bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a genomic classifier for predicting biochemical failure following postoperative radiation therapy in high-risk prostate cancer.
Authors: Den Robert Benjamin , Feng Felix Yi-Chung , Showalter Timothy Norman , Mishra Mark Vikas , Trabulsi Edouard John , Lallas Costas D. , Gomella Leonard G. , Birbe Ruth C. , McCue Peter , Ghadessi Mercedeh , Knudsen Karen E. , Dicker Adam 
Published: February 2017

10 Background: Radiation therapy (RT) is commonly offered in the post radical prostatectomy (RP) setting, however response varies. We hypothesized that the genomic classifier ([GC] Decipher) score would predict biochemical failure (BF) and distant metastasis (DM) in men receiving post−RP RT. Methods: Under an institutional review board approved protocol, 223 men who underwent post−RP RT at the Kimmel Cancer Center of Thomas Jefferson University for pT3 or margin positive disease from 1990 to 2009 were identified. RNA was extracted from 143 patients with paraffin−embedded specimens and expression quantified from the highest Gleason grade tumor focus using a high−density oligonucleotide microarray. Excluding men who received neo−adjuvant therapy, 139 patients remained for GC calculation. Area under the receiver operating curve (AUC), decision curves, cumulative incidence accounting for competing risks, and multivariable Cox regression analyses were used to assess GC for predicting BF and DM after RT in comparison to nomograms. Results: The AUC of CAPRA-S was 0.67 (95% CI 0.58−0.77) and 0.65 (95% CI 0.44−0.86) for BF and DM, respectively. Integration of GC improved AUC to 0.75 (95% CI 0.66−0.84) and 0.77 (95% CI 0.64−0.91) for BF and DM, respectively. Cumulative incidence of BF at 8 years post-RT was 21%, 48%, and 81% for low (less than 0.4), intermediate (0.4 to 0.6), and high (more than 0.6) GC, respectively (p<0.00001). In multivariable analysis, patients who received RT early (pre−RT prostate-specific antigen [PSA] less than 1 ng/mL) had a BF benefit with a significantly reduced hazard ratio (HR) of 0.32 (95% CI 0.11−0.96, p<0.042). Patients with high GC had an HR of 14.73 for BF (95% CI 4.90−44.31, p<0.00001). Earlier PSA recurrence was observed in patients with high GC score that received salvage compared to adjuvant RT with median BF survival post-RT of 4.67 versus 8.78 years (p<0.04). This held true after adjusting for CAPRA-S score. Conclusions: This is the first validation of the GC in the post−RP RT setting. GC improved risk stratification above clinical classifiers. Patients with high GC received significant benefit from early RT intervention. For those patients with high pre-RT PSA and high GC, exploration of intensified therapy is warranted.
Cohort compassionate-use program (CUP) and early access program (EAP) with cabazitaxel (Cbz) plus prednisone (P; Cbz + P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D): Analysis by age group.
Authors: Malik Zafar , di Lorenzo Giuseppe , Bracarda Sergio , Ardavanis Alexandros , Basaran Mert , Parente Phillip , de Schultz Wito , Saad Fred , van Oort Inge , Gerritsen Winald R. , Antón Aparicio Luis M. , Matus Geoffrey , Hitier Simon , Heidenreich Axel , Bahl Amit 
Published: February 2017

109 Background: Cbz + P demonstrated an overall survival benefit vs mitoxantrone + P in pts with mCRPC in the Phase III TROPIC trial. The CUP (CABAZ_C_05005) and EAP (NCT01254279) (both funded by Sanofi) were established to allow access to Cbz ahead of commercial availability. The programs are also evaluating Cbz safety in a real-world population. Data analyzed by age group (≤75 and >75 years) are presented here. Methods: Expected enrolment across both programs is 1,450 pts from 236 centres worldwide. Pts received Cbz 25 mg/m2 IV Q3W + P 10 mg QD until disease progression, death, unacceptable toxicity or physician/pt decision. G-CSF is administered as per ASCO guidelines. Results: As of May 30, 2012, 1,301 pts have enrolled (≤75 years: 1,061 pts [81.6%]; >75 years: 240 pts [18.4%]). Eastern Cooperative Oncology Group performance status and incidence of visceral metastases were generally balanced between treatment groups. The most frequent reasons for discontinuation were disease progression (46.8%) followed by adverse events (AEs; 24.4%) in pts ≤75 years, and AEs (36.4%) followed by disease progression (31.1%) in pts >75 years. Time from initial diagnosis to inclusion was greater in pts >75 years (median 79.66 months) than in pts ≤75 years (median 53.94 months), but time from mCRPC diagnosis to inclusion was approximately equivalent (>75 years: median 22.6 months; ≤75 years: median 20.94 months). G-CSF use was more frequent in pts >75 years (cycle 1: 62.9% of pts) compared with pts ≤75 years (cycle 1: 52.2% of pts). AEs of clinical concern were more frequent in the older age group (Grade ≥3 AEs: >75 years 64.2%; ≤75 years 54.8%). Grade ≥3 neutropenia was observed in 25.8% of pts >75 years and in 17.0% of pts ≤75 years. Conclusions: We observed several differences between age groups in baseline and on-treatment parameters, suggesting differences in the natural history of mCRPC (faster disease progression in pts ≤75 years than in pts >75 years) and secondary to treatment (AEs more frequent in pts >75 years compared with pts ≤75 years). Clinical trial information: NCT01254279.
Is clinical stage T2C prostate cancer intermediate- or high-risk disease?
Authors: Klaassen Zachary , Singh Abhay A , Howard Lauren , Terris Martha K. , Aronson William J , Cooperberg Matthew R. , Amling Christopher L , Kane Christopher J , Banez Lionel Lloyds , Freedland Stephen J. 
Published: February 2017

110 Background: Clinical stage T2c (cT2c) is an indeterminate factor in the algorithm for prostate cancer (CaP) risk stratification. According to the D’Amico risk stratification and the American Urological Association (AUA) guidelines, cT2c is high−risk, whereas the National Comprehensive Cancer Network (NCCN) and EUA classify cT2c as intermediate−risk. Since determining whether cT2c is intermediate- or high-risk has implications for treatment, it is important to define what exact risk cT2c portends. Thus, we sought to assess whether cT2c tumors, without associated other high−risk factors (cT2c not otherwise specified (cT2c−nos)), behave as intermediate− or high−risk by analyzing biochemical recurrence (BCR) after radical prostatectomy (RP). Methods: We retrospectively analyzed 2,759 men who underwent RP from 1988 to 2011 from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Comparisons in time to BCR between cT2c−nos patients and intermediate−risk (prostate-specific antigen [PSA] 10 to 20 ng/ml or Gleason sum (GS) =7 or cT2b), and high−risk (PSA greater than 20 ng/ml, GS 8 to 10, cT3) patients was performed using log−rank test and Cox proportional hazards analyses. Given changes in CaP, we adjusted for year of surgery (continuous) and to adjust for case mix among centers contributing to SEARCH we included a categorical term for center. Results: A total of 99 men (4%) were classified as cT2c−nos. During a median follow-up of 66 months (IQR: 34−101 months), cT2c−nos patients had similar BCR risk as intermediate-risk (p=0.27), but significantly lower BCR risk versus high-risk patients (p<0.001, Figure). After adjusting for year and center and compared to low-risk disease, the HRs for cT2c−nos patients was similar to those with intermediate-risk (HR 1.90 vs. 2.28). When specifically compared to intermediate-and high-risk patients, and after adjusting for year and center, cT2c−nos patients had outcomes comparable to intermediate−risk (p=0.44), but significantly better than high-risk patients (HR 0.55; 95%CI 0.38,0.78; p=0.001). Conclusions: BCR risk for patients with clinical stage T2c was comparable to men who had intermediate-risk disease and significantly better than men with high-risk CaP. These findings suggest men with cT2c disease should be offered treatment options for intermediate-risk CaP.
A quantitative image analysis model of prostate biopsies for predicting clinical risk in men enrolled in an active surveillance program.
Authors: Khan Faisal M , Fernandez Gerardo , Scott Richard , Lance Raymond S. , Cordon-Cardo Carlos , Klotz Laurence , Donovan Michael J. 
Published: February 2017

111 Background: Quantitative image analysis of the prostate needle biopsy (PNB) has proven to be a robust and predictive platform for prostate cancer (PCa) prognosis. We sought to determine the performance of quantitative metrics in identifying which patients enrolled in an active surveillance (AS) program are most likely to present with significant clinical risk, including subsequent biopsy Gleason grade (GG) upgrading and/or a short (less than 24 month) prostate-specific antigen (PSA) doubling time (PSADT). Methods: One hundred sixty two AS patients (median age 70, 94% cT1-T2a, 85% <=GS6, median PSA 5.9 ng/mL) with overall 8 year median follow up and available diagnostic PNB specimens were analyzed. Computerized image analysis derived quantitative biometric features representing PCa morphology and immunofluorescent (IF) biomarkers from the PNB. Multivariate models predicting either GG upgrading on a subsequent PNB or a PSADT less than 24 months were evaluated. The AUC/concordance index (CI), sensitivity, specificity and hazard ratio (HR) were used to assess performance. Results: Univariate distribution of selective features, notably expression levels of AR and Ki67, were reflective of a low risk cohort.A multivariate model with three quantitative imaging metrics was trained with a CI of 0.77. Men at high risk within 24 months of the PNB were identified with 80% sensitivity and 73% specificity, HR of 5.7. The most important feature measured the relative proportion of tumor epithelial nuclei that were both Androgen Receptor and alpha-methylacyl-CoA racemase positive. The other two features were morphological assessments of epithelial cellular area compared to luminal area. Of note, clinical features such as age, GG and PSA were not selected in competition with the imaging metrics. Conclusions: Quantitative image analysis of morphology and IF biomarker expression in the PNB outperformed standard clinical features in a multivariate model to accurately predict which AS patients are at risk for Gleason upgrading and/or a shortened PSADT. Identifying such patients may prove beneficial in the primary treatment decision process.
Predictive factors associated with Gleason score underestimation on prostate biopsy in a monocentric cohort of 3,062 patients treated by mini-invasive radical prostatectomy.
Authors: Audenet Francois , Rozet Francois , Resche-Rigon Matthieu , Bernard Rémy , Lizee Daphne , Lacarriere Emeric , Prapotnich Dominique , Sanchez-Salas Rafael , Galiano Marc , Barret Eric , Cathelineau Xavier 
Published: February 2017

113 Background: Gleason score (GS) on prostate biopsy is a critical factor in the initial evaluation of patients with prostate cancer (PC), and can lead to different therapeutic options. However, it may differ from the final pathologic result on radical prostatectomy (RP) specimen in up to 30 to 50% of cases. The aim of this study was to explore the clinicopathological features and outcomes associated with Gleason upgrading from biopsy to RP in a contemporary cohort and to develop an upgrading risk tool available preoperatively. Methods: Using a monocentric prospectively maintained database, we included 3,062 patients who underwent minimally invasive RP between 2005 and 2012. All biopsies and surgical specimens were analyzed by dedicated pathologists. We explored clinicopathological features and outcomes associated with Gleason upgrading from biopsy to RP. A multivariate logistic regression was used to develop a nomogram predicting upgrading for Gleason 6 PC. Results: The median number of biopsy cores was 12 (10 to 13). The GS on biopsy was respectively 6, 7, and more than 7 in 58.5%, 37.4%, and 4.1%. The GS on biopsy was consistent with the specimen in 42.7%. The GS was upgraded in 37.8% and the primary pattern was upgraded in 14.1%. Patients upgraded from biopsy Gleason 6 to Gleason 7 on RP had a longer time to biochemical recurrence than those with Gleason 7 on both biopsy and RP, but a shorter time to BCR than those who remained Gleason 6 on RP (p<0,0001). On multivariate analysis, variables predicting upgrading for Gleason 6 PC were: age (p=0.0014), abnormal digital rectal examination (p<0.0001), prostate-specific antigen density (p<0.0001), percentage of positive cores (p<0.0001) and body-mass index (p=0.037). A nomogram was generated and validated internally. Conclusions: Biopsy GS is misleading in one third of cases. Gleason upgrading from biopsy to PR seems to have consequences on the clinical outcomes. A nomogram using clinicopathological features can be useful to recognize the probability of upgrading in patients with Gleason 6 PC at initial evaluation. This could help to better choose therapeutic options in low-risk PC.
A study of two ODM-201 formulations with a safety and tolerability extension phase in patients with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC).
Authors: Massard Christophe , Tammela Teuvo L. J. , Vjaters Egils , Lietuvietis Vilnis , Bono Petri , Penttinen Heidi , Nykänen Pirjo , Snapir Amir , Mattila Leena , Fizazi Karim 
Published: February 2017

115^ Background: This open phase I trial assessed the bioavailability, and the effect of food on the bioavailability of ODM-201 600mg tablets compared to a 600mg capsule formulation. Efficacy, safety, and tolerability of ODM-201 were studied in the extension period. Methods: The study had two parts: a pharmacokinetic (PK), and a safety and tolerability part. Dosing was 600mg bid with or without food. In the PK part, three single doses of ODM-201 were given over 3 weeks. In the extension part patients could continue treatment until disease progression or until an intolerable adverse event or condition that prevented further dosing of ODM-201. Results: Thirty men with metastatic chemotherapy-naïve castration-resistant prostate cancer (CRPC) were enrolled, the median age was 68. The median prostate-specific antigen (PSA) was 18.2 ng/mL and testosterone 23.1 ng/dL at baseline. Food interaction was observed when ODM-201 formulations were administered after a high fat content breakfast compared to administration at fast. AUC and Cmaxvalues were about 50% lower after fast. Twenty nine patients have completed the 4-week visit. The PSA response rate (50% or more PSA decline) was 86%, with a median PSA decrease of -66% (-96, 5) at week 4 (N=18/21). Most commonly reported adverse events so far are fatigue, abdominal pain, diarrhea, hematuria, and nausea. Conclusions: ODM-201 600mg bid as tablets has comparable PK to capsules used in the phase II ARADES trial. It is well tolerated and has good PSA response in chemotherapy-naïve patients with CRPC . Clinical trial information: NCT01784757.
Preferences for treatment to delay bone metastases (BM) in patients with castration-resistant prostate cancer (CRPC) at high risk of developing BM.
Authors: Qian Yi , Hauber A. Brett , Gonzalez Juan Marcos , Posner Joshua , Mohamed Ateesha F , Tombal Bertrand , Body Jean-Jacques , Gatta Francesca , Arellano Jorge 
Published: February 2017

117 Background: Limited treatments are available for patients with non-metastatic CRPC. Prophylactic treatment may be associated with adverse events (AE). We evaluated patient preferences for a medication delaying bone metastases (BM) with a risk of AE.Methods: UK and Swedish adults with CRPC at high risk for BM (on androgen-deprivation or hormone therapy for ≥ 3 yrs) completed an online discrete-choice experiment with 10 choice questions. Patients were asked if they would prefer to receive a hypothetical prophylactic medication (HPM) with a risk of osteonecrosis of the jaw (ONJ) to prevent BM or to decline HPM thus not receiving any treatment benefit or risk. HPMs were defined by delay in BM (0-23 months) and risk of ONJ (0-9%). The proportion of patients who chose HPM with different combinations of BM delay and ONJ risk was calculated. To further evaluate the impact of BM to patients, time tradeoff was used to assess patients’ willingness to trade off between life years with and without bone complications (i.e., skeletal-related events, including spinal cord compression, surgery or radiation to bone, and pathologic fracture).Results: A total of 201 UK patients and 200 Swedish patients completed the survey. As shown in the table, even a HPM with the lowest level of BM delay (5 months) and the highest level of ONJ risk (9%) was acceptable to the majority of patients in both countries. Furthermore, when asked about the tradeoff between life years with and without bone complications, 52% of UK patients and 26% of Swedish patients were willing to trade off 5 months of survival to avoid bone complications; nearly three-quarters of the patients were willing to trade off 3 months of survival to avoid bone complications. Conclusions: A majority of patients in the UK and Sweden were willing to take HPMs to delay BM, despite a treatment-related risk of ONJ and were willing to trade off 3 to 5 months of survival to avoid bone complications. [Table: see text]
Feasibility of multimodal molecular characterization of the androgen receptor (AR) in circulating tumor cells (CTCs) from patients with castrate-resistant prostate cancer (CRPC).
Authors: VanderWeele David James , Isikbay Masis , Reyes Edwin , Duggan Ryan , Wyche Alicia J. , Stadler Walter Michael , Vander Griend Donald , Szmulewitz Russell Zelig 
Published: February 2017

133 Background: Despite the wealth of agents targeting the androgen receptor (AR) signaling pathway in castrate-resistant prostate cancer (CRPC), emergence of resistance is common. Mechanisms for resistance are diverse and likely include quantitative alterations in AR as well as alterations in nuclear localization. Clinical interrogation of such events is challenged by difficulties in biopsying metastatic sites and limitations in available circulating tumor cell (CTC) platforms. We set out to explore different methodologies of AR interrogation within CTCs. Methods: CTCs and cultured prostate cancer cells were isolated from nucleated blood cells using fluorescence associated cell sorting (FACS) targeting the Epithelial Cell Adhesion Molecule (EpCAM) with CD45 negative selection. In addition to standard immunofluorescence imaging, ImageStreamX spectral flow analysis was used to analyze AR protein expression and nuclear localization. Targeted DNA sequencing and TaqMan copy number evaluation were used for downstream analysis of AR alterations. Patients with highly refractory disease were enrolled for these assay development studies. Results: Thirteen of 15 (87%) patients in an initial feasibility cohort had CTCs isolated for downstream evaluation. Targeted DNA sequencing of as few as 10 C4-2 cells isolated from nucleated blood cells confirmed specificity for prostate cells by identifying a known AR mutation. TaqMan copy number evaluation revealed AR amplification in two out of four evaluable patients. Fluorescence microscopy demonstrated feasibility of AR staining, with 10 of 10 patients exhibiting AR staining above negative control and 50% staining above that of AR+ LAPC4 cells. Though the numeric variability in AR expression using ImageJ software was high, AR protein interrogation with ImageStreamX allowed for more precise evaluation of nuclear localization of the AR revealing that in CRPC patients there can be distinct CTC populations with respect to AR localization. Conclusions: Identifying mechanisms of AR derangement is crucial for the precision management of advanced prostate cancer. CTCs are a promising way to evaluate molecular characteristics of AR in patients with late stage disease.
The effect of prior abiraterone (Abi) treatment on subsequent response to docetaxel in men with castrate resistant prostate cancer (CRPC).
Authors: Schweizer Michael Thomas , Zhou Xian Chong , Wang Hao , Bassi Sunakshi , Carducci Michael Anthony , Eisenberger Mario A. , Antonarakis Emmanuel S. 
Published: February 2017

136 Background: Taxanes are hypothesized to mediate their effect in CRPC, at least in part, by disrupting androgen receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents (e.g., Abi) and Tax. Methods: We retrospectively evaluated Tax efficacy in CRPC patients (N=119) who did (Abi+Tax; n=24) or did not (Tax; n=95) receive prior Abi. To ensure a contemporaneous control group, this analysis only included men who started Tax between 12/2007 (the date we began using Abi at our center) and 5/2013. Univariate and propensity score-weighted multivariable analyses for PSA progression-free survival (PSA-PFS) and all-cause progression-free survival (PFS) were conducted to evaluate the effect of prior Abi on responses to Tax. Results: Men in the Abi+Tax group had a significantly higher risk of progression than those in the Tax group. In univariate analysis, PSA-PFS was shorter in the Abi+Tax group (HR 2.00; 95%CI 1.13–3.52; P=0.016), as was PFS (HR 1.97; 95%CI 1.13–3.41; P=0.016). Median PSA-PFS was 4.1 mo in the Abi+Tax group and 6.3 mo in the Tax group (P=0.014). Median PFS was also shorter in the Abi+Tax group (4.1 vs 6.8 mo; P=0.014). In multivariable analysis, prior Abi treatment remained a predictor of shorter PSA-PFS and PFS (Table). PSA declines ≥50% were also less frequent in the Abi+Tax group (37% vs 63%, P=0.04). Conclusions: Men receiving Abi prior to Tax were more likely to develop progression on Tax (and less likely to have a PSA response) than Abi-naive patients. Cross-resistance between Abi and Tax may limit taxane efficacy in Abi-pretreated patients. [Table: see text]