bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for a field effect in early prostate cancer (PCa): Gene expression profiles in normal-appearing prostate tissue (NT) adjacent to tumor (T) as predictors of clinical outcome.
Authors: Klein Eric A. , Falzarano Sara Moscovita , Zhang Nan , Knezevic Dejan , Maddala Tara , Lawrence H. Jeffrey , Cherbavaz Diana B. , Pelham Robert J. , Millward Carl , Lee Mark , Magi-Galluzzi Cristina 
Published: March 2020

5029 Background: We previously identified genes whose expression predicts aggressive PCa (clinical recurrence (cR), prostate cancer death (PCD), adverse pathology) when assessed in histologically heterogeneous tumor foci and in biopsies (Klein ASCO 2012). These results enabled the definition of a multi-gene Genomic Prostate Score (GPS), which has been clinically validated (Cooperberg AUA 2013). There is interest regarding a possible field effect in PCa, i.e. molecular alterations throughout the gland that may influence PCa development. We conducted exploratory analyses to evaluate gene expression, including GPS, in adjacent normal-appearing tissue (NT) for prediction of cR and PCD. Methods: Cohort sampling was used to select 127 patients with and 374 without cR from 2,641 patients treated with RP for T1/T2 PCa. Expression of 732 genes was measured by qRT-PCR separately in T and NT (defined as > 3 mm from T) specimens. GPS (0-100 units) was determined using the genes and algorithm from the validation study. Analysis used Cox proportional hazards models and Storey’s false discovery rate (FDR) control. Results: 410 evaluable patients had paired T and NT. Of the 405 genes which were predictive of outcome in T (FDR < 20%), 289 (71%) showed similar but weaker effects in NT. 47 genes were associated with cR in NT (FDR < 20%), of which 34 also concordantly predicted cR in T (FDR < 20%). GPS assessed in NT significantly predicted time to cR (HR/20 units = 1.8; 95% CI: 1.3-2.4; p< 0.001) and PCD (HR/20 units = 1.9; 95% CI: 1.2-3.0; p = 0.005) but was less predictive than GPS in T (HR/20 units = 4.8 for cR; 95% CI: 3.7-6.2; p < 0.001 and HR/20 units = 6.9 for PCD; 95% CI: 4.4-10.7; p < 0.001). The strongest components of GPS in predicting cR and PCD in NT were stromal response and androgen signaling genes (p < 0.05); proliferation and cellular organization genes did not consistently provide a significant contribution in NT. Conclusions: These data indicate that gene expression profiles, including GPS, can predict outcome in NT, albeit more weakly than in tumor. These findings suggest that there is an underlying field effect associated with the development of aggressive PCa.
Pain analyses from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases.
Authors: Nilsson Sten , Sartor A. Oliver , Bruland Oyvind S. , Fang Fang , Aksnes Anne-Kirsti , Parker Chris 
Published: March 2020

5038 Background: Bone metastases (mets), present in > 90% of patients (pts) with CRPC, may cause severe pain. In a phase 2 dose-response study with a single injection of Ra-223, pain response was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase 3 ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n = 614; placebo, n = 307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR = 0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The Cox proportional hazards model was used to analyze time to initial opioid use and time to EBRT. Pts with no opioid use at baseline were included in the pain analyses. All pts were included in the analysis for the prespecified endpoint time to EBRT. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Pain-related QOL was analyzed based on the sum of 4 questions within FACT-P prostate cancer subscale (PCS) (Cella 2009) using ANCOVA. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer with Ra-223 vs placebo (HR = 0.670; 95% CI, 0.525-0.854). Despite a longer observation time, fewer Ra-223 pts (50%) than placebo pts (62%) reported bone pain as an AE. At baseline, 269 Ra-223 pts and 139 placebo pts did not use opioids. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38%, compared to placebo (HR = 0.621; 95% CI, 0.456-0.846). Fewer Ra-223 pts (36%) than placebo pts (50%) required opioids for pain relief. The QOL pain score indicated reduced pain for Ra-223 pts relative to placebo pts at week 16 (P = 0.001). Ra-223 pts had significant pain reduction relative to baseline at weeks 16 (P < 0.001 ) and 24 (P = 0.001). Conclusions: These results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in CRPC pts with bone mets. Clinical trial information: NCT00699751.
A randomized phase II study of cediranib (CED) alone versus CED plus dasatinib (DAS) in patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Spreafico Anna , Chi Kim N. , Sridhar Srikala S. , Smith David C , Carducci Michael Anthony , Kavsak Peter , Wong Tracy S , Wang Lisa , Ivy S. Percy , Mukherjee Som Dave , Kollmannsberger Christian K. , Hotte Sebastien J. 
Published: March 2020

5039 Background: Activation of the Vascular Endothelial Growth Factor Receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of CRPC in preclinical models. CED and DAS are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of CED (Karakunnel et al ASCO 2009) and DAS (Yu et al Urology 2011) in CRPC have shown single agent activity. Methods: Docetaxel-preteated CRPC pts were randomized to arm A: CED alone (20 mg/day) vs arm B: CED (20 mg/day) plus DAS (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12 week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results: 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles = 4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A vs 18 % in arm B (p = 0.03). Median PFS in months (arm A vs B) was: 5.2 vs 2.6 (95% CI: 1.9-6.5 vs 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in both arms A and B. Conclusions: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in pts with CRPC. Clinical trial information: NCT01260688.
Use of bone scans during initial prostate cancer (CaP) workup, downstream procedures, and associated Medicare costs.
Authors: Falchook Aaron David , Salloum Ramzi George , Hendrix Laura H. , Chen Ronald C. 
Published: March 2020

5040 Background: Bone scans are not recommended in the routine workup for patients with apparent low and intermediate risk CaP. We quantified the use of bone scans in low and intermediate risk patients, uses of other imaging and procedures after the bone scan, and costs to Medicare. Methods: Patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed with CaP from 2004 to 2007 were included. PSA, Gleason score and clinical T stage were used to define D’Amico risk categories. Patients with metastatic disease were included because the decision to order a staging bone scan for patients with apparent low and intermediate risk cancers occurs before knowledge about metastasis. We report use of bone scans from the date of diagnosis to the earlier of treatment or 12 months. In patients who received bone scans, we report use of X-ray, CT, MRI, and bone biopsy following bone scan to the earlier of treatment or 12 months. Cost was estimated using Medicare reimbursement rates. Results: 28% and 47% of patients with apparent low- and intermediate-risk prostate cancer received a bone scan (Table); <1% of these patients were found to have metastatic disease after work-up. A high proportion of patients had other imaging studies or biopsies after bone scan. For low and intermediate risk patients, the combined cost to Medicare of bone scan, X-ray, and bone biopsy as part of initial workup is estimated at $11,000,000 per year. The cost from CT and MRI after bone scan costs Medicare approximately $15,400,000 per year. Conclusions: Overuse of bone scans is common in workup of apparent low and intermediate risk CaP, even with an almost 0% risk of metastatic disease. X-rays, bone biopsies, and perhaps additional scans such as CT and MRI may result from bone scan findings, which are mostly false positives for these patients. These unnecessary procedures are costly to Medicare. [Table: see text]
Value of cell cycle progression (CCP) score to predict biochemical recurrence and definitive post-surgical pathology.
Authors: Schlomm Thorsten , Sangale Zaina , Lanchbury Jerry S. , Gutin Alexander , Reid Julia E. , Graefen Markus , Haese Alexander , Tennstedt Pierre , Steurer Stefan , Sauter Guido , Stone Steven 
Published: March 2020

5043 Background: Prostate cancer (PCA) has a highly variable natural history and better tools are needed to more appropriately match treatment to a patient’s risk of progression. A prognostic mRNA expression signature composed of genes involved in cell cycle progression (CCP) has been previously developed. Here, we tested the utility of this signature to predict biochemical recurrence (BCR) and definitive post-surgical pathological stage. Methods: The eligible patient population was treated for PCA by radical prostatectomy at a single high volume center (2005-2006). We randomly selected 390 patients for the study. From each patient we prepared a ‘simulated biopsy’ by removing a tissue cylinder (0.6mm) from the post-surgical FFPE block containing the largest tumor foci. 249 patients remained eligible for analysis after excluding patients for either insufficient tumor in the biopsy, poor quality molecular data, or receiving neoadjuvant therapy. The median follow-up time for patients who did not recur was 60.8 months. 46 patients experienced BCR. CCP scores were generated as in previous studies. Cox PH models and logistic regression were used to evaluate CCP associations with outcome. Results: The CCP signature was a highly significant univariate predictor of BCR (HR=2.03; 95%CI: 1.48-2.79; p=3.1x10-5). After adjusting for clinical parameters including biopsy Gleason and PSA, the hazard ratio for CCP score remained significant (HR=1.6; 95%CI: 1.15-2.24; p=0.0068). In a multivariate model including PSA, biopsy Gleason, and clinical stage, CCP score was also an independent predictor of pathological stage (pT2 vs. pT3, p=0.029). In this analysis, PSA was the most predictive variable, but CCP score and clinical stage also provided important and non-redundant information. Conclusions: The CCP score has predicted PCA outcomes in multiple patient cohorts and different clinical settings. In this study, we have extended the demonstrated clinical utility to a modern patient cohort from Europe, and for the first time, provided evidence that the score can be used to predict definitive post-surgical tumor stage. The CCP expression score is an emerging and important component in evaluating PCA prognosis.
ASP9521, a novel, selective, orally bioavailable AKR1C3 (type 5, 17ß-hydroxysteroid dehydrogenase) inhibitor: In vitro and in vivo characterization.
Authors: Kikuchi Aya , Enjo Kentaro , Furutani Takashi , Azami Hidenori , Nimi Tatsuya , Kuromitsu Sadao , Kamiyma Yoshiteru 
Published: March 2020

5046 Background: Aldo–keto reductase 1C3 (AKR1C3), also known as type 5, 17β-hydroxysteroid dehydrogenase, is reported to be highly expressed in human normal prostate and prostate cancer (PC) and the expression increases along with increasing malignancy or grade of PC. Since AKR1C3 converts the adrenal androgen, androstenedione (AD) into testosterone (T), combination with a GnRH analogue and AKR1C3 inhibitor would be expected to provide total androgen blockade in the treatment of castration-resistant prostate cancer (CRPC). We obtained a lead compound having a non-steroidal scaffold by high throughput screening (HTS) approaches for targeting enzyme activity of AKR1C3. After optimization of the lead compound, we found ASP9521 as a potent, selective, and orally bioavailable AKR1C3 inhibitor. Methods: The inhibitory effect of ASP9521 on enzymatic conversion from AD to T by AKR1C3 was evaluated in vitro, and in CWR22R xenograft models. Effect of PSA production and proliferation on LNCaP cells stably expressing AKR1C3 was examined. Pharmacokinetics in various animals were also investigated. Results: ASP9521 showed potent inhibitory effect on enzymatic conversion from AD to T by both human AKR1C3 and cynomolgus monkey homologues in a concentration-dependent manner, with IC50 values of 11 and 49 nmol/L, respectively ASP9521 suppressed both AD-dependent PSA production and cell proliferation in LNCaP cells exogenously expressing AKR1C3 in vitro. The bioavailability of ASP9521after oral administration of 1mg/kg were 30% and 78% in rat and dog, respectively. Furthermore, ASP9521 single oral administration of 3 mg/kg suppressed AD-induced intratumoral T production in CWR22R xenografted castrate nude mice, and this inhibitory effect was maintained for 24 h. In addition, ASP9521 was rapidly eliminated from plasma after oral administration while its intratumoral concentration remained high in tumors expressing AKR1C3. Conclusions: These preclinical in vitro and in vivo data are consistent with a potent inhibition of 17β-hydroxysteroid dehydrogenase. The results suggest that ASP9521 should be investigated further to elucidate its role as treatment for PC.
A phase I dose-escalation trial of AEZS-108 in taxane- and castration-resistant prostate cancer (CRPC).
Authors: Pinski Jacek K. , Schally Andrew V. , Tsao-Wei Denice D , Dorff Tanya B. , Groshen Susan G. , Xiong Shigang , Quinn David I. , Tai Yu-Chong , Engel Juergen , Liu Stephen V. 
Published: March 2020

5062 Background: The receptor for luteinizing hormone releasing hormone (LHRH-R) is highly expressed on CRPC cells and is a potential therapeutic target. AEZS-108 is an LHRH-cytotoxic hybrid that covalently couples an LHRH agonist with doxorubicin. We report the completed Phase I trial of AEZS-108 in men with taxane-resistant CRPC. We explored visualization of AEZS-108 internalization into circulating tumor cells (CTCs) exploiting the auto-fluorescence of doxorubicin and also tested LHRH-R expression on CTCs. Methods: This was a dose escalation Phase I trial in men with taxane-resistant CRPC to confirm the dose established in a phase I trial in women. Standard 3+3 design was used with planned expansion at the MTD to ensure 6 patients received 2+ courses without DLT. Eligibility criteria included progression of disease despite prior LHRH agonist and taxane therapy. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity. The primary endpoint was safety. CTCs were captured with a novel slot microfilter and identified by PSA and DAPI staining. AEZS-108 internalization was visualized by fluorescence microscopy. Results: Eighteen men with a median of 2 prior chemotherapy regimens (range 1-5) and a median PSA of 106.4 ng/mL (range 8.4-1624.0) enrolled from November 2010 to August 2012. The dose was escalated from 160 mg/m2 to 210 mg/m2 then to 267 mg/m2. There were 2 DLTs in the 7 men receiving 267 mg/m2 (grade 4 neutropenia), prompting de-escalation to 210 mg/m2 where 1 of 8 men experienced a DLT (grade 4 neutropenic fever), establishing 210 mg/m2 as the MTD. Significant non-hematologic toxicities included a case of grade 3 nausea. No cardiotoxicity was seen on serial evaluation and 6 patients completed 6 cycles. Internalization of AEZS-108 was consistently visualized in CTCs 1-3 hours after dosing. Maximal PSA response was stable or decreased in 8 of 18 men. Conclusions: The MTD of AEZS-108 in men with taxane-resistant CRPC is 210 mg/m2, which is below the MTD reported in women with refractory endometrial, ovarian and breast cancer. The activity of AEZS-108 was promising in this heavily pretreated population. The Phase II portion is currently accruing. Clinical trial information: NCT01240629.
Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial.
Authors: Vogelzang Nicholas J. , Helle Svein Inge , Johannessen Dag Clement , O'Sullivan Joe M. , Garcia-Vargas Jose E. , O'Bryan-Tear C. Gillies , Shan Minghua , Parker Chris 
Published: March 2020

5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 262; Pbo, n = 133); 526/921 (57%) received pD (Ra-223, n = 352; Pbo, n = 174). Median ages were 74 y (npD) and 69 y (pD). In pts with npD, median OS was 16.1 mo in the Ra-223 group vs 11.5 mo in the Pbo group (HR = 0.745; 95% CI, 0.562-0.987; p = 0.039). In pts with pD, median OS was 14.4 mo vs 11.3 mo in the Ra-223 and Pbo groups, respectively (HR = 0.710; 95% CI, 0.565-0.891; p = 0.003). Overall, there was a low incidence of myelosuppression. Incidences of neutropenia and thrombocytopenia were higher in pts with pD vs pts with npD. Conclusions: Ra-223 significantly prolonged OS and had a highly favorable safety profile in CRPC pts with bone mets, regardless of whether they had pD or npD. pD pts had a slightly increased rate of grade 3 and 4 bone marrow suppression with Ra-223. Clinical trial information: NCT00699751. [Table: see text]
Denosumab and zoledronic acid treatment in patients with genitourinary cancers and bone metastases.
Authors: Costa Luis , Fizazi Karim , Saad Fred , Brown Janet Elizabeth , Von Moos Roger , Oudard Stephane , Sternberg Cora N. , Ganju Vinod , Miller Kurt , Wang Huei , Maniar Tapan , Braun Ada 
Published: March 2020

5079 Background: Phase III trial results showed that denosumab is superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with cancer and metastatic bone disease (Lipton et al; 2012, Eur J Cancer). Genitourinary (GU) cancers are some of the most commonly diagnosed cancers worldwide. We now compare the efficacy and safety of denosumab (DMAb) or ZA in a subgroup analysis of patients with GU cancers enrolled in the pivotal phase III trials. Methods: Patients were randomized 1:1 to receive DMAb (120 mg, SC) or ZA (4 mg, IV, adjusted for renal function) every 4 weeks. Daily calcium and vitamin D supplements were strongly recommended. Time to 1st on-study SRE, using a Cox proportional hazards model, time to 1st and subsequent on-study SRE, using the Anderson-Gill model, and safety were evaluated for the GU subgroup in an ad hoc analysis. Results: 2,128 patients (1,052 DMAb; 1,076 ZA) had GU cancers (prostate = 1,901, renal = 155, bladder = 63, and transitional cell = 9). DMAb significantly delayed the time to 1st on-study SRE by 4.0 months compared with ZA (20.7 months vs 16.7 months) in patients with GU cancers (Table). DMAb also significantly delayed the time to 1st and subsequent on-study SRE. Time to disease progression and overall survival were similar between treatment groups. Adverse events (AEs) and serious AEs were reported by similar percentages of patients in both groups (AEs: 96.9% denosumab, 96.8% ZA; serious AEs: 62.8% denosumab, 60.2% ZA). 14.6% of DMAb pts and 15.9% of ZA pts had a renal AE. Hypocalcemia was reported for 12.9% of DMAb patients and 6.2% of ZA patients. There was no significant difference in the incidence of positively adjudicated osteonecrosis of the jaw between the DMAb (2.2%) and ZA (1.6%) groups (p=0.34). Conclusions: Among patients with GU cancers and metastatic bone disease, DMAb was superior to ZA in preventing SREs. Clinical trial information: NCT00330759 and NCT00321620. [Table: see text]
Sera cytokine levels to predict survival in men with progressive castration-resistant prostate cancer.
Authors: Subudhi Sumit Kumar , Heller Glenn , Danila Daniel Costin , Anand Aseem , Lacuna Kristine Peregrino , Samoila Aliaksandra , Fleisher Martin , Scher Howard I. 
Published: March 2020

5083 Background: Serum cytokines have been proposed as immunologic biomarkers of clinical responses based on their role in tumor biology. Recently, two whole blood mRNA signatures, which included immunomodulatory gene transcripts, were found to be predictive of survival in CRPC. This study explores serum cytokines, measured with analytically valid assays, as prognostic biomarkers in CRCP. Methods: Serum was collected from 75 progressive CRPC patients treated at MSKCC. A panel of 10 cytokines (M-CSF, IFN-γ, TNF-α, IL-1 β, IL-4, IL-5, IL-6, IL-10, IL-12 and IL-13) was measured in a CLIA-certified laboratory by clinically validated ELISAs. To create a risk group classification based on the 10 cytokines, a regression tree methodology was used with the intent to maximize the survival differences between risk groups. In addition to the cytokine risk groups, PSA, LDH, albumin, hemoglobin and CTC enumeration were also independently prognostic. The Cox model was developed to determine the factors that jointly predicted survival. The concordance probability estimate (CPE) was used to determine the discriminatory power of this model. Results: Among the 10 cytokines, M-CSF (stimulates monocytes and macrophages) and IL-10 (suppresses T-cell-mediated anti-tumor responses), were most predictive of overall survival in a 3 risk-group model. The relative risk for log CTC was 1.78 (95% CI 1.43 – 2.21). The combination of the cytokine risk groups and CTC enumeration provided the best discriminatory power for predicting survival, yielding a discrimination index measured by the CPE equal to 0.77 (se = 0.03). Conclusions: A risk group classification, based on two serum cytokines, M-CSF and IL-10, and log CTC measured by analytically valid assays, predicted survival in patients with progressive CRPC. These cytokines may reflect the biology within the tumor microenvironment, and may also serve as biomarker for clinical benefit. Independent validation in a similar cohort of patients is ongoing. [Table: see text]