of comorbidity presence and severity is important. The TIBI-CaP questionnaire measures comorbidity, with the aim of this analysis to validate TIBI-CaP in CRPC. Methods: Data were collected from 302 enrolled CRPC pts treated in academic and community-based sites under routine care. Baseline data collected included clinical history and self-reported demographics, comorbidities, and HRQoL. TIBI-CaP scores were analyzed based on correlation analysis and analysis of variance (ANOVA). Estimated correlations were used to verify the association of TIBI-CaP scores to scores on the SF-12v2 and FACT-P questionnaires. ANOVA models were run with SF-12v2 and FACT-P as response and quartile ranges for TIBI-CaP scores as predictor. Results: Mean age was 73.7 years. 84.7% were white; 13.9% were black. 87.8% had M1 CRPC at study entry. Mean (SD) TIBI-CaP score was 5.3 (2.72) [range 0-13], with 42.4% of CRPC pts presenting with moderate/severe comorbidity burden (higher scores). TIBI-CaP scores had statistically significant (p value < 0.0002) negative correlations with all SF-12v2 composite and domain scores. Correlation estimates for physical condition and mental condition scores were -0.46 and -0.23, respectively. TIBI-CaP scores also had statistically significant (p value < 0.02) negative correlations with FACT-P total scores and all subscales. FACT-P total scores had a -0.44 correlation estimate. F-tests showed significant differences across the four quartiles of TIBI-CaP scores and SF-12v2 and FACT-P (all p values < 0.05). Conclusions: At baseline, TIBI-CaP scores were negatively correlated with CRPC pts baseline functional status as measured by the SF-12v2 and FACT-P questionnaires. TIBI-CaP was strongly associated with HRQoL physical subscales. This analysis demonstrates validity of TIBI-CaP in CRPC pts.
Early docetaxel-resistance in metastatic hormone-sensitive prostate cancer.
Authors: Bukhari Nedal , Potvin Kylea R. , Ernst D. Scott , Sax Lori , Winquist Eric
Published: March 2017

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Background: The addition of docetaxel to standard androgen deprivation therapy (ADT) has been shown to improve the survival of men with metastatic hormone-sensitive prostate cancer (MHSPC) (Sweeney 2015, James 2016). We noticed PSA progression in some of our patients (pts) during docetaxel treatment and reviewed their outcomes. Methods: Men with MHSPC treated with docetaxel were identified from an electronic oncology pharmacy database. Eligible pts were prescribed docetaxel for metastatic adenocarcinoma of the prostate within 120 days of initiation of ADT. Pts with castration-resistant disease (CRPC), other histologies, and those without metastatic disease were excluded. Demographic, clinical, treatment and outcome data were extracted retrospectively from electronic medical records. Results: 31 eligible pts with MHSPC treated with docetaxel between August 2014 and July 2016 were identified. Median age was 65 years (53-83) and 28 (90%) had high-volume disease as defined by Sweeney et al (2015). Nadir PSA levels 6-7 months from ADT initiation were < 0.2, 0.2-4, and > 4 ng/mL in 29.0%, 36.7% and 36.7%, respectively. At median follow up of 85 weeks, 45.2% of pts had progressed to CRPC and 22.6% had died. Median time to CRPC was 59 weeks and median overall survival was 85 weeks. Seven pts with high-volume disease (25%) had PSA progression while receiving docetaxel treatment. The median overall survival of this group was 26 weeks (17 to 106+) and six have died. Three had visceral metastases. Nadir PSA was < 0.2 (1 pt), 0.2-4 (2 pts) and > 4 ng/mL (4 pts). After docetaxel 2 pts received BSC alone and 5 pts had 1st-line CRPC therapy. No response to abiraterone/enzalutamide was seen (3 pts). Two pts who discontinued docetaxel immediately at PSA progression and were switched to alternative chemotherapy survived > 1 year. Conclusions: A subset of men with MHSPC has lethal docetaxel-resistant disease characterized by early PSA rise. It is important to recognize these patients, but it is not clear if standard CRPC therapies are effective. An immediate early switch to alternative chemotherapy may be helpful. Further research to predict early docetaxel resistance, characterize response to current therapies and identify more effective treatment is needed.
Stereotactic body radiotherapy for patients with relapsing prostate cancer with bones or nodes oligometastases.
Authors: Laurent Pierre-Antoine , Martin Etienne , Cousin François , Quivrin Magali , Bidault Fabienne , Mazoyer Frederic , Bertaut Aurelie , Crehange Gilles
Published: March 2017

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Background: To analyze patients treated by stereotactic body radiotherapy (SBRT) for node or bone oligometastatic recurrence of a prostate cancer previously locally treated, To identify possible pronostic factors of early biochemical failure (BF) after SBRT. Methods: We reviewed patients with a rising PSA treated by SBRT between November 2011 and April 2016 for bone or node oligometastases, diagnosed on a 18F Fluorocholine positron emission tomography-computed tomography (PET-CT) following biochemical failure of a prostate cancer after a local curative treatment. Recurrence-free survival (RFS) was the primary end-point defined as the time interval between SBRT and biochemical failure. Biochemical failure was defined as 2 consecutive elevations of PSA with last dosage superior to PSA dosage before treatment, or clinical failure. PSA value before SBRT, location of metastases, number of lesions treated, concomitant androgen deprivation therapy were analyzed to identify pronostic factors of poor response to SBRT. Results: With a median follow-up from time of SBRT of 12 months, we treated 40 patients and 56 metastatic lesions, with a local-control rate of 85%. 19 patients were treated for 1 to 3 bone lesions and 21 patients for 1 to 3 node lesions. 8 patients with bone oligometastases and 13 patients with node oligometastases had a recurrence (p=0.55). The main sites of failure after SBRT were lymph nodes only (7 ; 33%), bone only (7 ; 33 %), and synchronous node and bone (4 ; 19%). A 2nd and 3rdcourse of radiotherapy was delivered in 8 and 1 patients. Median RFS was 345 days (134-426) in the node SBRT group and 494 days (85-877) in the bone SBRT group (p=0.27). On bivariate analysis, a PSA nadir up to 0.51 ng/mL after SBRT was identified as a pronostic factor of a worse RFS (p=0.0038). This result was not confirmed in multivariate analysis (p=0.87). Conclusions: SBRT for node oligometastases showed a non significant lower rate of RFS when compared to SBRT in bone oligometastases. A larger cohort with a longer follow up is needed to determine whether node and bone oligometastases have similar outcomes after SBRT.
Association of time from definitive therapy (DT) to start of androgen deprivation therapy (ADT) for metastatic disease and survival outcomes in men with new metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Gill David Michael , Stenehjem David D. , Cheng Heather H. , Kessler Elizabeth Riley , Hahn Andrew W. , Gupta Sumati , Alex Anitha , Patel Shiven B. , Chittoria Namita , Twardowski Przemyslaw , Vaishampayan Ulka N. , Agarwal Neeraj
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Background: Few objective criteria are considered for risk stratification for treatment decision making in men with new mHSPC. Time between DT for localized disease, and start of ADT for new mHSPC may predict response to ADT, and prognosticate outcomes in this setting. Methods: In this multicenter study, men with newly diagnosed mHSPC with prior history of definite therapy for localized prostate cancer were included. Kaplan-Meier and Cox proportional hazard methods assessed time to castration resistance (CRPC) and overall survival (OS) from initiation of ADT, and correlated with the time elapsed from DT to initiation of ADT for new mHSPC. Results: A total of 112 men with new mHSPC initiating ADT, with prior definitive therapy were eligible (all median: age 68 yrs, Gleason score 7, PSA 14 ng/ml, ECOG 0, median time from DT to start of ADT for new mHSPC 54 months). In the univariate analysis, time from DT to start of ADT of < 60 months vs ≥ 60 months significantly correlated with duration of response to ADT and outcomes (Table). After adjustment for Gleason score and log PSA, time from DT to start of ADT for new mHSPC (<60 vs ≥60 months) remained an independent and a significant predictor of time to CRPC (HR 1.92 95% CI 1.02-3.90, p=0.044), and showed trends towards predicting OS (HR 1.77 95% CI 0.60-6.19, p=0.33). Conclusions: Time from DT for localized prostate cancer to initiation of ADT for new mHSPC independently predicts response to ADT, and may aid in risk stratification for treatment decision making in men with new mHSPC. These hypothesis-generating data require validation in a larger cohort. [Table: see text]
A video-based, personalized web page (VBPWP) as a complement to clinical trial (CT) patient management.
Authors: Mills Hannah , McKay Rana R. , Werner Lillian , Jacobus Susanna J. , Pace Amanda Fredericks , Prisby Judith , Walsh Meghara K. , Choudhury Atish Dipankar , Choueiri Toni K. , Pomerantz Mark , Sweeney Christopher , Polacek Laura , Taplin Mary-Ellen
Published: March 2017

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Background: Most advances in the diagnosis and treatment (Tx) of patients (pts) with genitourinary (GU) cancers are the result of pt involvement in CTs. There is a clear need to identify ways to improve CT processes for pts and research teams (RTs). The goal of this project is to assess the use of a VBPWP to improve pt compliance, safety, CT quality, and RT efficiency in GU CTs of oral agents. Methods: This is an unblinded, randomized trial using a VBPWP as an intervention (INT) for pts with advanced non-metastatic (M0) or metastatic (M1) GU cancers. Pts consented but not yet started on CTs of oral agents are randomized 2:1 to the INT or control arm. The INT includes videos of provider-pt encounters and educational videos related to dosing and adverse events (AEs). Target accrual is 99 pts. The primary end point is number of cumulative pt violations (PVs) over 4 cycles (4Cs) of INT. PVs are defined as improper dosing, non-compliance, and failure to report AEs or hospitalizations. Herein we report an early pooled analysis of pts who completed 4Cs. Results: 90 pts enrolled (61 M1, 67 prostate, 22 kidney). 58 pts completed ≥ 4Cs. 58% (n = 33) of pts had ≥ 1 PV on study (Table). Despite RT instructions, overall, 7%, 9%, and 3% of pts failed to return pill bottles or report AEs, missed a dose of Tx on 3 occasions, or took a wrong dose, respectively. Median total score of the Functional Assessment of Chronic Illness Therapy Tx Satisfaction-Pt Satisfaction (FACIT-TS-PS) measure was 72 (n = 45) at baseline (BL) and did not significantly change after 4Cs (73, n = 48). Scores of 73 indicate high levels of pt satisfaction. The Perceived Stress Scale (PSS) 10-Item indicated pt stress levels were highest at BL (score = 28) and improved after 1C of Tx (score = 24). Scores ≥ 20 indicate high stress. Stress levels did not significantly change after 4Cs. Conclusions: Longer follow up is needed to compare outcomes between pts randomized to the video INT compared to the control arm. Data show that the majority had ≥ 1 PV. This suggests the need to improve education for CT pts. The use of a VBPWP as a complement to standard CT pt education is feasible and may have the potential to increase pt safety and CT quality. [Table: see text]
Concordance in the relative mortality rates for prostate cancer and gastric cancer in African Americans.
Authors: Henegan John Clark
Published: March 2017

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Background: The racial disparity in outcomes for prostate cancer, gastric cancer, and multiple myeloma is demonstrated by these malignancies having the highest age-adjusted mortality rate ratio for black Americans versus white Americans. A variety of factors have been identified as contributing to this disparity, leading to our hypothesis that there would not be concordance, in respect to the mean, when the county-level age-adjusted black: white mortality rate ratio for a malignancy was compared to the other two malignancies. Methods: Publically available information from cancerrates.gov was used to obtain county-level data in regards to race-specific age-adjusted mortality rates for prostate cancer, gastric cancer, and multiple myeloma. Counties with potentially unstable age-adjusted mortality rates were excluded. A malignancy’s age-adjusted mortality rate for blacks was divided by the complementary rate for whites to determine the black: white mortality rate ratio. Across a county, malignancies were compared for concordance in mortality rate ratios relative to the mean ratio for that malignancy. After a preliminary inspection noted that all New Jersey counties had a markedly lower black: white mortality ratio for gastric cancer than other counties in the data set, the New Jersey counties were excluded from analysis and odds ratios for concordance were calculated. Results: All counties (n = 68) had a black: white age-adjusted mortality ratio of > 1 for each malignancy. In the analyzed counties (n = 52), there was a statistically significant concordance in black: white mortality rate ratios for prostate cancer and gastric cancer (OR = 3.26, p = 0.046). The black: white mortality rate ratios for neither prostate cancer (OR = 1.17, p = 0.78) nor gastric cancer (OR = 1.17, p = 0.78) demonstrated a statistically significant concordance with multiple myeloma. Conclusions: The concordance in the black: white mortality rate ratios for prostate cancer and gastric cancer in this dataset indicate that these two malignancies may share common clinical, environmental, or genetic factors in African-Americans. Future research is needed into what common factors may contribute to disparities in these two malignancies.
De novo metastatic prostate cancer: Patterns of PSA testing prediagnosis and disease characteristics.
Authors: Ged Yasser , Greene John Patrick , Murray Hazel , Malone Eoghan Ruadh , Calvert Paula , O'Connor Miriam , Horgan Anne M. , McDermott Raymond S.
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Background: A small proportion of men with prostate cancer (PCa) will present with metastatic disease at first presentation, termed de novo metastatic PCa. PSA screening is not a national policy, yet PSA testing is commonly performed and national guidelines are available to guide subsequent management. We sought to investigate this group of men to determine if prior PSA testing had been previously performed, and if elevated, to determine if appropriate referrals were being made. We also sought to further characterise and analyse associated risk factors. Methods: A retrospective review of pts who presented with de novometastatic PCa over a three year period was performed in three cancer centres in Ireland. Characteristics such as demographics, Gleason score, symptoms at presentation and disease volume (high v low) were obtained. PSA results done in the primary care for a period of 12-24 months and > 24 months prior to diagnosis were recorded. Results: 100 pts with de novo metastatic PCa were identified between 2013 and 2015. Median age at diagnosis was 72 years (49-90), 77 pts (77%) presented with high volume disease, 11 pts (11%) had evidence of visceral metastasis with a median age of 62 years (51-72). Median PSA level at diagnosis was 106, and 91% of pts (n = 74) had a Gleason score of ≥ 8. Symptoms at presentation were evaluable in 88 pts with the majority of pts presenting with pain (n = 49, 55.6%) and lower urinary tract symptoms (n = 33, 37.5%). 22 pts (22%) had a PSA level done within 12-24 months prior to diagnosis which was higher than 4.0 ng/ml in 18 pts (82%). 57 pts (57%) had a PSA level done over 24 months prior to diagnosis which was higher than 4.0 ng/ml in 35 pts (61.4%), PSA measurement was only repeated in 18 pts (51%) out of 35 pts with high PSA levels prior to diagnosis. Having elevated PSA levels over 4.0 ng/ml within 12-24 months and over 24 months prior to diagnosis was not associated high volume metastatic disease (P = 0.88). Conclusions: A sizeable proportion of pts diagnosed with de novo metastatic PCa had PSA measurements performed more than one year prior to diagnosis which was elevated. Optimization and adherence to national guidelines regarding PSA testing is needed to decrease the number of pts diagnosed with de novo disease.
An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi K , Snyder Lawrence B , Bookbinder Mark , Chen Xin , Crew Andrew P , Crews Craig M , Dong Hanqing , Gordon Deborah A , Raina Kanak , Rossi AnnMarie K , Taylor Ian , Vitale Nicholas , Wang Jing , Willard Ryan R , Zimmermann Kurt
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Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR PROTAC. Methods: Medicinal chemistry efforts yielded a small molecule AR PROTAC that simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and degradation of AR. This molecule has been characterized in in vitro and in vivo preclinical studies. Results: Our lead oral AR PROTAC degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentration (DC50) < 1 nM. AR degradation suppresses the expression of AR-target gene PSA, inhibits cell proliferation, and induces potent apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3. While enzalutamide loses its activity in the presence of elevated androgens, AR PROTAC maintains its antiproliferative activity. Further, AR PROTAC is able to degrade all clinically relevant mutant AR proteins. A robust oral bioavailability is observed across multiple species and overall ADME properties are encouraging. Approximately 95% AR degradation is observed in AR-amplified VCaP xenografts at doses as low as 10 mg/kg. Congruent with AR degradation, a dose responsive tumor growth inhibition is observed in AR-dependent xenograft studies. Conclusions: In summary, we report the first orally bioavailable AR PROTAC that robustly degrades AR in vitro and in vivo.