bluuebunny/crossref_metadata_2025 huggingface dataset:
Nationwide analysis of genitourinary expert opinions on active surveillance for localized prostate cancer.
Authors: McClelland Shearwood , Sandler Kiri A , Degnin Catherine , Chen Yiyi , Mitin Timur
Published: February 2018

29

Background: The ProtecT trial has provided Level 1 evidence supporting active surveillance for prostate cancer patients with low-risk and intermediate risk disease. The impact of these findings on the opinions of North American genitourinary (GU) experts regarding the role of active surveillance for these patients has not been previously examined. Methods: A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to knowledge about and personal opinions on the role of active surveillance in patients with low-risk and intermediate-risk (Gleason 3+4) disease. Opinions regarding active surveillance were correlated with practice patterns using Fisher’s exact test. Results: Analysis was conducted on 42 radiation oncologist respondents. Forty percent have been in practice for 20+ years; 90% practice at an academic center. Forty-five percent see 20+ patients/month in consultation. More than 95% recommended active surveillance for Gleason 6 disease, while only 17% recommended active surveillance for Gleason 3+4 disease. There were no significant demographic differences between supporters or opponents of active surveillance regarding monthly patient volume, practice type, self-identification as an expert brachytherapist, belief in advanced imaging techniques, or preferred default EBRT dose/fractionation for low-risk or intermediate-risk disease. However, opposition to active surveillance for Gleason 3+4 disease approached significance for experts having practiced 10+ years versus < 10 years (p = 0.085). Conclusions: Active surveillance is well-regarded among North American GU experts for low-risk but not intermediate-risk prostate cancer, despite the results of the ProtecT trial providing Level 1 evidentiary support for active surveillance in both risk groups. There were no significant differences between experts supporting versus opposing active surveillance for either low-risk or intermediate-risk disease. These preferences may affect the design of future clinical studies, influencing the adoption of active surveillance in North American clinical practice.
Post marketing surveillance study of cabazitaxel (CBZ) in Japanese patients with castration resistant prostate cancer (CRPC) in real world settings.
Authors: Matsuyama Hideyasu , Matsubara Nobuaki , Taguchi Tomoyuki , Seto Takeshi , Suzuki Kazuhiro
Published: February 2018

290

Background: The study evaluated safety and efficacy of CBZ in Japanese patients (pts) with CRPC in real world settings. Methods: This prospective, observational study targeted all CRPC pts receiving CBZ in daily practice between September 2014 and June 2015. Observation period was 1 year after first dose of CBZ given. Adverse drug reactions (ADRs) were evaluated for safety by CTCAE 4.0. Overall survival (OS), time to treatment failure (TTF) and prostate specific antigen (PSA) response rate (≥30% PSA decrease) were the efficacy endpoints. Two groups, those given 25mg/m2 of CBZ as initial dose (C25) and those given 20mg/m2 of CBZ (C20), were comparatively analyzed. This study was supported by Sanofi. Results: Of 662 enrolled pts with CRPC treated with CBZ, 660 pts were analyzed. ADRs occurred in 511 pts (77.4%). Most frequent all grade ADRs were neutropenia (49.2%), febrile neutropenia (18.0%) and anemia (14.2%). Median OS and TTF were 319 and 116 days, respectively. Of 540 PSA evaluable pts, 158 (29.3%) achieved PSA response. Populations for post hoc analysis were 159 pts for C25 and 190 pts for C20. Patient characteristics were similar C25 and C20 groups. Statistical significant differences were observed between C25 and C20 groups for OS (Hazzard Ratio [HR] = 0.71) and TTF (HR = 0.78) in favor of C25 group. Initial dose of CBZ remained as the independent prognostic factor for OS and TTF in univariate and multivariate analysis. There was no significant difference for PSA response rate. ≥ Grade 3 ADRs with C25 and C20 occurred in 129 pts (81.1%) and 116 pts (61.1%), respectively. Conclusions: Safety profile of CBZ was generally consistent with clinical studies conducted before approval in Japan. Although there are some limitations of studies done in real world settings, there were significant differences for OS and TTF between C25 and C20. Less ADRs occurred with C20. [Table: see text]
Epidemiology and survival disparities of prostate cancer in Appalachian Kentucky.
Authors: Myint Zin , Huang Bin , Chen Quan , Wang Peng
Published: February 2018

292

Background: Prostate cancer is the most common cancer in men in the United States. When comparing the incidence and mortality rates of prostate cancer in Appalachian Kentucky and general population in the United States, Appalachian Kentucky had lower incidence (113 per 100,000 rate vs. 137 per 100,000) but higher mortality rate (23.08% vs. 21.79%) from Surveillance Epidemiology and End Results (SEER) data in 2005-2014. The aim of our study is to further characterize the epidemiology and survival disparities of prostate cancer between Appalachian and non-Appalachian Kentucky. Methods: All stages of prostate cancer patients diagnosed between 2007-2011 were identified through Kentucky Cancer Registry (KCR). Baseline characteristics and survival outcome were compared between Appalachian Kentucky and non-Appalachian Kentucky. Kaplan-Meier plots and cox regression analyses were performed in this population-based study. Results: Out of 12871 patients studied, 3482 patients (26.8%) were Appalachian Kentucky whereas 8489 patients (73.2%) were non-Appalachian Kentucky. Caucasians were the most predominant in both groups. Most Appalachian Kentucky patients fell in the age group between 65-74. Appalachian Kentucky had high Gleason score, high prostate specific antigen (PSA), aggressive histologic grade, more distant disease, high comorbidity score, low high school education and high poverty rate compared to non-Appalachian Kentucky. There was a 5-year survival difference between Appalachian Kentucky and non-Appalachian Kentucky in unadjusted analysis (p < 0.0001). After adjusting with cox regression analysis, no survival difference was seen (p = 0.3866). However, statistical significance in survival was seen in high GLS, high PSA, distant stage, high charlson comorbidity score, and low high school education (p < 0.0001). Conclusions: Our study shows a significant difference in prostate cancer survival between Appalachian and non-Appalachian Kentucky. The difference was not related to geographic location, rather it was more related to high comorbidity score, high poverty rate, low education and less knowledge of health care. Additional research is needed to understand the health care in Appalachia.
Experience of 1,000 patients.
Authors: Iorio Julieta , Eleta Martin , Bambacci Florencia , Cuneo Lucrecia , Polillo David
Published: February 2018

294

Background: The aim of this study is to present our experience between the correlation of 18 fluorocholine (FCH) positron emission tomography (PET)/computed tomography (CT) findings and PSA levels in detecting local recurrence, lymphatic/haematogenous involvement in patients with prostate carcinoma. Methods: 1075 patients with prostate cancer were enrolled between July 2012 and August 2017. Patients were separated in two main groups: biochemical progression 913 (85%) and 162 (15%) staging. Each group was divided in three subgroups according to PSA levels: ≤1 ng/ml; ≥ 1-5ng/ml and > 5 ng/ml. All of them underwent “Dual phase” PET-CT consisting of intial pelvis starting 20 minutes after the injection of 18 F-Choline followed by 1 hour delayed PET-CT of the whole body. Results: 1641 lesions showed increased uptake on FCH-PET and were interpretated as local recurrence or metastases .According to biochemical progression we identified for each subgroup: 118 patients (13%) (≤1 ng/ml); 265 patients (29%) (≥ 1-5ng/ml); 530 patients (58%) ( > 5 ng/ml) and for staging we identified for each subgroup: 81 patients (50%) (≤1 ng/ml); 47 patients (29%) (≥ 1-5ng/ml); 20 patients (34%) ( > 5 ng/ml). The results are shown on table 1: Patients presenting biochemical progression the majority of them have PSA levels of 5 ng/ml or more and the most frequent site of metastases were pelvic lymph nodes, on the other hand, for staging patients we have found that most of them have PSA levels of ≤1 ng/ml and we detected that they most commonly have local compromise. Conclusions: In our experience 18 FCH PET/CT is a useful tool to detect lesions in patients with biochemical progression but it seems to have limited value for staging. [Table: see text]
Influence of CHAARTED, STAMPEDE, and LATITUDE eligibility criteria on utilization of abiraterone (A) and docetaxel (D).
Authors: Parshad Shruti , Emmenegger Urban
Published: February 2018

301

Background: A and D improve the survival of men with high-risk localized or metastatic hormone-naïve prostate cancer (HNPC) when combined with androgen deprivation therapy (ADT). However, the two drugs differ regarding side effects, treatment duration, and associated costs. Furthermore, different eligibility criteria were used in the seminal phase III studies. Since the latter may impact on drug access in many constituencies, we decided to study how applying the eligibility criteria of CHAARTED, STAMPEDE and LATITUDE for drug funding purposes might influence the utilization of A versus D. Methods: 102 men with HNPC were referred from 06/2014 to 09/2017 to the medical oncology service at Odette Cancer Centre (Toronto/ON, Canada) for consideration of additional systemic therapy secondary to ADT. After extraction of baseline patient characteristics, we applied the eligibility criteria of CHAARTED (both high-volume [HV] and low-volume [LV] definition), STAMPEDE, and LATITUDE to determine the rate of men qualifying for treatment with A, D, or either of the two agents. Results: 98.0, 69.6, 28.4, and 47.1 percent of all 102 men fulfilled the STAMPEDE, CHAARTED-HV, CHAARTED-LV, and LATITUDE criteria, respectively. Considering that A funding for HNPC therapy is pending in Ontario, and that D funding is limited to men with CHAARTED-HV disease, the rate of D therapy was 62.0, 69.0, and 77.1 percent of patients conforming to STAMPEDE, CHAARTED-HV, and LATITUDE, respectively. 42 of 48 men (87.5%) conforming to LATITUDE would also be candidates for D, whereas 42 of 71 CHAARTED-HV patients (59.2%) would be eligible for A as alternative treatment. Hence, while all men fulfilling the STAMPEDE criteria (100 of 102, 98%) could be considered for either A or D, only 42 of 102 patients (41.2%) would be candidates for both of the drugs if the CHAARTED-HV and LATITUDE criteria were applied. Conclusions: In our patient population, applying the more restrictive CHAARTED-HV and LATITUDE criteria - as opposed to STAMPEDE - would result in around 30% or 50% fewer men offered D or A secondary to ADT, respectively. In addition, only around 40% of men would conform to both CHAARTED-HV and LATITUDE, and thus be candidates for both drugs.
Activity of VERU-111, an novel oral α and β tubulin inhibitor, against paclitaxel sensitive and resistant prostate cancer.
Authors: Getzenberg Robert H. , Dalton James T. , Miller Duane D. , Steiner Mitchell S.
Published: February 2018

302

Background: Following proven efficiacy of docetaxel against hormone sensitive advanced prostate cancer (CHAARTED and STAMPEDE studies), the use of docetaxel for the treatment of hormone sensitive and castrate resistant metastatic prostate cancer has increased. Unfortunately, the utility of taxanes in prostate cancer has been limited because of the development of resistance, the need for IV infusion, and the associated treatment toxicity. VERU-111 is a highly orally available, novel α and β tubulin inhibitor, developed using a rationale design strategy to bind through hydrogen bonds to the α and β subunits of tubulin. VERU-111 inhibits tubulin polymerization and is not a substrate for multi-drug resistance proteins, a common mechanism for taxane resistance. Methods: In this study, dosing regimens of VERU-111 (oral) were tested in comparison with docetaxel (IV) and a vehicle (oral) in PC3 as well as in paclitaxel resistant PC3 (PC3-TXR). xenograft models. VERU-111 was evaluated at 3.3 mg/kg (5 days/week), 10 mg/kg (3 days/week), 15 mg/kg (2 days per week), 15 mg/kg (3 days per week) and 20 mg/kg (1 day/week). The animals were treated for 28 days and tumor volume and percentage size were calculated. Results: In the parental PC-3 model, animals treated with oral VERU-111, in all of the dose schemes tested, performed statistically indistinguishably from the IV docetaxel administration. In the PC3-TXR model, IV docetaxel had no impact on tumor growth whereas oral VERU-111 resulted in almost complete inhibition of tumor growth at 3.3 mg/kg (5 days/week) and 10 mg/kg (3 days/ week) as well as 20 mg/kg (1 day/week). In early toxicity studies, the animals treated with VERU-111 did not suffer any significant safety signals and gained weight during treatment. Conclusions: VERU-111 is a novel, oral α and β tubulin inhibitor that has drug characteristics making it an ideal candidate to be a therapeutic option for hormone sensitive and castrate resistant advanced prostate cancer. VERU-111 can be administered, with efficacy, as infrequent as once per week and will not require daily dosing. Additional toxicity studies are currently being performed with a Phase 1/2 study being planned to begin later this year.
Safety of continued administration of enzalutamide in patients with prostate cancer who showed benefit from prior exposure: A phase 2 open-label extension study.
Authors: Lam Elaine Tat , Szmulewitz Russell Zelig , Appleman Leonard Joseph , Tolcher Anthony W. , Krivoshik Andrew , Baron Benoit , Malan Niel , Ghicavii Vitalii
Published: February 2018

303

Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.
DNA damage and repair (DDR) gene variants and outcomes in localized and metastatic prostate cancer (mPC).
Authors: Bernard Brandon David , Gray Kathryn P. , Shaw Grace , MacConaill Laura E , Evan Carolyn , Hamid Anis , Choudhury Atish Dipankar , Sweeney Christopher
Published: February 2018

304

Background: Moderate frequencies of DDR gene variants exist in mPC. Their prognostic role in localized and mPC is unclear. This study aims to characterize DDR variants in a cohort of hormone sensitive localized and mPC and assess for association with outcome. Methods: A retrospective cohort of men with PC and ≥ 2 follow up visits at DFCI and targeted next generation sequencing of prostate or metastatic tissue was identified. Biomarker (BM) positive was defined as pathogenic changes in the following DDR genes: ATM BAP1 BRCA1 BRCA2 BRIP1 CHEK2 MSH2 MSH6 PALB2 PMS2. For localized PC, outcome endpoints included event-free survival (EFS) (time from prostate biopsy to PSA relapse/metastasis/death), metastasis-free survival (MFS) (time to metastasis/death), time to castration resistance (CRPC), and death (OS); for mPC, outcome events included time from androgen deprivation start to CRPC and OS. BM status was descriptively summarized. Kaplan-Meier method and Cox regression model assessed associations of BM status with clinical outcomes. Results: Of the 237 men included, 16 (7%) were BM positive; 12 (6%) in 205 localized PC, 6 (14%) in 43 mPC. BM positive genes included 9 (4%) ATM, 6 (3%) BRCA2, and 2 (0.8%) CHEK2. In men with localized PC, EFS events occurred in 58% (7/12) BM positive vs 34% (66/193) BM negative at median follow up of 3.1 years; BM positive trended toward a shorter EFS (median 1.9 vs 5 years) than BM negative (HR 2.17, 95%CI 0.99-4.76). MFS events were observed in 17% (2/12) BM positive vs 7% (15/193) BM negative. CRPC events occurred in 17% (2/12) BM positive vs 6% (11/193) BM negative. In men with mPC, there were CRPC events in 100% (6/6) BM positive vs 67% (25/37) BM negative at median follow up of 3.3 years; BM positive trended toward a shorter time to CRPC (median 4 vs 8.8 months) compared to BM negative (HR 1.87, 95%CI 0.76-4.64). There was no association between BM status and OS. Conclusions: DDR variants appear infrequently in localized PC but may portend a shorter time to PSA relapse and metastasis. Similarly, DDR variants in mPC may be associated with a shorter time to CRPC. Low frequency of variants and short follow up limit these analyses. The prognostic value of DDR variants remains unclear and requires further research.
Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer.
Authors: Prophet Malshundria , Xiao Kun , Gourdin Theodore Stewart , Nagy Rebecca J , Kiedrowski Lesli Ann , Ledet Elisa , Sonpavde Guru , Sartor A. Oliver , Lilly Michael B.
Published: February 2018

306

Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.
Assessment of immunohistochemical testing for androgen receptor splice variant 7 as a biomarker to predict resistance to androgen receptor signaling inhibitors in metastatic prostate cancer.
Authors: Vyas Ojas Harihar , Butler Matthew James , Bowhay-Carnes Elizabeth Ann , Pathan Muhammad , Datta Paromita
Published: February 2018

308

Background: Androgen receptor splice variant 7 (AR-V7) has been shown to confer resistance to androgen receptor signaling inhibitors (ARS-I) such as enzalutamide (enza) and abiraterone (abi). Resistance can be observed at the time of initial treatment, or may be acquired later in the disease course. Prior research has primarily focused on AR-V7 expression in circulating tumor cells (CTCs) but the utility of more affordable immunohistochemical (IHC) testing to predict for primary resistance to ARS-I remains unknown, which is of particular relevance as ARS-I gain use as initial therapy. Methods: We identified patients in the South Texas Veterans Health Administration Tumor Registry with metastatic, castrate-resistant prostate cancer who received ARS-I since 2011. IHC for AR-V7 staining was validated on controls and performed on tissue from the most recent tissue specimen (diagnostic biopsy, prostatectomy, or biopsy of a metastatic site) on all identified patients with adequate tissue available. Results: 25 of 42 (60%) patients receiving abi had PSA response with median duration of response (DOR) of 231 days. 14 of 26 (54%) of patients receiving enza experienced PSA response with a median DOR of 165 days. IHC is currently being interpreted on stored tissue specimens to assess predictive efficacy of AR-V7 staining. The de-novo rate of AR-V7 expression and correlation with response to ARS-I in the veteran population will be reported with final results. Conclusions: IHC testing for AR-V7 may provide a cost-effective biomarker to identify patients resistant to ARS-I, thus avoiding thus avoiding time-consuming and costly treatment with ineffective therapy. Further study is warranted to assess cost-effectiveness and reduction in unnecessary toxicity by the use of IHC testing for AR-V7 in the front-line setting to predict primary resistance for patients that would otherwise qualify for ARS-I.
Cell surface GRP78 activation by anti-GRP78 autoantibodies in relation to prostate tumour growth via tissue factor activation.
Authors: Al-Hashimi Ali , Austin Richard , Shayegan Bobby
Published: February 2018

31

Background: Prostate cancer (PC) is characterized by increased prothrombotic state due to enhanced tissue factor (TF) expression/procoagulant activity (PCA). We and others observed that GRP78, a molecular chaperone, is expressed on the surface of PC cells where it functions as a signaling receptor to promote cell proliferation and survival. Further, exposure of GRP78 on the surface of PC cells stimulates the production of anti-GRP78 autoantibodies in PC patients. We have reported that binding of these autoantibodies to cell surface GRP78 enhances TF PCA. We hypothesize that this autoantibody/cell surface GRP78 complex interaction increases PC progression and that disruption of this complex would represent a viable target for the treatment of advanced PC. Methods: Wild type, TF knockdown DU145 cells, and NOD/SCID mouse model system was used to investigate the effect of anti-GRP78 autoantibodies on tumor growth. Protein expression was determined using western blotting and qRT-PCR. TF activity was determined using the TF PCA continuous assay. Blood samples from patients diagnosed with PC were obtained from the Ontario Tumour Bank and St. Joseph’s Hamilton. Results: Pre-prostatectomy patients demonstrated high levels of anti-GRP78 autoantibodies (60-100µg/ml) vs. healthy individuals (5-10µg/ml). These titers were significantly reduced 24-weeks post prostatectomy. We show here that anti-GRP78 autoantibodies upregulate TF and its PCA through a mechanism involving depletion of ER Ca2+ stores. This very effect on ER Ca2+ stores also caused activation of the unfolded protein response, a pro-survival cellular pathway. Furthermore, these autoantibodies were shown to accelerate tumor growth in a NOD/SCID mouse model. Finally, heparin and low molecular weight heparin were shown to interfere with the binding of these antibodies to cancer cells and prevent PC cell activation. Conclusions: We have identified the function of an agent in patients' blood, anti-GRP78 autoantibodies, that correlate with PC stage in patients and increase TF PCA and promote PC progression in mice. The effect of this autoantibody can be reversed using heparin, thus, this acts as a new potential therapeutic target for PC.
NGS, RNA-Seq, TIL, and PTEN analyses in prostate cancer specimens from patients enrolled in the study of the Akt inhibitor ipatasertib (Ipat) combined with abiraterone acetate (AA).
Authors: Zhang Liangxuan , Koeppen Hartmut , Maslyar Daniel J. , Fillos Dimitri , Xu Na , Chan Wai Y. , Font Pous Albert , Jinga Viorel , Massard Christophe , Bracarda Sergio , Radavoi George Daniel , De Giorgi Ugo , Arranz Arija Jose Angel , Riisnaes Ruth , Nava Rodrigues Daniel , De Bono Johann S. , Gendreau Steven
Published: February 2018

310

Background: In Phase III studies, ipilimumab did not extend OS in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) (Kwon, 2014; Beer, 2014), suggesting that successful cancer immunotherapy development strategies require the evaluation of treatment effects in biomarker-driven segments. In addition, PTEN loss has been identified as a potential mechanism of resistance to immunotherapy (Peng, 2016). Therefore, we explored possible associations between cancer immunity (CI)-related biomarkers and PTEN loss in mCRPC samples. Methods: Tumor samples obtained in the Phase II study of AA ± Ipat in patients with mCRPC (de Bono, ESMO 2016) were retrospectively profiled. DNA alterations and tumor mutational burden (TMB) were assessed by FoundationOne. RNA-seq analysis of multiple CI-related expression signatures was performed. Tumor-immune lymphocyte (TIL) scores were analyzed in 3 compartments (stromal, sTIL; intratumoral, iTIL; peritumoral, pTIL) based on H&E stained specimens. Up to 10 evenly distributed fields were examined; the average of these fields was used to estimate the %TILs for each compartment. Results: Strong associations were observed between multiple CI-related signatures (e.g., INFγ-induced, immune checkpoints, Treg, checkpoint inhibitors). Fewer than 10% of the samples had a high level (≥ 10% of the tumor area) of TIL infiltration in any compartment (Table). TIL scores, TMB values, PTEN status and Gleason score all appeared to be independently associated, and none were associated with CI-related gene signatures, except for a possible association between pTILs and the B-cell signature (ρ = 0.49, P < 0.0001). Conclusions: Comprehensive high-content profiling of prostate cancer samples suggests that PTEN status and CI-related biomarkers were independently associated, while TMB and TIL values were generally not associated with CI-related signatures. Clinical trial information: NCT01485861. [Table: see text]
Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew W , Patel Darshan , Gill David Michael , Froerer Camryn , Nussensveig Roberto , Poole Austin , Hale Peter , Farnham James M. , Maughan Benjamin Louis , Cannon-Albright Lisa A , Agarwal Neeraj
Published: February 2018

311

Background: Currently, there are no predictive biomarkers of response to AA in mCRPC routinely used in the clinic. SLCO2B1 encodes a sodium-independent organic anion transporter that mediates transport of endogenous sex hormones and drugs, including AA, into tissue. Single nucleotide polymorphisms (SNPs) in SLCO2B1 are a validated predictive biomarker of response to androgen deprivation therapy in hormone sensitive prostate cancer. In a recent pre-clinical study, the AA/AG genotype for rs12422149 and the AA genotype for rs1789693 of SLCO2B1 had significantly higher mean tissue abiraterone levels. We hypothesize that the variant allele for rs12422149 and rs1789693 are predictive of improved response to AA in mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed pre-specified multivariate Cox regression analyses to assess the independent predictive value of SLCO2B1 rs12422149 and rs1789693 on PFS on AA (table). Results: 76 men with mCRPC treated with first-line AA were included. In a multivariate analysis for rs12422149, a trend towards improved median PFS was seen with the AG genotype (11.2 months) vs. the GG genotype (6.4 months) (HR 0.50, 95% CI 0.24-1.02, p=0.056). No such correlation was seen with rs1789693 genotypes. Conclusions: Consistent with pre-clinical studies, the AG genotype in rs12422149 of SLCO2B1 may be predictive of response to AA in men with mCRPC. This hypothesis-generating data needs further interrogation in larger and independent cohorts. [Table: see text]
Targeting DNA damage response to overcome taxane resistance.
Authors: Chao Olivia , Goodman Oscar B.
Published: February 2018

312

Background: Overcoming taxane resistance in metastatic castrate-resistant prostate cancer (mCRPC) is an unmet need. We and others have observed that a significant proportion of patients with docetaxel (Dox)-refractory disease exhibit sensitivity to DNA-damaging agents. Conversely, loss of DNA repair proteins has been shown to confer resistance to anti-microtubule agents. We hypothesize that Dox exposure alters expression of DNA damage response (DDR) genes, promoting Dox-resistance; and targeting these changes would restore Dox sensitivity. Methods: Dox-resistant prostate cancer cells were developed by exposing DU145 cells to stepwise increasing Dox concentration. Resistance was confirmed by comparing viability (MTT assay) of DU-R (Dox-resistant) and DU-P (age-matched parent) cells after 72 h exposure to Dox (0.1 – 100 nM). Changes in gene expression between DU-DR and DU-P were measured using a DDR-specific 84 gene PCR array. Genes with > 2-fold change in expression were confirmed by RT-PCR and immunoblotting. Sensitivity to Dox of DU-DR was measured in presence of candidate gene inhibitors. Effects of Dox + inhibitor on cell cycle and apoptosis were analyzed by flow cytometry. Results: DU-DR was significantly more resistant to Dox than DU-P (IC50 DU-DR vs DU-P: > 100nM vs 0.86 nM), cabazitaxel (Cab) (9.48 nM vs 0.32 nM), and etoposide (Eto) (4.67 μM vs 1.32 μM) but not 4-hydroperoxy cyclophosphamide (4-HC) (4.50 μM vs 3.16 μM). DDR PCR array revealed three genes were significantly upregulated ( TP73, PRKDC, CDK7) and two downregulated ( BBC3, MSH3); and confirmed by RT-PCR and immunoblotting. DNA-PKc inhibitor, NU7441, treatment significantly increased sensitivity of DU-DR cells to Dox (IC50 = 30.7 nM). Similarly, NU7441 also re-sensitized DU-DR cells to Cab and Eto but not 4-HC. Dox did not induce apoptosis in DU-DR cells (sub-G1 = 2.54 ± 0.15 %; Annexin V+/PI- = 3.60 ± 0.58%) unlike in DU-P (sub-G1 = 39.4 ± 0.28 %; Annexin V+/PI- 28.6 ± 1.1%). NU7441 increased sub-G1 (15.8 ± 0.99 %) and Annexin V+/PI- (14.5 ± 1.4 %) population in Dox-treated DU-DR cells. Conclusions: Targeting prostatic DNA-PKc restores sensitivity to taxanes in vitro. Co-targeting these genes may lead to novel mCRPC therapies.
Real world experience of docetaxel in elderly patients with advanced prostate cancer.
Authors: Fu Simon Yuen Fai , Barlow Paula , Jacobs Carmel Maree , Hanning Fritha J. , Fong Peter C.C.
Published: February 2018

313

Background: Docetaxel (D) chemotherapy is a standard of care in men with advanced prostate cancer (APC), both metastatic castration sensitive (CS) and castration resistant (CR) disease. The risk of significant toxicities may deter D use in elderly patients. We aim to evaluate the real world efficacy and tolerability of D in men with APC. Methods: Between 04/2014 and 05/2017, data from men aged ≥75 with APC treated at Auckland City Hospital with 3 weekly D were retrospectively collected from the genitourinary medical oncology database. Results: 33 (CS 12, CR 21) men were identified. 70% had PSA decline ≥50% (CS 92%, CR 57%). Median time to next line of therapy was 0.5 y in the CR arm. One third (n = 2/6) of CR patients on opioid had improved pain control with D. 75% had upfront dose reduction (DR). The median dose intensity was 21 mg/m2/wk (CS) and 18 mg/m2/wk (CR). 9 patients had dose escalation after upfront DR, all but 3 needed DR later, and none was escalated to 75 mg/m2. 58% (CS 75%, CR 48%) completed 6 cycles, and only 6% (n = 2) completed 6 cycles at 75 mg/m2. 24% had ≥G3 hematological toxicities. Febrile neutropenia rate was 12% (CS 8%, CR 14%). Pegfilgrastim was used in 1 CS and 1 CR men. Admission rate was 39% (CS 25%, CR 48%), 77% (CS 100%, CR 70%) was treatment related, and 23% (CR 30%) due to malignancy. 15% (CS 25%, CR 9%) required RBC transfusions. 33% CR men progressed while on treatment, and two deaths from pneumonitis and disease progression were noted. Conclusions: Docetaxel is active in elderly men with APC. Toxicities are manageable but can be life-threatening. Admission is frequent especially in CR patients. Proactive dose reduction should be considered to balance benefits vs. risks in this population. [Table: see text]
Biological significance of novel populations of prostate cancer circulating tumor cells (CTC).
Authors: Davis Ian D. , Pezaro Carmel Jo , Wardan Hady , Sluka Pavel
Published: February 2018

315

Background: Decisions regarding selection and sequencing of treatment in advanced prostate cancer (PC) are often made empirically, without information on the PC molecular profile at the time of treatment. CTC provide real time information regarding contemporaneous biologically relevant cancer subtypes. Current assays often rely on EpCAM or other epithelial markers and may underestimate or exclude other CTC populations of clinical relevance. We devised a novel, simple, rapid and cheap method for isolation of CTC subsets including those without epithelial markers. Methods: Five mL of blood was processed as follows: CD45+ depletion (RosetteSep Human CD45 Depletion Cocktail, Stemcell Technologies); Ficoll centrifugation; antibody staining (mix of EpCAM-PE, PSMA-APC, N-cadherin-AF488, E-cadherin-PerCP/Cy5.5, CD45-APC-H7); Sytox Blue live/dead cell stain; followed by sorting (Becton Dickinson FACSAria Fusion cell sorter). Live cells were sorted into 4 categories denoted E, E+P, P, N (Table). N and P are not identifiable using existing conventional CTC techniques. CTC were assayed for prostate markers ( AR, FOLH1 (PSMA), KLK3 (PSA), TMPRSS2, AMACR) and malignant markers ( PTEN copy number) using digital droplet PCR. Results: Preliminary data are derived from 62 patient samples providing 47 sorted populations. Details are in the Table. Spiking experiments reliably identified as few as 10 CTC / 7.5 mL of blood. P cells were detected in all patients, often outnumbering sum of E and E+P; E and N were never co-expressed. P and N samples frequently expressed prostate markers. Only 1/27 showed no expression of any of these five prostate markers. PTEN deletion assays are in progress. Conclusions: “Unconventional” EpCAMneg CTC appear to be derived from PC and can be detected using broader cell selection criteria. These CTC may provide information on treatment resistance or escape mechanisms. [Table: see text]
Evaluation of ability of OR51T1 expression to predict primary hormone therapy efficacy among men with hormone-naïve metastatic prostate cancer.
Authors: Mochizuki Taku , Miyoshi Yasuhide , Kawahara Takashi , Yokomizo Yumiko , Hayashi Narihiko , Yao Masahiro , Miyamoto Hiroshi , Uemura Hiroji
Published: February 2018

317

Background: The olfactory receptor gene (OR) superfamily is the largest in the human genome. ORs are expressed not only in the neurons of the olfactory epithelium, but also in various other tissues in which their functions are largely unknown. We here investigated OR51T1 expression as a potential biomarker for predicting primary hormone therapy efficacy among men with metastatic hormone-naïve prostate cancer (mHNPC). Methods: Sixty-nine men with bone metastatic HNPC diagnosed from 2006 to 2015 were enrolled in this retrospective study. All patients had received hormone therapy as first-line treatment. Prostate cancer tissue obtained by needle biopsies before treatment were immunohistochemically stained for OR51T1. Correlations between the baseline clinical factors of age, PSA, Gleason score, T stage, N stage, extent of disease on bone scan (EOD), OR51T1 expression and primary hormone therapy efficacy (time to castration-resistant prostate cancer [CRPC]) were investigated by multivariate analysis using the Cox proportional hazard model. Continuous variables were classified as dichotomous. Results: Median age and PSA were 73.7 years and 263 ng/mL, respectively. Distribution of Gleason score of 9–10/6–8, T4/≤3, N1/0, and EOD 3–4/1–2 were 30 (43.5%)/39 (56.5%), 12 (17.4%)/57 (82.6%), 28 (40.6%)/41 (59.4%), and 26 (37.7%)/43 (62.3%), respectively. Median time to CRPC was 13.6 months. Patients with high OR51T1 expression had significantly shorter time to CRPC than those with low expression. Multivariate analysis showed that EOD (3–4 vs. 1–2, HR 3.1, 95% CI 1.6–6.2, p = 0.001) and OR51T1 expression (high vs. low; HR 2.3, 95%CI 1.2–4.4, p = 0.014) were significant biomarkers for predicting time to CRPC. Conclusions: OR51T1 expression could be a potential biomarker for predicting primary hormone therapy efficacy among men with mHNPC.
Advanced age and prostate cancer specific mortality among geriatric patients with metastatic prostate cancer.
Authors: Lu-Yao Grace L. , Kelly William Kevin , Chapman Andrew E.
Published: February 2018

319

Background: Data from clinical trials has shown that octogenarians are at increased risk for prostate cancer specific mortality (PCSM). Patients with significant comorbidities were excluded from the trials; consequently, the findings from clinical trials may not be applicable to the general population. Data on patients age 80+ with metastatic prostate cancer in the general population are limited. This population-based study assesses PCSM for metastatic prostate cancer patients diagnosed at age 70+. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, identified 418,982 patients diagnosed with prostate cancer at age 70+ between 01/01/2004-12/31/13, of which 12,749 had metastatic prostate cancer. The SEER database covers about 28% of the US population from all racial/ethnic groups. We used Cox proportional hazards (PH) model to calculate cause specific hazard ratio adjusted by age, race, marital status, urban-rural classification, income level, insurance type, primary cancer therapy, stage, and diagnosis period. Results: Of the 12,749 patients, 49.4% of the patients were in their 70's and 8.3% in their 90's+, with 79.1% of patients white and 57.1% married. About 17% of these patients received radiotherapy as their primary cancer treatment. The distribution of M1 subtype is: M1a (4.2%), M1b (68.5%), M1c (22.7%), M1 Not Otherwise Specified (or NOS,4.6%). The median survival for patients with M1 prostate cancer aged 70-79, 80-89 and 90+ were 25, 15, and 7 months, respectively. Compared to patients diagnosed in their 70's, there was 38% and 109% increase in PCSM among those diagnosed at ages 80-89 and 90+ respectively (Table). Conclusions: PCSM increases among geriatric patients with metastatic prostate cancer after accounting for potential confounding factors. Further investigation is needed to shed light on the underlying biological mechanisms. [Table: see text]
Patterns of response to androgen deprivation therapy in younger patients with locally advanced or metastatic prostate cancer.
Authors: Keating Matthew , Giscombe Lisa , Desouza Andre , Mukkamalla Shiva Kumar Reddy , Rathore Ritesh
Published: February 2018

324

Background: Androgen deprivation therapy (ADT) remains a standard of care in the treatment of locally advanced prostate cancer. But thanks to a few key trials (STAMPEDE, CHAARTED, and LATITUDE) reported within the past three years, docetaxel and abiraterone now have roles in extending overall survival in a patient population traditionally treated with ADT alone. These treatments when combined with ADT have been shown to extend overall survival in metastatic hormone-sensitive prostate cancer patients. The role of ADT in relation to other therapies continues to evolve rapidly. We intend to revisit ADT’s longstanding role in prostate cancer treatment using a national cancer database. Our aim is to look beyond traditional standards of care to identify patients more likely to have overall survival benefit from ADT. Are there any subgroups of patients with intermediate or high risk disease that have improved survival outcomes with androgen deprivation therapy, besides patients with localized disease that underwent radiation? Could there be other variables besides PSA and localization of the prostate cancer that should be considered when identifying ADT treatment candidates, or identifying survival trends in these groups? Methods: We are currently analyzing variables present in the National Cancer Database to retrospectively identify predictive factors for overall survival and progression to metastatic castrate resistant prostate cancer in locally advanced prostate cancers treated with ADT. We will evaluate time-to-death from the initiation of ADT and from the diagnosis of metastatic castrate resistant prostate cancer. The following variables in localized, locally advanced, and metastatic prostate cancer will be analyzed with Statistical Analysis Software: age, locally advanced, site-specific metastasis (M1a, M1b, M1c), Gleason score, local treatment (radical prostatectomy or radiation), stage (T, N, and M), prostate lobe (one vs. both; T2a/b vs. T2c), chemotherapy (date, time from M1 stage), comorbidity score, ethnicity, facility type, insurance, and risk groups (low/intermediate/high as per NCCN guidelines).
Treatment and clinical outcomes of very elderly (≥ 80 yrs) metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A single-institution retrospective analysis.
Authors: Caffo Orazio , Kinspergher Stefania , Maines Francesca , Macrini Sveva , Veccia Antonello
Published: February 2018

327

Background: The development of mCRPC is generally observed in senior adults and in the daily clinical practice it is frequent to treat pts ≥ 80 yrs. In this population comorbidities can influence the treatment choices and, consequently, the clinical outcomes. The aim of this retrospective study was to describe management and clinical outcomes in mCRPC pts ≥ 80 yrs treated in the daily clinical practice. Methods: We retrospectively evaluated all mCRPC pts treated in our Institution from 02/2002 to 06/2015 and recorded their medical history, anticancer treatments and survival outcomes. Results: We evaluated a consecutive series of 45 pts aged ≥ 80 yrs: median age was 83 yrs (range 81-90 yrs). At the time of mCRPC development bone, nodal, and lung mets were present in 84%, 60%, and 9% of the cases, respectively; no pts with liver mets were observed. Pain was present 53.3% of the pts, the ECOG PS 2 rate was 17.1%. These baseline characteristics were not statistically different compared to those of the younger counterpart. Most of the elderly pts received docetaxel (78%), although this rate was significantly higher (96%) in the younger population (p < 0.0001); similarly elderly pts received less frequently cabazitaxel (CAB) (2% vs 16%, p = 0.01). On the contrary elderly population received more frequently only new generation hormonal agents [abiraterone (AA) or enzalutamide ENZ)] without any chemotherapy (22% vs 4%, p < 0.0001). The median cumulative overall survival (OS) from the start of the first treatment line for mCRPC was 20.5 mos (compared to 21.1 of younger pts). In the elderly population a significant different median OS was observed by comparing pts who received the new agents [NAs (AA, CAB, ENZ, Radium 223)] e those who did not (22.9 vs 13.0 mos, p = 0.001). Conclusions: Although the limitation due to its retrospective nature, our analysis showed that mCRPC pts ≥ 80 yrs were managed differently than younger ones. Nevertheless, the survival outcomes did not differ from the younger counterpart and also very elderly pts benefitted from the introduction of NAs in the daily clinical practice.
Approaches to shared decision-making for PSA screening in primary care practice.
Authors: Litvin Cara B , Ornstein Steven M. , Nemeth Lynne
Published: February 2018

33

Background: In April 2017, the United States Preventive Services Task Force published a draft statement recommending that clinicians inform men ages 55 to 65 about the potential benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer. The HIT-OVERUSE study is an ongoing 2 year group randomized study in 20 primary care practices to test a practice-based intervention to reduce overuse, including avoidance of routine PSA screening without shared decision making. The purpose of this report is to present qualitative findings about approaches participating practices have adopted to facilitate shared decision-making for PSA screening. Methods: Eleven practices in ten states randomized to the HIT-OVERUSE intervention group have hosted on-site visits for academic detailing and participatory planning and sent two practice representatives to a one day meeting to share ‘best practices.’ Detailed notes from site visits, follow-up emails, and the ‘best practice’ meeting were reviewed to identify strategies adopted by practices to facilitate shared decision-making for PSA screening for prostate cancer screening. Results: All practices adopted at least one strategy to promote shared-decision making for PSA screening. Four practices removed standing orders for routine PSA screening. Four practices educated their clinical staff about the test; three developed scripts for staff to use when asked by patients about the test. Six practices began using patient education handouts about PSA screening. One provider started showing a brief YouTube video with patients, while another practice developed a slide show to show in the waiting room. Most providers in nearly all practices reported modifying their conversation about PSA screening with patients to include some discussion about the benefits and the harms of screening. Conclusions: Primary care practices participating an intervention to reduce overuse have adopted varied approaches to facilitate shared-decision making for prostate cancer screening. While having face-to-face conversations is one approach, other strategies may employ staff or utilize patient education or videos to convey the benefits and harms of screening.