bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of decipher test on adjuvant treatment decision-making among men with high-risk pathology at radical prostatectomy: Results from a multicenter prospective PRO-IMPACT study.
Authors: Gore John L. , du Plessis Marguerite , Santiago-Jimenez Maria , Yousefi Kasra , Thompson Darby , Chen David , Clark William , Franks Michael , Karsh Lawrence Ivan , Kibel Adam S. , Kim Hyung Lae , Lane Brian R. , Lotan Yair , Lowrance William Thomas , Maroni Paul , Perrapato Scott David , Trabulsi Edouard John , Waterhouse Robert J. , Davicioni Elai , Lin Daniel W.
Published: March 2017

24

Background: The decision to provide adjuvant therapy to men with high risk pathology after radical prostatectomy (RP) is confounded by tremendous uncertainty. We prospectively evaluated the impact of the Decipher test, which predicts metastases after RP, on men and providers decision quality. Methods: 150 adjuvant pts were enrolled by 43 urologists from 19 practices. Pts with pathologic T3 stage or positive surgical margins (SM+) after RP were included. Participating physicians provided a treatment (Tx) recommendation before and after exposure to Decipher test results. Pts completed validated surveys on health-related quality of life, decisional conflict, and PCa-related anxiety. Results: Median patient age at RP was 64 years; 67% and 50% had pT3 and SM+ pathology, respectively. Decipher classified 46%, 22% and 32% of men as low-, intermediate- and high-risk, respectively. Pre-Decipher, observation was recommended for 89%. Post-Decipher, 18% (95% CI 12-25%) of Tx recommendations changed. Men’s Decisional Conflict Scale (DCS) scores decreased (indicating higher decision quality) after exposure to Decipher results (median DCS pre-Decipher 25 [IQR 8-44], median DCS post-Decipher 19 [IQR 2-30], p<0.001), with greatest decreases in the subdomains of decision uncertainty and decision support. Low-risk Decipher results experienced a trend toward decreased PCa-specific anxiety (p=0.13) and a significant reduction in fear of PCa recurrence (p=0.02). Physicians’ median DCS scores decreased from 32 [IQR 28-36] to 28 [IQR 12-42] (p<0.001). Decipher results were associated with the decision to pursue ART in an MVA analysis (OR 1.48; 95% CI 1.19-1.85, p<0.001). Conclusions: Observation is the predominantly prescribed management strategy for men with high risk features at RP. Knowledge of Decipher results was associated with Tx decision-making: men at low risk for metastasis had higher rates of observation recommendations and men at high risk had higher rates of ART recommendations. Decision quality was improved and PCa-specific anxiety was decreased for men exposed to Decipher results. Clinical trial information: NCT02080689.
Charlson Score as prognostic factor in patients with castration-resistant prostate cancer.
Authors: Jankilevich Gustavo , Gennari Luciana , Salazar Matias , Graziano Claudio , Saravia Eduardo , Belinky Javier , Rey Horacio , Chirino Daniel
Published: March 2017

242

Background: Tumor stage, Gleason score, PSA, Performance Status have been identified as important predictors of survival in prostate cancer. The Charlson Comorbidity Index (CCI) is a validated score used to stratify patients according to comorbidities. To evaluate the prognostic role of CCI in patients with CPRC. Methods: A retrospective study based on an analysis of medical records of 212 patients with CRPC treated at Durand Hospital between 2010-2015. The CCI was calculated for each patient and a correlation with overall survival was performed. Statistical analysis included univariate analysis and multivariate analysis (Cox regression). Patients were stratified according CCI ≤ 7.6 or ≥ 7.6. Survival analysis was performed using the Kaplan-Meier curve. Results: We analyzed records of 212 patients with prostate cancer, of which 59 were resistant to castration. Median age 69 years, the PFS with androgen blockade was 32.4 months. Patients with CPRC 54% perform chemotherapy as first-line treatment of castration resistance and 46% performed treatment of hormonal manipulation (Enzalutamide or Abiraterone Acetate). Median overall survival of patients with CCI < 7.6 was 75 months versus 62 months for those with CCI > 7.6 HR: 1.19 (1.03 to 1.36) p: 0.01. In multivariate analysis the ICC was an independent predictor of mortality in these patients HR: 1.23 (1.03 to 1.48) p: 0.02. (Table 1) CCI ≤ 7,6 was predictor to subsequent lines in CPRC setting. Gleason score, PS were independent predictors of survival. Conclusions: Based on our results we can consider the CCI as an independent predictor of survival in CPRC patients. CCI could be an useful tool useful to select patients in clinical trial and community settings. [Table: see text]
Impact of income in stage IV prostate cancer.
Authors: Ahmed Aabra , Malouff Timothy Dean , Walters Ryan W , Marsh Sydney , Silberstein Peter T.
Published: March 2017

244

Background: There is growing evidence of the impact of socioeconomic status on survival in cancer patients. To our knowledge, this is the largest study to examine demographics and the association between income and survival in patients with stage IV prostate cancer. Methods: Using the National Cancer Database, 50,639 patients diagnosed with stage IV prostate cancer between 2004-2011 were identified. Income was evaluated using the median income of the patient’s zip code. Between-income survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Survival differences were indicated between all income quartiles. Median survival was highest for patients in zip codes with a median income ≥ $63,000 and lowest for patients in zip codes with an income < $38,000 (46.1 months vs. 31.6 months, respectively; p < .001). As such, 41% of patients in zip codes with a median income ≥ $63,000 were alive five years following diagnosis, compared to 31% of patients in zip codes with median income < $38,000. Additionally, compared to patients in zip codes in which the median income was < $38,000, patients in zip codes with a median income ≥ $63,000 had a higher rate of zero comorbidities (81% vs. 76%), a greater percentage of patients living in an area where >93% people have a high school degree (58% vs 1%), and a lower proportion of African Americans (8% vs 41%). Conclusions: Compared to patients with a median income < $38,000, patients in zip codes with a median income > $63,000 had a median survival nearly 15 months longer, had 10% more patients alive after 5 years, and had fewer comorbidities. [Table: see text]
Eligibility criteria requirements and adherence in advanced prostate cancer trials.
Authors: Wong Sarah , Sweeney Christopher , Sridhar Srikala S.
Published: March 2017

245

Background: Eligibility criteria for advanced (metastatic and locally advanced) prostate cancer trials vary between trials and are specific to the therapy evaluated, and may not represent the general population. This reduces comparability between studies, generalizability of results, and may contribute to high screen failure rates (~25%). In this study, we aimed to better understand the eligibility criteria across trials and adherence to eligibility criteria. Methods: We compared eligibility criteria between trials and collected baseline demographics to assess for adherence to criteria for 13 phase III advanced prostate cancer trials published from 1999-2016. Results: Disease characteristics, age, performance status, tumor markers, and most hepatic, renal, and hematological criteria were consistent across trials. However, discrepancies in hemoglobin, absolute neutrophil count, glomerular filtration rate (GFR) and bilirubin criteria were observed (Table). Overall, 8/13 trials included patients that did not meet criteria but were analyzed by intent-to-treat. Criteria that were not followed included: hemoglobin and albumin (lower than permitted); while testosterone, serum creatinine, pain scores, and ECOG performance status were higher (more unwell) than permitted. Conclusions: Specific eligibility criteria vary across the trials, and a number of trials accrued ineligible patients. After accounting for drug-specific criteria, greater standardization of and consideration of general population for eligibility criteria is needed to improve homogeneity of trial populations across studies, generalizability of results, and possibly reduce screen failure rates in prostate cancer trials. [Table: see text]
ODM-204 a novel dual inhibitor of CYP17A1 and androgen receptor: Early results from phase I dose escalation in men with castration-resistant prostate cancer.
Authors: Fizazi Karim , Jones Robert Hugh , Massard Christophe , Vjaters Egils , Peltola Katriina Johanna , Nykänen Pirjo , Vuorela Annamari , Oksala Riikka , Pohjanjousi Pasi , Mustonen Mika VJ , Bono Petri
Published: March 2017

246

Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression, various AR mutations and persistent activation of AR signaling axis by residual tissue androgens and other steroids. Inhibiting both the AR and androgen biosynthesis may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and the AR that has shown activity in nonclinical tumor models. Methods: We report early data of the DUALIDES phase I dose escalation part (NCT02344017), in which patients with metastatic CRPC (mCRPC) were enrolled into ODM-204 dose levels of 50, 100, 200, 300, 500 mg twice daily. Data cut-off was Oct 14th2016. Results: In the trial 23 patients with progressive mCRPC received increasing doses of ODM-204. At baseline, the median age of patients was 70 yrs (57-84 yrs), and median PSA was 46.5 ng/mL (0.7-249.6 ng/mL). Median time on treatment was 11.6 weeks (0.3-60.4 wks). Nine (39%) patients continued treatment for more than 12 weeks, and 4 (17.4%) patients were still receiving treatment at the time of data cutoff. ODM-204 was generally well tolerated, and the most commonly reported adverse events (AEs) were fatigue (n = 6, 26%), nausea (n = 6, 26%), decreased appetite (n = 5, 22%,) diarrhea (n = 5, 22%), and vomiting (n = 5, 22%). Two patients discontinued treatment due to an AE. The AUCt and Cmax values of ODM-204 in plasma increased with dose up to 300 mg after a single dose. Steady state values on day 8 were unexpectedly decreased in most patients, especially at higher doses, contrary to what was observed in the nonclinical monkey studies. Further, decreased predose concentrations were observed on day 29. PSA decreases were seen in 7 (30%) patients, and the median decrease was 47% (2-99%). At 12 weeks, 3 (13%) patients had a PSA response ( ≥ 50% reduction from baseline). Conclusions: Although evidence of anticancer activity was provided with ODM-204 in mCRPC, decreasing steady state concentration was observed. Clinical trial information: NCT02344017.
Novel biomarker of specific castration-resistant prostate cancer (CRPC) by exploring the proteome analysis.
Authors: Uemura Hiroji , Arakawa Noriaki , Itoh Yusuke , Kawahara Takashi , Miyoshi Yasuhide , Akiba Shouhei , Ohtake Norihisa
Published: March 2017

247

Background: It is well known that prostate specific antigen (PSA) level has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for the development of castration resistant prostate cancer (CRPC). The aim of this study is to explore novel biomarkers to predict the development of CRPC by using proteomics from secreted proteins from human prostate cancer cells. Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured. Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDDP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDDP, was significantly higher in CRPC than those in BPH and untreated PCa (P < 0.01). ROC analysis also showed that the AUC of GDDP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDDP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDDP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDDP-1 may be a novel biomarker for CRPC. Conclusions: GDDP-1 shows potential as a novel biomarker for CRPC.
Impact of circulating tumor cell (CTC) nucleus size on outcomes with abiraterone acetate (AA) therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gill David Michael , Agarwal Neeraj , Hahn Andrew W. , Johnson Eric , Poole Austin , Carroll Emma , Boucher Kenneth M. , Salama Mohamed E. , Agarwal Archana M.
Published: March 2017

253

Background: CTC enumeration but not CTC morphology has been reported to predict outcomes to treatment in men with mCRPC. Recently Chen JF et. al (Cancer, 2015) showed an association with nuclear size and incidence of visceral disease in metastatic prostate cancer. In this study, we investigate the impact of CTC nucleus size on outcomes in men treated with AA for mCRPC. Methods: In a cohort of men with mCRPC treated with first-line AA, who had CTCs identified by CellSearch (CS) analysis prior to initiating treatment, we retrospectively quantified the nuclear size of CTCs by ImageJ/Fiji 1.46 software and correlated with progression free survival (PFS) on AA. We analyzed with univariate in addition to pre-specified multivariable analysis adjusted for Gleason score and baseline log PSA to assess independent predictive value of CTC nuclear size on PFS. Median PFS was calculated by Kaplan-Meier analysis and p-values were determined from Cox proportional hazards model. Results: 22 men treated with AA for mCRPC were included. Median nucleus size was 23.8 µm. Patients were divided in to 2 cohorts: small nuclear cohort (CTC nucleus size < 23.8 µm) vs large nuclear cohort (CTC nucleus size ≥23.8 µm). There was a non-significant trend towards worsened PFS (5.8 versus 6.8 months) in the larger nuclear size arm (Table). Conclusions: In this cohort of men with CRPC treated with AA, there is a non-significant trend towards decreased PFS associated with larger CTC nucleus size. Data are hypothesis generating and require further interrogation in a larger cohort. [Table: see text]
Patients with metastatic castration-resistant prostate cancer (mCRPC) who are long-term responders (LTR) to the new agent (NA)-based second line: Clinical outcomes and prognostic factors of subsequent treatment with another NA.
Authors: Caffo Orazio , Bria Emilio , De Giorgi Ugo , Tucci Marcello , Biasco Elisa , Fratino Lucia , Rossetti Sabrina , Iacovelli Roberto , Mucciarini Claudia , Zucali Paolo Andrea , Vicario Giovanni , Carrozza Francesco , Sirotova Zuzana , Messina Caterina , Amadio Placido , Maestri Antonio , Sacco Cosimo , Veccia Antonello , Sperduti Isabella , Zagonel Vittorina
Published: March 2017

254

Background: Three NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] are able to significantly prolong their overall survival (OS) after docetaxel failure. A quote of pts can obtain a prolonged disease control over 12 months with a second line NA and it is unclear if a clinical benefit may result from a subsequent treatment with another NA. The present study is aimed to assess the clinical outcomes and prognostic factors of subsequent NA treatment in those pts LTR to a second line NA. Methods: We collected data of pts who received sequentially two NAs after DOC. For each pt we recorded the clinical outcome of treatments received after DOC. We consider as LTR pts without progression over 12 months from the start of the NA second line. We assessed the independent prognostic value of a series of third-line baseline covariates, in terms of progression free survival (PFS) and OS by Cox regression analysis. Results: A consecutive series of 476 mCRPC pts received a NA-based second line: AA (261 pts), CABA (151), and ENZ (64): we identified 116 LTR pts (AA 71 – CABA 28 – ENZ 17). All pts received a subsequent NA-based third line: 27 received AA, 59 CABA, and 30 ENZ. Comparing the third-line outcomes of LTR and no-LTR pts , no statistically significant differences were observed in terms of both biochemical and objective response rate, and PFS, while LTR showed a statistically significant longer OS (median 18 vs 11.4 mos; p< 0.0001). The third line OS was statistically significant different (p = 0.01) according to the sequence adopted (Table). At the multivariate analysis , performance status (PS) and the presence of visceral metastases were independent prognostic factors for PFS in third line, while PSA, PS and lactate dehydrogenase were independent prognostic factors for OS. Conclusions: In our experience, NA-based third line is active also in mCRPC LTR population with highest benefit in sequences with CABA and some factors may help in selecting patients with higher probability of achieving a disease control. [Table: see text]
Short- and long-term outcomes of salvage lymph node dissection in patients with clinically recurrent prostate cancer.
Authors: Gandaglia Giorgio , Fossati Nicola , Stabile Armando , Bandini Marco , Zaffuto Emanuele , Dell'oglio Paolo , Suardi Nazareno , Montorsi Francesco , Briganti Alberto
Published: March 2017

255

Background: Salvage lymph node dissection (sLND) has been proposed to improve oncologic outcomes in nodal recurrence after radical prostatectomy (RP). We aimed at reporting the results of sLND in patients with recurrent PCa limited to the nodes. Methods: 140 patients treated with sLND for nodal recurrence after RP documented by PET/CT scan between 2002 and 2016 were identified. Transfusions, length of stay (LoS), and 30-day complications were analyzed. Biochemical response (BR) was defined as PSA < 0.2ng/ml at 40-day. Clinical recurrence (CR) was defined as positive findings at postoperative imaging. Kaplan-Meier and Cox regression analyses were used. Results: Median age sLND was 66 years. Median PSA at sLND was 2.0ng/ml. Overall, 58.6, 14.4, and 15.0% patients had positive spots in the pelvic, retroperitoneal, and pelvic + retroperitoneal regions. Overall, 19.3, 2.9, and 77.8% patients received a LND in the pelvic, retroperitoneal, and pelvic + retroperitoneal regions. The median number of nodes removed was 27. Overall, 107 (76.4%) patients had positive nodes at sLND. Overall, 10 (7.1%) experienced grade 3-5 complications according to Clavien-Dindo and 12 (11.8%) patients received blood transfusions. Median LoS was 7 days. Median follow-up was 71 months. Overall, 54 (38.6%) patients achieved BR. The 8-year BCR free-survival rate in patients with BR was 44.7%. CR and CMS was observed in 50 and 25 patients. The 8-year CR and CSM-free-survival rates were 43.2 and 66.4%. In the preoperative model, retroperitoneal spots (Hazard ratio [HR]: 1.89; 95% confidence interval [CI]: 1.02-3.69) and the number of positive spots (HR: 1.26; 95%CI: 1.04-1.57) were predictors of CR. In the postoperative model, BR (HR: 0.33; 95%CI: 0.17-0.72), retroperitoneal involvement (HR: 3.48; 95%CI: 1.22-8.19), and the number of positive nodes (HR: 1.03; 95%CI: 1.01-1-06) were predictors of CR. Conclusions: sLND was associated with a low rate of high-grade complications. At 8-year, more than 40% of patients were free from CR. Retroperitoneal involvement and nodal burden were predictors of response. sLND might represent a therapeutic option for selected patients with nodal recurrence after RP.
Genomic architecture of radioresistant prostate cancer.
Authors: Chua Melvin , Holgersen Erle , Sabelnykova Veronica , Salcedo Adriana , Meng Alice , Fraser Michael , Van Der Kwast Theodorus , Boutros Paul Christopher , Bristow Robert G.
Published: March 2017

26

Background: Spatial intra-tumoral heterogeneity of prostate cancer is secondary to genomic diversity and multi-clonality. These unique features potentially promote resistance to treatment. Here, we investigated if clonal selection or adaptation of new clones dominates in prostate cancer at the time of recurrence following radiotherapy. Methods: We identified 11 patients with biopsy-proven multifocal recurrent prostate cancer following radiotherapy. Copy number aberration (CNA) profiling was performed on 33 anatomically distinct tumor foci with 11 matched-normals. 4 cases had matched pre-radiotherapy tumors for CNA profiling to assess for clonality. We evaluated for recurrent gene amplifications and deletions, and determined genomic instability by percent genome aberration (PGA). We also compared these genomic indices against 373 sporadic prostate cancers from the Canadian Prostate Cancer Gene Network. Results: We observed large intra- and inter-patient variation (p <0.001, one-way ANOVA) in PGA scores among the radioresistant tumors. Interestingly, although total CNA counts did not differ between the radioresistant and sporadic cohorts (median = 40, radioresistant vs 33, sporadic, p = 0.20], there was a trend for increased genomic instability in the radioresistant cohort (median PGA = 8.8 vs 4.9, p = 0.059). Spatial resolution of gene-level CNAs revealed the acquisition of CNAs that were both common and non-recurrent in the multi-focal radioresistant tumors, thus suggesting a common clonal origin, with subsequent divergent evolution. Importantly, we observed a mixture of CNAs, including known prognostic genes in prostate cancer, namely NKX3-1, PTEN, TP53, CDKN1B, and CDH1,that was shared between pre-treatment and radioresistant tumors, favoring clonal selection. We also discovered a novel deleted region on Chr3p, consisting of RAD18 and FANCD2, which was uniquely present in the radioresistant tumors. Conclusions: Our novel observations in a small cohort of radioresistant prostate cancers favor the model of clonal selection, as opposed to new-onset tumors. These results support the discovery of biomarkers a priori, and targeted treatment of these radioresistant clones to improve the therapeutic ratio of precision radiotherapy.
Challenges in enrolling to metastatic castration-resistant prostate cancer (mCRPC) studies that require androgen receptor splice variant (AR-V) positivity.
Authors: Schweizer Michael Thomas , Haugk Kathleen , Cheng Heather H. , Maes Jessica L , Dumpit Ruth F , Nelson Peter , Montgomery Robert B. , Plymate Stephen R , Yu Evan Y.
Published: March 2017

264

Background: AR-Vs are truncated androgen receptor (AR) isoforms that lack the ligand-binding domain (LBD) and are associated with resistance to drugs targeting the ligand-AR LBD interaction (e.g. abiraterone [Abi], enzalutamide [Enza]). Preclinical studies have shown that niclosamide, an anthelminticsdrug, is able to overcome AR-V mediated drug resistance. Methods: We are conducting a Phase I dose-escalation study testing high-dose niclosamide in combination with the FDA-approved dose of Enza. Niclosamide is given three-times-daily by mouth at one of the following dose-levels: 500, 1000 or 1500 mg. All patients are required to have mCRPC, have received prior Abi, and have detectable AR-V transcripts in circulating tumor cells (CTC) as determined using the AdnaTest ProstateCancerSelect/ProstateCancerDetect assay. Patients are permitted to start Enza prior to the addition of niclosamide. The primary objective is to assess safety. Niclosamide’s pharmacokinetic profile will also be determined. Results: From December 2015 to October 2016 we screened 14 patients. All patients previously progressed on Enza, with 13/14 patients demonstrating a rising PSA on Enza at screening. Two had previously documented AR-Vs as determined from prior transcript profiling studies; however, only one of these patients was AR-V positive (AR-V5-6) at the time of study enrollment. Of the 12 patients without prior evidence of AR-V, none were found to be AR-V+. All patients (14/14) were positive for actin and 10/14 were positive for full-length AR using the AdnaTest. To date, one patient has completed treatment with high-dose niclosamide. No study drug-related adverse events have been observed. Conclusions: Rates of AR-V positivity have been lower than expected in our cohort of patients that have progressed on Abi and Enza – challenging study accrual. Multicenter studies are needed to confirm rates of AR-V positivity in mCRPC populations. Furthermore, in order to ensure enrollment expectations are met, novel biomarkers (e.g. AR-V status as determined using AdnaTest) should undergo pre-study confirmatory testing within institutions prior to use as enrollment criteria. Clinical trial information: NCT02532114.
Sequencing in metastatic castration-resistant prostate cancer (mCRPC): Updated results of the FLAC International Database.
Authors: Delanoy Nicolas , Angelergues Antoine , Efstathiou Eleni , Gyftaki Revekka , Wysocki Piotr Jan , Lainez Nuria , Gonzalez Iria , Castellano Daniel E. , Ozguroglu Mustafa , Garcia Carbonero Iciar , Flechon Aude , Borrega Pablo , Guillot Aline , Campos Balea Begona , Le Moulec Sylvestre , Esteban Emilio , Munarriz Javier , Barker Claire , Birtle Alison J. , Oudard Stephane
Published: March 2017

267

Background: Optimal sequencing of new androgen-receptor targeted agents (ART) abiraterone and enzalutamide with docetaxel (DOC) and cabazitaxel (CABA) is unknown. In this large retrospective cohort of mCRPC patients (pts) treated with CABA after docetaxel (DOC), we evaluated the impact of 3 different sequences: DOC → CABA (group 1, n = 267) Or DOC → ART → CABA (group 2, n = 183) Or DOC → CABA → ART (group 3, n = 124). Methods: Records of 574 consecutive mCRPC patients were retrospectively collected in 44 centres in 6 European countries (France, Spain, UK, Greece, Poland, Turkey) from August 2012 to July 2016. Disease history and clinical characteristics at initiation of DOC therapy and outcomes were collected. Factors influencing OS were evaluated using multivariate stepwise logistic regression. Results: At DOC initiation, median age was 67 years, 83% of pts were ECOG 0-1, 45.1% had pain and 10.8% had visceral metastases. Median number of DOC cycles was 7 (6 in group 2, 7 in groups 1 and 3). Median number of CABA cycles was 6 (6 in groups 1 and 2, 7 in group 3). Median duration of ART treatment was 5.9 and 4.4 mths in groups 2 and 3, retrospectively. Median OS from first DOC cycle were 30.1, 37.1 and 40.1 mths in groups 1, 2 and 3, respectively. Factors influencing OS are summarized in the table below. Conclusions: Results of this retrospective cohort suggest that patients receiving DOC → CAB → ART show the greatest OS. High baseline PSA, short response to first-ADT and clinical progression of pts are major prognostic factors of OS at DOC initiation. The window of opportunity for chemotherapy should not be missed. [Table: see text]
Long-term androgen deprivation therapy (ADT) with leuprorelin and quality of life in patients with advanced prostate cancer (PCa).
Authors: Hammerer Peter , Manka Lukas , Wirth Manfred
Published: March 2017

268

Background: LHRH analogs are the gold standard for treatment of patients with hormone-sensitive advanced PCa. In this study, we investigated the quality of life (QoL) of PCa patients under long-term treatment with leuprorelin acetate in microcapsules (1, 3, and 6 month depot formulation) for up to 19.8 years. Methods: Observational and retrospective analysis of data from 536 PCa patients treated with leuproreline and 116 patients of a control group (CG, ≥ 77 years of age, > 5 years urological treatment, no cancer, no ADT). Data was collected in 30 German office based urological practices using EORTC questionnaires QLQ-C30 and QLQ-PR25. Results: Mean treatment duration was 8.6 years (range: 4.5 - 19.8 years). Mean age ± SD of PCa patients (79.6 ± 6.3 years) was comparable to CG (80.5 ± 3.1 years), as were body height, weight, BMI, and Karnofsky-Index (88.0 ± 12.7 vs. 88.4 ± 12.0). The general health status (QLQ-C30) was comparable for PCa patients vs. CG: 64.6 ± 20.5 vs. 66.8 ± 20.3; p = 0.3117. Marginal differences were observed regarding physical functioning (73.2 ± 23.1 vs. 78.1 ± 21.0; p = 0.0402) and role functioning (70.6 ± 30.4 vs. 74.4 ± 25.7; p = 0.1648). PCa patients rated fatigue (33.6 ± 25.1 vs. 28.8 ± 23.3; p = 0.0629), dyspnoea (24.0 ± 28.5 vs. 19.6 ± 26.9; p = 0.1307), and insomnia (28.9 ± 32.6 vs. 23.7 ± 27.2; p = 0.0751) slightly worse than CG. As assessed by QLQ-PR25, PCa patients scored lower on sexual activity (12.0 ± 20.6 vs. 23.7 ± 25.7; p < 0.0001) and sexual function (43.3 ± 25.8 vs. 55.9 ± 27.0; p = 0.0067) compared to CG. PCa patients had less urinary tract symptoms (28.2 ± 19.8 vs. 31.2 ± 19.2; p = 0.1472) but stronger symptoms of androgen deprivation (21.4 ± 17.3 vs. 10.8 ± 13.2; p < 0.0001), and they had a higher need of incontinence aids (29.6 ± 34.2 vs. 16.7 ± 20.5; p = 0.0056) – however, 136 of the 536 PCa patients had a prostatectomy. Conclusions: In this study, PCa patients treated with leuprorelin for up to 19.8 years (8.6 years on average) had an overall QoL comparable to an age-matched control group. As expected, sexual activity and sexual function were lower in PCa patients under ADT. Overall, treatment with leuprorelin is a well-tolerated long-term therapy for patients with hormone-sensitive advanced PCa. Clinical trial information: ENA E005(a) / DE-N-LEU-019(a).
Statin inhibits the proliferation of human castration-resistant prostate cancer cells by controlling NFkB-LIN28B-let7 miRNA signaling pathway.
Authors: Jeong Chang Wook , Ku Ja Hyeon , Kim Hyeon Hoe , Kwak Cheol , Kang Minyong
Published: March 2017

269

Background: Although statin use has been associated with improved outcomes in prostate cancer, the molecular mechanism of this action is still unclear. Based on previous findings, we aimed to investigate the potential role of NFkB-Lin28B-let7 miRNA signaling pathway in human prostate cancer, particularly, castration-resistant prostate cancer (CRPC) cells, as a molecular mechanism of statin effect. Methods: Various human CRPC cell lines (PC3, DU145, 22Rv1, C42B) were used in this study. Proliferation of prostate cancer cells were measured by MTT assay and colony formation assay. Lin28B and NF-κB expression were controlled by siRNA transfection and the expression on Lin28 and let-7 miRNA were quantitated using RT-PCR and western blotting. Results: Notably, simvastatin treatment on various CRPC cell lines decreased cell viabilities in a dose dependent manner. It also significantly inhibited cell growth in clonogenic assay. In these CRPC cells, LIN28 gene was highly expressed in mRNa and protein levels. Conversely, micro RNA (miRNA) expressions of let7 family were remarkably downregulated in CRPC cells. By simvastatin treatment, mRNA and protein level of Lin28B were decreased, while let7 miRNA expressions were restored, which was the key finding of the current study. Considering NFkB is the upstream molecule of Lin28B, we found that the double treatment of statin and NF-κB inhibitor (CAPE) resulted in decreased cell viability, Lin28B and cyclin D1 expression, synergistically. Of note, let-7 miRNA levels were restored after simvastatin treatment, and further increased their expression levels by CAPE double treatment. In order to confirm this mechanistic clue, we specifically inhibited Lin28B and NF-κB genes, respectively, resulting in increased cell apoptosis signaling in the Lin28b or NF-κB knock down cells by combined treatment with simvastatin. Conclusions: In conclusion, simvastatin inhibited the cell growth of various human CRPC cell lines by controlling NFkB-LIN28B-let7 miRNA signaling pathway, and therefore; concurrent NF-κB inhibition with simvastatin treatment induce the synergistic anti-cancer effects in human CRPC cells.
Characterization of cancer family history among patients with PCa cancer.
Authors: Ernst Emma M. , Ledet Elisa M. , Schiff Joshua , Lin Shuwen , Garvey Cathryn E. , Sartor Oliver
Published: March 2017

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Background: Family history (FH) is a well-documented risk factor for prostate cancer (PCa). Certain cancers (Ca) are also shown to co-segregate in families. This study evaluated Ca FH in PCa patients (pts) and the impact of FH on clinical covariates. Methods: FHs were collected from 535 PCa pts at Tulane Hospital between 2015 and 2016. Incidence rates of familial Cas were analyzed. Age at diagnosis (dx), Gleason score, and the presence of metastases at any time were documented. Chi-square and the Mann-Whitney U tests were performed to identify correlations between clinical parameters and FH. Results: 435 pts (81.3%) had a Ca FH. 281 pts (52.5%) had ≥2 relatives with Ca. Rates of breast, lung, colorectal, pancreatic Ca, and leukemia FH did not vary between pts diagnosed at ≤55 and those diagnosed over 55. Pts with PCa FH were more likely than pts with no PCa FH to have an age of dx ≤55 (p= 0.0169). Median age at dx was 59 for pts with PCa FH and 64 for pts with no PCa FH. PCa FH did not affect Gleason score or the presence of metastases. Conclusions: PCa, breast, lung, and colorectal were the most common familial Cas reported. Pts with PCa FH were younger at dx than those without PCa FH. Further studies are needed to understand the co-segregation of PCa with other Cas and genetic studies are needed to clarify the mechanisms of these trends. [Table: see text]
A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).
Authors: Bellmunt Joaquim , Kerst Jan M. , Morales Rafael , Vazquez Mazon Federico , Grande Enrique , Medina Ana , Gonzalez Gragera Belen , Rubio Gustavo , Anido Urbano , Fernandez Calvo Ovidio , Gonzalez-Billalabeitia Enrique , van den Eertwegh Alfonsus Johannes Maria , Pujol Eduardo , Perez-Gracia Jose Luis , Gonzalez-Larriba Jose-Luis , Collado Ricardo , Los Maartje , Macia Sonia , De Wit Ronald
Published: March 2017

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Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first line. Vinflunine is EMA approved and used in several European countries. Docetaxel is widely used in second line. Cabazitaxel is a taxane with clinical activity in docetaxel-refractory cancers. A randomised study was conducted to compare its efficacy vs vinflunine. Methods: This was a multicenter, randomised, open-label, phase II/III study, following a Simon’s optimal method with early stopping rules based on an interim futility analysis. The study (NCT01830231) was supported by a research grant from Sanofi. The trial was aiming at superiority of cabazitaxel compared to vinflunine in patients progressing to platinum. ECOG, anemia and liver metastases were stratification factors. The primary objective for the phase II study was overall response rate (ORR), and overall survival (OS) for the phase III. Secondary objectives included safety and progression free survival (PFS). Results: 70 patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Mean age 63 years; 56 (80%) were men. No statistically significant differences were detected between arms for ORR (p=0.26). Three patients (13%) obtained a partial response on cabazitazel (95% CI, 2.7–32.4) and six patients (30%) in the vinflunine arm (95% CI, 11.9–54.3). Median PFS for cabazitaxel was 1.9 months versus 2.9 months for vinflunine (p=0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for OS benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3-4 related adverse events were seen in 41% patients with no difference between arms. The most frequent toxicities associated with cabazitaxel were asthenia, diarrhea, anemia and febrile neutropenia. Conclusions: This phase II/III second line bladder trial comparing cabazitaxel with vinflunine was closed early when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those observed in the phase III. Clinical trial information: NCT01830231.
Subtyping muscle-invasive bladder cancer to assess clinical response to trimodality therapy.
Authors: Efstathiou Jason A. , Gibb Ewan , Miyamoto David Tomoaki , Wu Chin-Lee , Drumm Michael , Lehrer Jonathan , Ashab Hussam Al-Deen , Erho Nicholas , du Plessis Marguerite , Ong Kaye , Bhat Akshay , Mouw Kent William , Davicioni Elai , Shipley William U.
Published: March 2017

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Background: Trimodality therapy with TURBT followed by chemoradiation is an acceptable alternative to cystectomy for muscle invasive bladder cancer (MIBC). Recently, genomic profiling has demonstrated MIBC can be divided into three or more subtypes with differing responses to chemotherapy, suggesting genomic subtype may impact therapeutic response. Here, we explore the utility of genomic information to better select patients for bladder-sparing trimodality therapy. Methods: Transcriptome-wide gene expression profiles were generated for 189 MIBC TURBT samples from patients undergoing trimodality therapy at the Massachusetts General Hospital. Of these, 108 passed microarray QC and 100 had complete clinical information. The patient tumors were classified as basal, basal claudin-low, infilrated luminal or luminal subtype. The subtype and the expression of a number of bladder cancer genes were assessed for their association with need for salvage cystectomy and for overall survival. Finally, transcriptome-wide differential expression analysis was used to explore gene set enrichment in trimodality therapy response groups. Results: Our chemoradiation cohort (n = 108) was classified into the four subtypes: basal (n = 45), basal claudin low (n = 13), infiltrated luminal (n = 17) and luminal tumors (n = 33). Survival analysis (n = 100) showed that patients of the luminal subtype trended to better overall survival, but did not reach significance (HR = 0.63, p = 0.1). Fewer patients with infiltrated luminal tumors (12%) required a salvage cystectomy compared to all other subtypes (34+/-1.5%, p = 0.08). We found high expression of BLACAT1 and NORAD (a lncRNA with a role in genome stability) correlated with worse (p = 0.01) and better prognosis (p = 0.008), respectively. Likewise, patients with high levels of the luminal-associated PPARG showed a significant increase in overall survival (p = 0.0002). Gene set enrichment revealed differential regulation of immune pathways in the trimodality therapy responders relative to the non-responders (p < 0.05). Conclusions: Preliminary data exploring MIBC subtyping suggests the possibility of using genomics to predict response to trimodality bladder-sparing therapy.
Small cell carcinoma of the bladder (SCCB): Clinical, histopathologic, and genomic predictors of clinical outcomes.
Authors: Teo MinYuen , Hao XueLi , Desai Neil , Ostrovnaya Irina , Arora Arshi , Funt Samuel , Gopalan Anuradha , Chen Yingbei , Fine Samson , Bochner Bernard H. , Dalbagni Guido , Taylor Barry S. , Berger Michael F. , Solit David B. , Tickoo Satish , Reuter Victor E. , Bajorin Dean F. , Rosenberg Jonathan E. , Al-Ahmadie Hikmat , Iyer Gopa
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Background: SCCB is a rare, aggressive subtype of bladder cancer. We reviewed our center’s experience in SCCB management and investigated potential markers of clinical outcomes. Methods: SCCB cases were identified and re-reviewed for confirmation by detailed histologic evaluation. A subset of SCCB was sequenced with MSK-IMPACT ( > 279 genes) (Cheng et al J Mol Diagn 2015). Clinical stage, treatment response and proportion of neuroendocrine component (%NE) were correlated with progression-free (PFS) and overall survival (OS), calculated from the time of cystectomy. Distribution of somatic alterations (alts) was compared between responders ( ≤ ypT1pN0) and nonresponders. Results: Between 1985 and 2015, 214 SCCB patients (pts) were identified. Median age was 68 years (range: 38 – 94) and 78% were male. Of 199 pts with sufficient data, 147 (74%) were nonmetastatic (M0) and 52 pts (26%) had metastatic disease (M1). 14 pts did not receive SCCB-directed therapies. Of M0 pts, 108 underwent cystectomy: 71 received neoadjuvant (NAC), 14 received adjuvant, 14 had definitive chemoradiotherapy and 23 did not receive chemotherapy. Of M1 pts, 47 received chemotherapy. Cystectomy only pts were older than NAC pts (76 vs 67 years, p < .01). NAC improved PFS and OS compared to cystectomy only (HR 0.55, p = .04 and HR 0.41, p < .01) although only OS remains significant after adjusting for age (p = .01). For NAC pts, pT0pN0 and ≤ pT1pN0 rates were 38% and 48%, respectively. Responders had superior PFS (HR 0.26 p < .01) and OS (HR 0.32 p = .02). Median %NE was 100 (range: 10 – 100) and did not correlate with NAC response. %NE ≥ 95 is more prevalent among M1 pts (85% vs 68%, p = .04). Genomic data were available for 31 NAC pts (44%). Responders were enriched with alts in ERBB2 (33% vs. 0%, p = .02), PI3K pathway ( PIK3CA, PTEN, AKT1, TSC1, TSC2) (33% vs. 6%, p = .02) and histone acetyltransferases (60% vs. 25%, p = .07). Of 22/31 tumors sequenced with a larger gene set (n = 341), ERCC2 and RBM10 alts were enriched in responders (54% vs. 11%, p = .07) and nonresponders (44% vs. 0%, p = .02), respectively. Conclusions: In SCCB, NAC improves survival and response might be characterized by specific somatic alts. M1 pts had higher %NE but it is not predictive of outcome.
Punctuated evolution of copy-number alterations to define two molecular subtypes of muscle-invasive urothelial carcinoma.
Authors: Faltas Bishoy , Prandi Davide , Tagawa Scott T. , Nanus David M. , Molina Ana M. , Beltran Himisha , Demichelis Francesca , Rubin Mark A.
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Background: Somatic copy-number alterations (SCNAs) are distinct molecular events occurring in muscle-invasive urothelial carcinoma (UC). Defining the biologic role and the timing of SCNAs in UC’s evolution is critical for precision therapy. Methods: To examine whether distinct SCNAs define specific subtypes of UC and characterize the evolutionary dynamics of SCNA acquisition, we conducted whole-exome sequencing (WES) of a discovery cohort of 44 advanced UC tumors and matching germline samples, including 13 pairs of matched primary and metastatic tumors prospectively collected before and after chemotherapy. We queried WES data from 285 UCs from The Cancer Genome Atlas (TCGA) as a validation cohort. We performed a novel in-depth allele-specific copy-number analysis in 2503 cancer genes using the CLONET computational framework, which accounts for tumor ploidy and cellularity to infer the clonal hierarchy of SCNAs. Results: Analysis of SCNAs from tumor pairs within each patient revealed punctuated evolution of SCNAs occurring early in UC’s development followed by minor changes (clonal stasis) throughout the tumor’s lifetime. Two distinct clusters of UCs with strikingly different SCNA profiles in the discovery cohort emerged. Cluster A was defined by diploid copy number background and focal deletions in the 9p21 region (CDKN2A, CDKN2B and MTAP). Cluster B was defined by genome-wide duplications and several enriched amplifications including 1q21.1 (SETDB1 and MLLT11), (P = 0.0002) and 6p22.3 (E2F3), (P = 0.001). TP53 mutations (P = 0.0001) were enriched in the cluster B, consistent with the role of functional p53 as a “guardian of the genome” preventing chromosomal instability. SCNAs clusters A and B were confirmed in the TCGA validation cohort. Cluster A was enriched with tumors belonging to TCGA bladder cancer cluster III (“basal/squamous-like”) (P = 0.02). Conclusions: Using novel allele-specific SCNAs analysis, we define two distinct clusters of UC presenting a framework for understanding this aspect of UC’s biology. In contrast to somatic mutations, SCNAs are clonally static during each tumor’s evolution. This data has important implications for precision medicine for UC.
DNA damage response (DDR) gene mutations (mut), mut load, and sensitivity to chemotherapy plus immune checkpoint blockade in urothelial cancer (UC).
Authors: Galsky Matt D. , Uzilov Andrew V. , McBride Russell Bailey , Wang Huan , Patel Vaibhav G. , Sfakianos John , Wang Li , Akers Nicholas , Iyer Gopa , Solit David B. , Saito Takuro , Castillo-Martin Mireia , Hahn Noah M. , Pal Sumanta K. , Fleming Mark T. , Hauke Ralph J. , Losic Bojan , Gnjatic Sacha , Chen Rong , Bhardwaj Nina
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Background: Somatic mut in DDR genes have been associated with increased sensitivity to cisplatin in UC. Higher mut load has correlated with response to immune checkpoint blockade. We hypothesized that DDR mut result in higher mut load and DDR mut UC may be particularly sensitive to both chemotherapy and immune checkpoint blockade. Methods: Three cohorts were utilized: (1) TCGA UC cohort (n = 389), (2) Mount Sinai (MS) cohort (n = 67) of UC (cystectomy) specimens subjected to targeted exome sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab (GCI) in metastatic UC from which 28/36 enrolled patients (pts) had specimens suitable for whole exome sequencing. DDR mut were defined as somatic alterations in one of 52 genes. Deleterious (del) mut were defined as nonsense, frameshift, splice site, or hotspot point mut. Results: The mut load using all genes in the TCGA cohort, and restricted to the 341 IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between del DDR mut and mut load are shown (Table). In the MS cohort, CD8+cells/mm2 by IHC were higher in tumors with del DDR mut versus no DDR mut (p = 0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative predictive value of a del DDR mut for objective response to treatment was 40.9% (95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 12.6-56.6%), respectively. Median progression-free survival in the GCI cohort was 308 days (95% CI 270-NR) in del DDR mut and 196 days (95% CI 185-372) in others (p = 0.24). Notably, 2/9 pts with del DDR mutations, and with the highest mut loads, achieved complete responses after GCI and are alive without evidence of disease at 2.1+ and 1.8+ years. Conclusions: DDR mut are associated with higher mut load in UC, a high likelihood of response to GCI, and may identify a subset of pts achieving durable disease control. GC plus PD-1/PD-L1 blockade should be explored in DDR mut UC. Clinical trial information: NCT01524991. [Table: see text]