bluuebunny/crossref_metadata_2025 huggingface dataset:
Perioperative outcomes of aspirin use in radical prostatectomy.
Authors: Ingham Matthew D. , Krasnow Ross E , Mossanen Matthew , Wang Ye , Chang Steven Lee
Published: February 2018

150

Background: Increasing cardiovascular disease has led to increases in the patient population on anti-platelet therapy who require urologic surgery. We sought to study perioperative outcomes for those undergoing radical prostatectomy (RP) while taking or not taking perioperative aspirin (pASA). Methods: A retrospective review of patients undergoing RP was performed on the Premier Hospital Database from 2003 to 2015, with survey projection weighting resulting in a cohort of 157,674 patients. Two groups were formed – those continued on pASA (group 1, n = 4400) and those with no pASA (group 2, n = 153,274). In-hospital complication rates were studied: major bleeding, overall transfusion, day-of-surgery transfusion, prolonged ( > 4 days) length of stay (LOS), and prolonged ( > 285 minutes) operative time. We also assessed 90-day rates of: cardiovascular catastrophe, readmission, major complication, and DVT/PE. Unadjusted rates were calculated for all RP patients and further subdivided into open and minimally invasive RP. Adjusted odds ratios (OR) were then calculated between groups 1 and 2. Results: Group 1 was older (51.5% vs 41.8% ≥65 years, p = 0.002) and less healthy (13.8% vs 5.3% with a CCI score ≥2, p < 0.0001) vs those in group 2. Group 1 patients were more likely to receive an open RP (42.3% vs 28.1%, p < 0.0001). For in-hospital outcomes for all RPs, no significant differences were noted regardless of surgical approach. For 90-day outcomes, those in group 1 were more likely to suffer a MI (OR 5.88, CI [3.4-10.18], p < 0.001), major complication (OR2.95, CI [1.58-5.5], p < 0.001), or be readmitted (OR 1.63, CI [1.18-2.26], p < 0.05). The disparity in both MI and major complication rates appeared to be largely driven by those undergoing minimally invasive RPs, with an OR of 7.92 and 4.02 noted, respectively. Conclusions: This large, retrospective, database review of both academic and community hospitals provides an important assessment of the impact pASA has on RP outcomes. In-hospital outcomes were equivalent between groups but those on pASA saw increased rates of MI, major complication, and readmission. Despite this, this study lends support to the belief that pASA should likely not be considered an absolute contraindication to RP.
Preliminary results of a study on focal low dose rate prostate brachytherapy using Cesium 131.
Authors: Moran Brian Joseph , Braccioforte Michelle H.
Published: February 2018

151

Background: Prostate cancer patients continue to seek out minimally invasive therapies with equal disease eradication, but with less morbidity, lower cost and multiple salvage options. Our objective was to evaluate PSA response and determine rate of prostate specific antigen (PSA) kinetics in patients undergoing permanent low dose rate (LDR) focal prostate brachytherapy at a single institution. Methods: Between 4/2015 – 1/2017, 52 patients, of which 25% of patients were diagnosed with prostate cancer using a stereotactic transperineal mapping biopsy approach, while 75% had a standard transrectal prostate biopsy, were treated with LDR focal prostate brachytherapy. Dose to target was 115 Gy using Cesium-131. 30 patients (57.7%) were considered low risk, 21 pts (40.4%) were intermediate, and 1 patient (1.9%) was high risk. Treatment was limited to the side of the gland where the cancer was diagnosed. Because there is no agreed upon standard regarding PSA control, we are choosing to call the percent change in PSA the “Impact PSA”. Results: Median pre-treatment prostate volume was 51.6 cm3 (range 18 – 129 cm3), while the median target volume was 17.8 cm3 (range 7.6 – 39.4 cm3). Additionally, the median prostate volume treated was 33.73% (range 17.6 – 95.3%). Our data demonstrates that patients in whom 25-50% of the gland treated, resulted in an Impact PSA of approximately 25% - 50% decrease in total PSA between 3 - 6 months, with continued decreases of 55% at 1 year, and 77% at 2 years. Conclusions: Focal therapy outcomes are highly variable and related to volume of ablation. For low volume disease, LDR focal brachytherapy may be a viable option for patients. Optimal outcome assessment after focal therapy is yet to be determined. Since there is untreated gland with the potential to produce PSA, perhaps stable patterns in PSA kinetics, rather than a nadir, is more valuable. We will continue to follow-up with this cohort to report long term results and closely study the Impact PSA.
Impact of USPSTF recommendations on utilization of PSA screening in Medicare beneficiaries.
Authors: Khairnar Rahul Ramesh , Mishra Mark , Onukwugha Ebere
Published: February 2018

166

Background: Previous studies assessing the impact of the United States Preventive Services Task Force (USPSTF) recommendations on utilization of prostate-specific antigen (PSA) screening have not investigated longer-term impacts of the 2008 recommendations nor have they investigated the impact of the 2012 recommendations in the Medicare population. The study aim was to evaluate change in utilization of PSA screening, post USPSTF recommendations of 2008 and 2012, and to assess trends and determinants of receipt of PSA screening in the Medicare population. Methods: This retrospective study of male Medicare beneficiaries utilized Medicare Current Beneficiary Survey (MCBS) data and linked administrative claims from 2006-2013. Beneficiaries aged ≥65 years, with continuous enrollment in Parts A and B for each year they were surveyed were included in the study cohort. Beneficiaries with self-reported or claims-based diagnosis of prostate cancer were excluded. Beneficiaries with Medicare eligibility due to end stage renal disease or disability were also excluded. The primary outcome was receipt of PSA screening. Other measures include age groups (65-74 and ≥75), time periods (pre- and post-2008 and 2012 recommendations), and sociodemographic variables. Results: The study cohort consisted of 11,028 beneficiaries, who were predominantly white (87.56%), married (69.25%), and unemployed (84.4%); 52.21% beneficiaries were aged ≥75. Declining utilization trends for PSA screening were observed only in men aged ≥75 after 2008 recommendations and in both age groups after 2012 recommendations. The odds of receiving PSA screening declined by 17% percent in men aged ≥75 after the 2008 recommendations and by 29% in men aged ≥65 after the 2012 recommendations. Conclusions: The USPSTF recommendations of 2008 and 2012 against PSA screening were associated with declines in utilization of PSA screening during the study period. USPSTF recommendations play a significant role in affecting utilization patterns of health services. Future studies should evaluate if the proposed 2017 update to these recommendations advocating shared decision-making for PSA screening in men aged 55-69 increase utilization in this age-group.
Dose escalation with high-dose-3D-conformal/IMRT (HD-3D-CRT/IMRT) compared with low-dose 3D-conformal/IMRT plus HDR brachytherapy (LD-3D-CRT/IMRT+HDR-B) for intermediate- or high-risk prostate cancer: Disease control, survival, and toxicity.
Authors: Guix Ines , Bartrina Jose Maria , Tello Jose Ignacio , Garcia Ivan , Quinzaños Luis , Lacorte Teresa Maria , Guix Teresa , Guix Benjamin
Published: February 2018

169

Background: To report early and late toxicity and biochemical outcome in a prospective series of 1,465 patients with intermediate- or high-risk clinically localized prostate cancer treated with either HD-3D-CRT/IMRT or with LD-3D-CRT/IMRT+HDR-B. Methods: Between 12/1999 and 10/2011, 1,465 pts (pts) with PSA›10, Gleason score›6 and/or T2b-T3 N0 M0 prostate cancer entered the study. Pts were prospectively assigned to one of the two treatment groups: 76 Gy HD-3D-CRT or IMRT to the prostate in 38 fractions (group 1; 733 pts) or 46 Gy LD-3D-CRT or IMRT followed by 16 Gy HDR-B given in 2 fractions of 8 Gy (group 2, 732 pts), limiting the maximum rectal dose to 85% of the prescribed dose. Both groups were well balanced taking into account patient’s as well as tumors’ characteristics. Toxicities were scored by the EORTC /RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done. Results: All pts completed treatment. None pts included in the group 1 or 2 experienced grade 3 or more rectal toxicity. 94 pts of group 1 (12.8%) and 20 pts of group 2 (2.7%) developed grade 2 rectal toxicity (rectal bleeding or urgency). 49 pts in group 1 (6.7%) and 10 pts in group 2 (1.3%) developed grade 1 rectal bleeding (less than 2 times/week). With a mean follow-up of 102 months, the 10-year free-from-failure survival was 90.7% and 98.3% (p<0.002) in group 1 and 2 respectively; free-from-metastases survival 95.9% and 97.8% (p<0,006)for group 1 and 2 respectively; and cause-specific survival 97.1% and 98.2% (p<0.08). Conclusions: High-dose 3D-EBRT + HDR brachytherapy was a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute as well as late rectal complications were significantly reduced with the combined treatment, compared with what was observed with high-dose conventional, 3D-conformal radiotherapy. Control rates were significantly better with in the HDR-boosted patients as expected by higher effective-dose.
The application of artificial intelligence and machine learning to automate Gleason grading: Novel tools to develop next generation risk assessment assays.
Authors: Donovan Michael Joseph , Scott Richard , Khan Faisal m , Zeineh Jack , Fernandez Gerardo
Published: February 2018

170

Background: Postoperative risk assessment remains an important variable in the treatment of prostate cancer (PCA). Advances in genomic risk classifiers have aided clinical-decision making; however, clinical-pathologic variables such as Gleason grade and pathologic stage remain significant comparators for accurate prognostication. We aimed to standardize the descriptive pathology of PCA through automation of Gleason grading with artificial intelligence and image analysis feature selection Methods: Retrospective study using radical prostatectomy (RP) tissue microarrays from Henry Ford Hospital and Roswell Park Cancer Center with 8-year median follow-up. Samples were stained with a multiplex immunofluorescent assay: Androgen Receptor (AR), Ki67, Cytokeratin 18, Cytokeratin 5/6 and Alpha-methylacyl-CoA racemase); imaged with a CRI Nuance FX camera and then analyzed with proprietary software to generate a suite of morphometric - attributes that quantitatively characterize the Gleason spectrum. Derived features were univariately correlated with disease progression using the concordance index (CI) along with the hazards ratio and p-value. Results: Starting with a training cohort of 306 patients and a 15% event rate, MIF PCA images were subjected to a machine learning analysis program which incorporates a graph theory-based approach for characterization of gland / ring fusion and fragmentation of tumor architecture (TA) with biomarker quantitation (BQ) (i.e. AR and Ki67). 19 unique image features with 7 TA and 12 TA+BQ were identified, by univariate CI, all TA features were strongly associated with Gleason grading with CI’s reflecting degree of tumor differentiation (CI 0.29-.33, p-value = 0.005). Four TA+BQ features were selected in a training risk model and effectively replaced the clinical Gleason features. By comparison, dominant RP Gleason had a CI of 0.31. Conclusions: Image-based feature selection guided by principles of machine learning has the potential to automate and replace traditional Gleason grading. Such approaches provide the necessary foundation for next generation risk assessment assays.
Pelvic lymph node metastases in prostate cancer: Preoperative detection with dynamic contrast-enhanced magnetic resonance imaging compared with postoperative pathologic result of pelvic lymph node dissection.
Authors: Hwang Jinho , Kim Jung Jun , Oh Jong Jin , Jeong Chang Wook , Lee Sang Eun , Byun Seok-Soo , Lee Sangchul
Published: February 2018

171

Background: To evaluate the accuracy of preoperative magnetic resonance imaging (MRI) in patients who underwent pelvic lymph node dissection (PLND). Methods: The data of 1528 patients who underwent radical prostatectomy and PLND from 2003 to 2017 in our institution were retrospectively reviewed. We evaluated the various clinicopathologic variables including preoperative MRI and pathologic lymph node metastasis (LNmet). The prediction model for pathologic lymph node (LNmet) was assessed using logistic regression analyses and the areas under receiver operating characteristic curves (AUCs) were evaluated. Results: The mean age of our cohort was 66.4 ± 6.7 years. Positive preoperative MRI finding was observed in 9.4% (145/1528) of patients. 5.3% (81/1528) of patients accompanied confirmed final pathologic LNmet. Sensitivity and specificity of preoperative MRI were 30.8% and 91.7%, respectively. Multivariate analysis showed that preoperative MRI findings, clinical stage, and biopsy Gleason score were independent predictors for pathologic LNmet. Preoperative PSA, which was significantly related to pathologic LNmet in univariate analysis, failed to achieve independent predictor status in multivariate analysis. A better prediction model with greater accuracy was achieved by applying multivariate ROC analysis that included MRI findings, clinical stage, and biopsy Gleason score (AUC: 0.799 vs 0.613, p<0.01). The corresponding newer prediction model showed better sensitivity(77.78%) and specificity(70.74%) within threshold value range when it was compared with the predictor model using conventional Partin triad. Conclusions: Preoperative MRI findings for pathologic LNmet showed limited prediction power, yet the predicting power was significantly increased when additional factors such as clinical stage, and biopsy Gleason score were included in the analysis. [Table: see text]
Testosterone (T) suppression by weight and age groups in four pivotal trials of in-situ forming polymer-delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).
Authors: Tagawa Scott T. , McLane John A. , Atkinson Stuart , Boldt-Houle Debbie , Sartor A. Oliver
Published: February 2018

172

Background: In-situ forming polymer-delivered, subcutaneous leuprolide acetate (SC-LA) has previously been shown to suppress serum T levels to ≤20ng/dL in advanced PCa patients. Currently, luteinizing hormone releasing hormone agonists are dosed independently of body weight (BW) or age. Reaching nadir T<20ng/dL within the first year of androgen deprivation therapy (ADT) is associated with improved clinical outcomes such as time to progression and disease specific survival (Klotz 2015). As maintaining castrate T levels during ADT is important, it is of interest to understand if factors such as BW or age should be considered when selecting a therapy. This study aims to determine if patient BW and age correlate with the pharmacodynamic profile of all SC-LA formulations. Methods: In 4 open-label, prospective single-arm, fixed dose, pivotal studies, 438 PCa patients were treated with either 7.5, 22.5, 30, or 45mg SC-LA lasting 1, 3, 4, or 6 months. Blood was sampled at screening, baseline, 2, 4, 8 hours post dosing, day 1, 2, 3, 7, and every other week until end of study and assayed for total T by radioimmunoassay. Results: Mean BW of 86 kg (range 49-146) and age of 73 years (range 40-86) was similar across the 4 studies. >90% of patients in all age groups (including 100% of those <60 years) and ≥92% of patients in all BW groups (including 97% of those ≥90 kg) achieved T≤50ng/dL by week 4. When pooled, all age and BW groups achieved median T≤20ng/dL by week 4 and maintained until the end of the study (Table). Conclusions: The results demonstrate that all SC-LA dose formulations consistently achieve and maintain T≤20ng/dL across all BW and age subgroups, including those with the highest BW (>90 kg) and youngest age (<70 years). BW and age do not appear to have an impact on consistent drug delivery and T suppression by SC-LA. Consistent achievement of T ≤20ng/dL may have implications for improved clinical outcomes and progression free survival in PCa patients. [Table: see text]
Germline variant in HSD3B1 (1245 A>C) and response to abiraterone acetate plus prednisone (AA) in men with new onset metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew W , Gill David Michael , Nussensveig Roberto , Poole Austin , Farnham James M. , Cannon-Albright Lisa A , Agarwal Neeraj
Published: February 2018

173

Background: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, multiple reports validated the role of HSD3B1 (1245 A>C) variant in predicting response to androgen deprivation therapy (ADT) in castration sensitive prostate cancer. The objective of this study was to correlate HSD3B1 variantwith response AA in first-line therapy for men with mCRPC. Methods: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed as described by Hearn at al (Lancet Oncology, 2016). Primary endpoint was progression-free survival in first-line AA in men with mCRPC. We performed pre-specified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on PFS on AA (Table). Results: 76 men with mCRPC treated with first-line AA were included. In multivariate analysis, HSD3B1 (1245 A>C) did not predict response to first-line AA (Table). Conclusions: This hypothesis-generating data shows that inherited variant alleles in HSD3B1 do not predict response to first-line AA in mCRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling or our small sample size. [Table: see text]
Pharmacokinetic (PK) subgroup results from the phase 2 pharmacodynamic and bioequivalence study of abiraterone acetate fine particle formulation (AAFP) in patients with metastatic castration-resistant prostate cancer (mCRPC): The STAAR study.
Authors: Dunshee Curtis , Stein Cy Aaron , Nemeth Paul R. , Bosch Bill , Chapas-Reed Jillian , Dreicer Robert
Published: February 2018

176

Background: AAFP, a novel formulation, showed therapeutic equivalence to originator abiraterone acetate (OAA) in the Phase 2 STAAR study (Stein et al. Urologic Oncol). A patient-subgroup analysis compared steady-state PK parameters between AAFP and OAA. Methods: This multicenter, open-label, active-controlled study enrolled men with progressive mCRPC treated 1:1 with 500 mg AAFP tablets QD + 4 mg methylprednisolone BID, or 1000 mg OAA tablets QD + 5 mg prednisone BID for 9 days. Study drug was taken 2 hours post morning meal. On day 9, plasma abiraterone blood samples were collected at predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hr time points. Results: PK samples were evaluable for 13 of 14 patients (n=5, AAFP; n=8, OAA). Mean age was 67.4 and 73.3 years, respectively. Twelve patients completed the 12-week study without clinical disease progression. One OAA patient died from MI in week 4. PK parameters (AUC, Cmax, Cmin), were numerically lower but not statistically significantly different for those treated with AAFP vs OAA (Table). Conclusions: Clinical benefit in this subgroup of patients was consistent with the overall study results. High PK variability was observed in both groups. PK parameters were not statistically different between AAFP and OAA. 24-hour PK Parameters at Steady State Clinical trial information: NCT02737332. [Table: see text]
Association of androgen receptor (AR) copy number gain with ARV7 expression and response to chemotherapy.
Authors: Iddawela Mahesh Y. , Pezaro Carmel Jo , Sluka Pavel , Kraska Jenna , Pereira Michelle , Joshi Sachin Subhashrao , Jamil Shafaet , Khattak Muhammad Adnan , Ng Siobhan , Davis Ian D. , Ziman Mel , Risbridger Gail , Gray Elin
Published: February 2018

180

Background: Emerging data suggests that ARV7 mRNA (ARV7+) expression and AR copy number gain/amplification (AR+) are associated with resistance to androgen deprivation therapy. Most studies thus far have evaluated either AR copy number or ARV7 mRNA, but not both markers. It is likely that both markers are indicators of genomic changes that are seen in the prostate cancer cells in response to tumour evolution or treatment. Here we developed a digital droplet PCR (ddPCR) based assay to evaluate plasma ARV7 mRNA expression in the same samples used for AR copy number analysis in castrate resistant prostate cancer (CRPC). This assay was use to evaluate the role of AR+ and ARV7+ in CRPC using samples collected from multiple centers and correlated with outcome. Methods: We collected plasma samples from patients with CRPC treated with chemotherapy (C) or next generation androgen targeted agents (NAR) to evaluate circulating tumour DNA (ctDNA) for AR and plasma mRNA for ARV7. Some patients had sequential samples and we correlated PSA response (reduction PSA≥50 confirmed 3wks later (RR)) with AR and ARV7 status and clinical features. Results: A total of 52 samples were included from 26 patients, with matched samples from some patients at different time points. Of the CRPC patients, AR+ was seen in 70% (18/26), AR- in 30% (8/26), ARV7+ in 67% (12/18) and ARV7- in 33% (6/18). 75% (9/12) patients with AR+ also had ARV7+. In matched samples: 3/7 had change in AR status, 2/7 had change in ARV7 status, including 1 patient where both changed; and interestingly there was a group with no AR or ARV7 detected. Number of patients expressing both markers AR+/ARV7+ in 50% (9/18), AR+/ARV7- in 17% (3/18), AR-/ARV7+ 17% (3/18) and AR-/ARV7- in 11% (2/18). RR to C or NAR was 63% (12/19) for AR+ and 75% (9/12) for ARV7+ patients. In AR+ patients, response to NAR was 58% (12/16) but response to chemotherapy was 100% (5/5). Conclusions: AR gain/amplification in CRPC was associated with ARV7+ expression and leads to lower response to NAR compared to C. This approach can be used to undertake integrated DNA and mRNA analysis, has wide-scale utility and may be used for analysis of a larger number of circulating biomarkers.
Multicenter extension and switch study evaluating the safety of long-term treatment with abiraterone acetate fine particle formulation (AAFP) in patients with metastatic castration-resistant prostate cancer (mCRPC): The STAAR-E study.
Authors: Levin Richard , Given Robert , Nemeth Paul R. , Bosch Bill , Chapas-Reed Jillian , Oh William K.
Published: February 2018

181

Background: The STAAR-study results showed novel AAFP 500 mg is therapeutically equivalent to originator abiraterone acetate (OAA) 1000 mg in men with mCRPC (Stein et al. Urologic Oncol). This STAAR-extension study evaluates the safety of ≤ 1 year of additional AAFP treatment in men with mCRPC. Methods: Patients were enrolled in the extension if they had: 1) mCRPC; 2) successfully completed 84 days of treatment with either AAFP + methylprednisolone (MP) or OAA + prednisone (PDN) in the STAAR-study; and 3) received their last dose of STAAR-study treatment < 45 days of starting this extension study. All patients continued or switched to AAFP 500 mg QD + 4 mg MP BID. Serum testosterone and PSA levels are measured at 6 and 12 months. Safety evaluations include adverse event (AE) incidence, clinical laboratory test results, and vital signs. Results: 20 patients were enrolled in the ongoing study (11 were switched to AAFP from OAA and 9 continued on AAFP). Median age is 76.5 years, and median AAFP treatment duration (STAAR + STAAR-E) is 178 days as of 8/16/17. Ten patients have been treated with AAFP > 9 months; 3 of these for > 1 year. Three patients discontinued due to progressive disease (n=1), fatigue (n=1), and a fall (non-AAFP related) resulting in death (n=1). No adverse events related to liver enzyme or bilirubin increases have been reported (Table). Conclusions: In this extension study in men with mCRPC, the safety profile of AAFP, regardless of prior treatment with OAA or AAFP, is consistent with that of OAA reported in the literature. Based on these results, longer-term treatment with AAFP + MP has acceptable safety, and patients on OAA + PDN treatment can switch to AAFP + MP successfully. Clinical trial information: NCT02962284. [Table: see text]
Tumor suppressor aberrations and outcomes in localized and metastatic hormone sensitive prostate cancer (PrCa).
Authors: Hamid Anis , Gray Kathryn P. , Shaw Grace , MacConaill Laura E , Evan Carolyn , Bernard Brandon David , Choudhury Atish Dipankar , Sweeney Christopher
Published: February 2018

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Background: Aberrations of tumor suppressors (TS) TP53, PTEN and RB1 are recurrent genomic events in PrCa and associated with adverse clinical outcomes. Preclinical data suggest that cooperative functional loss of these genes drives development of even more aggressive disease phenotypes. Methods: We identified a retrospective cohort of men with PrCa who underwent DFCI Oncopanel targeted sequencing (NGS) on prostate gland (n = 230) or metastatic tissue (n = 7) for TP53, PTEN and RB1. Biomarker(BM)-positive was defined as copy number loss or likely deleterious mutation of ≥1 TS. For pts presenting with localized disease, Kaplan-Meier method estimated time from biopsy preceding local therapy to PSA relapse/metastasis/death (EFS), castration resistance (CRPC) and death (OS). Cox model assessed association of BM status and outcomes, adjusted for age, clinical stage and Gleason score in multivariate analyses (MVA). For M1 disease, time from ADT start to CRPC and death was estimated. We explored the association of cumulative BM-positive gene hits (0 vs 1 vs 2/3) with EFS (local disease) and OS (M1 disease). Results: Of pts presenting with localized disease (n = 205), 39% were BM-positive and 73 (36%) relapsed after median follow-up of 3.1 years. BM positivity was associated with significantly shorter EFS (driven by PSA relapse) (median 2.6 years, HR 1.95, 95% CI 1.22-3.13) and time to CRPC (HR 3.36, 95% CI 1.01-11.16). MVA confirmed the association with EFS (HR 1.84, p = 0.029). More gene hits lead to incremental risk of relapse (1 gene: HR 1.8, 95% CI 1.09-2.99; 2/3 genes: HR 2.68, 95% CI 1.27-5.63; both vs 0 hits) and this remained significant in MVA (1 gene: HR 1.75, p = 0.05; 2/3 genes: HR 2.74, p = 0.04). 43 patients had relapsed or de novo M1 disease. BM positivity (enriched at 63% of M1) was associated with poorer OS (10 deaths [of 27 BM-pos] vs 0 deaths [of 16 BM-neg] at median follow-up 3.3 years, HR not eval). A trend to incremental worse survival with cumulative gene hits was again observed. Conclusions: Deleterious TP53, PTEN and RB1 variants are associated with a short time to PSA relapse in localized disease, occur at a higher frequency in M1 disease and confer poorer OS. Worse outcomes are seen with cumulative gene hits.
Early versus delayed initiation of salvage androgen deprivation therapy and the risk of prostate cancer-specific mortality.
Authors: Mahal Brandon Arvin Virgil , Chen Ming-Hui , Renshaw Andrew A. , Kantoff Philip W. , D'Amico Anthony Victor
Published: February 2018

189

Background: We sought to ascertain whether there is an association between prostate cancer (PC)-specific mortality (PCSM) and salvage androgen deprivation therapy (ADT) timing amongst men with short versus long prostate-specific antigen doubling times (PSA-DT)s. Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC who were randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. Fifty-four men who received salvage ADT for PSA failure after a median follow up of 18.72 years following randomization defined the study cohort. Fine-Gray competing risks regression analyzed whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (IQR 3.05 - 9.56) following salvage ADT 49 of the 54 men (91%) died, 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate was associated with a decreasing risk of PCSM (adjusted hazard ratio [AHR] 0.33, 95% CI 0.13, 0.82; P=0.02). Amongst men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA>12ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (AHR 8.84, 95% CI 1.99-39.27; P=0.004); whereas for men with a short (<6 months) PSA-DT (AHR 1.16, 95% CI 0.38-3.54; P=0.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA recurrence in men with a PSA-DT of 6 months or more may reduce the risk of PCSM, arguing against the unproven assumption that patients with a short PSA-DT are those most likely to benefit from early initiation of salvage ADT. Clinical trial information: NCT00116220.
What is the role of microRNA-301A expression as a diagnostic and predictive marker of biochemical recurrence for prostate cancer?
Authors: Dervishi Adnan , Rai Samarpit , Nguyen Kristy Doan , FitzGibbon Thomas Michael , Knoll Paul , Shaheen Saad , Damodaran Chendil , Ankem Murali
Published: February 2018

19

Background: Prostate specific antigen (PSA) screening for prostate cancer (PCa) remains controversial, due to its association with an increase in overdiagnosis of clinically insignificant PCa, and overtreatment. Hence, the need for more specific biomarkers to detect PCa and determine its prognosis. MicroRNA expression has previously been demonstrated as a biomarker to detect several malignancies. Studies suggest that microRNA-301a (miR-301a) inhibits the pro-apoptotic function of RUNX3, a transcription factor, and consequently activates ROCK1-mediated survival signaling in PCa. This study establishes the role of miR-301a as a reliable biomarker that can distinguish between patients with benign prostate hyperplasia (BPH) and PCa, and predict biochemical recurrence (BCR) after definitive treatment of PCa. Methods: Serum samples and tissue from prostate biopsies were collected from patients with an elevated PSA prospectively. The expression of miR- 301a was measured via reverse transcriptase-polymerase chain reaction. Additionally, miR-301a expression was retrospectively evaluated in prostatic tissue of 50 patients with PCa, including benign tissue, and correlated with clinico-pathological characteristics to predict BCR. Immunohistochemistry was performed to confirm the molecular target of miR-301a in cancerous tissue. Results: miR-301a demonstrated a significantly higher expression (p = 0.013) in both PCa tissue (Gleason 6 & 7 PCa) and serum samples (p = 0.011) when compared to BPH. Expression of miR-301a in Gleason 6 & 7 prostatectomy specimens positively correlated with patients who developed BCR when compared to patients who did not. When compared to the current nomogram for the prediction of PCa (i.e., PSA, age, race, Gleason score, and family history), incorporation of miR-301a was associated with a superior prediction of BCR at three years post-prostatectomy. Conclusions: miR-301a expression is a valuable tool for diagnosing PCa in patients with an elevated PSA. Combining miR-301a with PSA is associated with better risk stratification of PCa patients, and may help facilitate clinical decision making.
Influence of aggressive-variant prostate cancer (AVPC) features on outcome of metastatic hormone-sensitive prostate cancer (mHSPC) treated by chemohormonal therapy (CHT).
Authors: Koczka Kim , Vanhie James , Ibrahim Andrea , Bukhari Nedal , Reaume M. Neil , Sehdev Sandeep R. , Potvin Kylea R. , Sax Lori , Ernst D. Scott , Vickers Michael M. , Canil Christina M. , Winquist Eric , Ong Michael
Published: February 2018

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Background: Outcomes of patients (pts) undergoing CHT for mHSPC are heterogeneous, with some rapidly developing castration-resistance (CRPC). While AVPC ("anaplastic") features are described in CRPC, less is known in the mHSPC setting. In this multi-institutional cohort, we explored pre-treatment factors associated with poor outcome. Methods: De-novo mHSPC pts treated with CHT from June 2014 to July 2017 at The Ottawa Hospital Cancer Centre (TOHCC) and London Regional Cancer Centre (LRCC) were retrospectively identified. AVPC features (defined below) were collected and cumulatively scored (0, 1, or 2+), along with baseline, treatment and outcome data. Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with CRPC and survival. Results: 92 pts (58 TOHCC, 34 LRCC) met inclusion for study; 83 (90%) had "high-volume" disease (≥4 bone lesions; or ≥1 visceral metastasis), 69/73 (95%) prostate biopsies scored Gleason 8-10, and 55 (60%) had AVPC features: >5 cm nodal/pelvic mass (28), visceral metastases (21), lytic bone metastases (16), elevated LDH (12), low PSA (4), or neuroendocrine differentiation (2). Pre-docetaxel PSA fall of <50, 50-75, 75-90, and ≥90% baseline occurred in 12, 13, 19, and 56% respectively. Docetaxel was initiated a median of 66 days after androgen-deprivation, with 82% completing 5 or 6 cycles. 9 pts (10%) progressed during docetaxel, and 31 pts (34%) developed CRPC < 12 months. Median time to CRPC was 18.4, 14.0, and 11.0 months for 0, 1, and 2+ AVPC features (log rank p=0.009). CRPC was also associated with pre-docetaxel PSA fall <75% (p<0.001) and high alkaline phosphatase (p=0.016). At 18 months median follow-up, 16/55 (29%) with AVPC features have died versus 1/37 (3%) without (log rank p=0.001). In multivariable analysis, AVPC features and pre-docetaxel PSA fall were independently (p<0.05) associated with survival. Conclusions: In our study, mHSPC pts with AVPC features and suboptimal (<75%) pre-docetaxel PSA decline had poor prognosis. These features should be validated in larger cohorts to potentially identify mHSPC pts suitable for further study in clinical trials.
Real-world evidence in patient-related outcomes (PROs) of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate plus prednisone (AA+P).
Authors: Gotto Geoffrey , Fradet Vincent , Drachenberg Darrel , Sabbagh Robert , Rendon Ricardo A. , Shayegan Bobby , Danielson Brita Lavender , Casey Richard , Chan Katherine , Camacho Fernando , Zardan Anousheh , Hew Huong , Feifer Andrew
Published: February 2018

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Background: Oral androgen biosynthesis inhibitor, abiraterone acetate plus prednisone (AA+P), has shown to improve survival and patient-related outcomes (PROs) in clinical trials. The COSMiC study (Canadian Observational Study in Metastatic Cancer of the Prostate; ClinicalTrials.gov: NCT02364531) set out to prospectively amass real-world data on mCRPC patients (pts) managed with AA+P in communities within Canada. Here, we report the interim analysis of their PROs. Methods: At planned data cutoff in Sept 2017 after a median follow-up of 33.8 months, 264 pts were enrolled in 39 sites across Canada. Their FACT-P (Functional Assessment of Cancer Therapy – Prostate) and MoCA (Montreal Cognitive Assessment) were evaluated at baseline as well as at weeks 12, 24, 48 and 72 after AA+P initiation. A 10-point decrease denotes clinically significant degradation in FACT-P and a total MoCA score of > = 26 is considered normal. Descriptive analysis was utilized with continuous variables. Changes from baseline were summarized using mean (SD). Results: At a median age of 77 among 264 pts, 230, 185, 110 and 63 pts were available for analysis at their week 12, 24, 48, and 72 assessments respectively. The mean baseline FACT-P total score was 111.2 (19.44) with a < 3-point absolute change from baseline at subsequent assessments, denoting no clinically significant change in functional status over time. The mean baseline MoCA score was 25.2 (4.50), yet all subsequent assessments scored above 26 and a mean absolute change from baseline of < 1, showing an absence of cognitive decline over time. PSA value was available for 221 pts, 64.3% (142/221) and 34.4% (76/221) achieved a PSA decline of > 50% and 90% respectively. All-grade treatment-related adverse events were reported in 63 pts, with 11% who have had AA+P discontinuation or interruption. Conclusions: COSMiC represents the largest Canadian mCRPC cohort treated with AA+P with real world prospective evaluation of PROs. This data demonstrated the maintenance in quality of life and cognitive status over the course of the study, and underscores the importance of PRO utilization in this complex patient population. Clinical trial information: NCT02364531.
Transcriptomic heterogeneity of androgen receptor activity in primary prostate cancer: Identification and characterization of a low AR-active subclass.
Authors: Spratt Daniel Eidelberg , Alshalalfa Mohammed , Weiner Adam , Fishbane Nick , Mehra Rohit , Walter Rayford , Erho Nicholas , Dicker Adam , Freedland Stephen J. , Karnes Jeffrey , Glass Andrew , Weinmann Sheila , Davicioni Elai , Ross Ashley , Den Robert Benjamin , Feng Felix Y , Schaeffer Edward M.
Published: February 2018

2

Background: Significant genomic diversity exists in the androgen receptor ( AR) and its activity (AR-A) in mCRPC. In localized prostate cancer, the biologic, prognostic, and therapeutic clinical implications of AR-A heterogeneity have yet to be interrogated Methods: Genome-wide expression profiles of FFPE RP or biopsy tumor samples were evaluated from a prospective registry cohort (n = 5,239, NCT02609269) and six retrospective institutional cohorts (n = 1,170). AR-A was calculated based on expression of 9 targets of AR.. Results: Utilizing 6,409 localized prostate adenocarcinomas with full transcriptomic data, we found there was marked inter-individual transcriptomic diversity in AR and AR-A expression, and weak correlation between them (r = 0.08 to 0.36 based on cohort), in contrast to mCRPC that has a strong correlation between AR and AR-A expression (r = 0.76). Additionally, serum PSA had no correlation to intratumoral AR-A (r = 0.06). Unsupervised hierarchical clustering identified a distinct subclass of low AR-A prostate tumors, which had increased markers of immunogenicity (decreased T-regs and MDSCs, and increased CD3 effector T-cells), increased neuroendocrine marker expression ( NCAM1, ENO2, and SCG2), and decreased DNA repair pathway expression (all p < 0.001). Clinically, low AR-A tumors had more rapid development of metastatic disease in three independent cohorts, were more prone to develop resistance to hormonal therapy and develop CRPC, and were found at an increased frequency in African-American men. Interrogating in vitro drug sensitivity analyses utilizing the NCI-60 panel, low AR-A tumors appear more sensitive to platinum chemotherapy and PARP inhibition, and less sensitive to hormone therapy and taxanes. Conclusions: The diversity in AR-signaling in localized prostate cancer represents important biological heterogeneity that is both prognostic and predictive of treatment response. These findings are provocative in that low AR-A tumors may be more susceptible to immunotherapy, PARP inhibition, platinum chemotherapy, and/or radiotherapy. Patients with low AR-A tumors warrant dedicated biomarker enhanced clinical trials.
Individual and joint effect of postdiagnostic metformin and statin use on prostate cancer mortality among patients with high-risk prostate cancer.
Authors: Lu-Yao Grace L. , E Jian-Yu , Lin Yong , Rebbeck Timothy , Lu Shou-En , Kelly William Kevin , D'Amico Anthony Victor , Stein Mark N. , Zhang Lanjing , Kim Isaac , Demissie Kitaw , Ferrari Anna C. , Tan Xiang-Lin
Published: February 2018

202

Background: Metformin and statin together may delay prostate cancer (CaP) metastasis. However, the joint effects on CaP mortality remain unknown. This study is to quantify individual and joint effects of post diagnostic statin and metformin use on CaP mortality in survivors with high-risk CaP. Methods: This population-based study includes patients identified from the SEER database linked with Medicare files diagnosed with high-risk CaP (T category ≥T2c or prostate specific antigen level ≥20 or Gleason score ≥8) in 2008-2011. Comparators did not have documented use of statin or metformin. Hazard ratios (HR) and 95% were calculated using a time-varying Cox proportional hazard model with competing causes of death. Results: Based on 12,700 patients, post-diagnostic use of statin and metformin was associated with a substantial reduction in CaP mortality (Table), with more pronounced effects in patients with obesity (HR=0.32) or M1 disease (HR=0.54). Effects of statins vary widely by brand, with atorvastatin being associated with the largest reduction in CaP mortality (HR=0.18, 95% 0.07-0.50). Conclusions: CaP mortality was substantially lower in post-diagnostic users of statin with high-risk CaP within 6 years of follow-up. Synergistic effect of statin and metformin was observed in M1 disease only. Randomized trials are warrant to confirm the findings.[Table: see text]
Nadir testosterone (T) following in-situ polymer delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).
Authors: Twardowski Przemyslaw , McLane John A. , Atkinson Stuart , Boldt-Houle Debbie , Tagawa Scott T.
Published: February 2018

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Background: Achieving and maintaining T suppression to castration level is the cornerstone of androgen deprivation therapy (ADT) for advanced PCa. Modern assay methodology found median T level after surgical castration to be 15ng/dL; the 2016 European Association of Urology guidelines define castration as T < 20ng/dL. Additionally, reaching nadir T < 20ng/dL is correlated with improved duration of response to ADT, time to progression or disease-specific survival (Klotz 2015), and prognosis for overall survival (Kamada 2015). To examine the effectiveness of in-situ polymer-delivered, subcutaneously-administered leuprolide acetate (SC-LA) on T suppression, nadir T was evaluated in 4 pivotal trials. Methods: Eugonadal patients with advanced PCa were treated with either 7.5 (6 doses), 22.5, 30, or 45mg (2 doses each) SC-LA lasting 1, 3, 4, or 6 months, respectively in 4 open-label, fixed-dose, pivotal trials. Serum T levels were evaluated byradioimmunoassay. T was measured 2-4 times on day 0 and once on days 1, 3, 7, and every week until the next dose, and repeated until end of study. The 45mg group had an additional measurement on day 2. LA was measured on days 0, 4, 7, 14, 21, 28, 35, 42, 49, and 56 post-injection. Nadir T was the lowest value obtained in the entire trial. Results: Across the SC-LA formulations, median LA levels were consistently between 0.1-1ng/mL from week 2 until the end of study. When pooled, 90-96% of patients achieved T≤20ng/dL by week 6 and 90-97% maintained T≤20ng/dL from weeks 6-24. Pooled analysis (n = 437) showed 99%, 97%, 91%, and 80% of patients reached nadir T≤20ng/dL, ≤10ng/dL, ≤5ng/dL, and ≤3ng/dL respectively with a median nadir T≤3 ng/dL. When comparing across all doses, > 88% of patients reached nadir T≤5ng/dL. Conclusions: Across all doses, SC-LA achieves consistent and prolonged serum LA drug delivery above 0.1ng/mL and provides favorable T suppression < 20ng/dL, which may be attributed to the in-situ forming polymeric delivery system. Multiple T measurements throughout the study confirmed that 91% of PCa patients achieved low nadir T≤5ng/dL, which may have implications for extending progression-free survival and duration of response to ADT.
Proportion of biochemically-recurrent prostate cancer patients with durable undetectable PSA after short-course androgen deprivation therapy.
Authors: Lim Daniel M. , Gulati Roman , Aleshin-Guendel Serge , Cheng Heather H. , Gawne Agnes M. , Wingate Jonathan T. , Etzioni Ruth Douglas , Yu Evan Y.
Published: February 2018

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Background: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate specific antigen (PSA) levels as a marker of efficacy. The proportion of patients and clinical relevance of those with a prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. Methods: The University of Washington Caisis database was queried for radical prostatectomy patients who received 6–12 months of ADT after biochemical recurrence (BCR), defined as PSA ≥ 0.2 ng/mL and no radiographically detectable metastasis. Proportions of patients with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death from any cause were evaluated by log-rank tests. Results: After ineligibility exclusions, data were abstracted from 93 patients. Proportions of patients with undetectable PSA 12 and 24 months after ending ADT were n=23/93 (24.7%; 95% CI 16.4–34.8%; P<0.001) and n=14/93 (15.1%; 95% CI 8.5–24.0%; P<0.001), respectively. Proportions of patients with undetectable PSA 12 and 24 months after testosterone recovery ≥ 50 ng/dL were n=16/65 (24.6%; 95% CI 14.8-36.9%) and n=10/65 (15.4%; 95% CI 7.6-26.5%), respectively. Being 1 year older at diagnosis was associated with an 11.5% (95% CI 3.1–21.9%; P=0.01) increase in the odds of having a detectable PSA after controlling for PSA at diagnosis, Gleason sum and time from initial therapy to BCR. Detectable PSA was associated with increased risk of metastasis (P=0.006) with marginal evidence of association with death from any cause (P=0.07). Conclusions: This single-institution retrospective analysis shows that it is not uncommon to have undetectable PSA 12 or 24 months after a short course of ADT. Additional analysis is needed to demonstrate the clinical value of this measure as a surrogate for prostate cancer outcomes and for consideration as a trial endpoint.