bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translating Prostate Cancer Working Group 2 (PCWG2) progression criteria into a quantitative response biomarker in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Anand Aseem , Bjartell Anders , Danila Daniel Costin , Martinez Danny Francisco , Edenbrandt Lars , Larson Steven M. , Scher Howard I. , Morris Michael J. 
Published: March 2017

170 Background: PCWG2 radiographic progression criteria, which are associated with survival, rely on lesion counting. There is a need for a fully quantitative assessment of tumor burden as a component of a true response biomarker for mCRPC. Here, we used the bone scan index (BSI) to fully quantitate the increase in skeletal disease burden at each radiographic milestone that constitutes the PCWG2 criteria. Methods: mCRPC patients (pts) from clinical trials using PCWG2 criteria to determine progression (PD) were assessed. Pts were required to have baseline (BL) and at least two follow-up (FU) bone scans. The EXINI automated platform was used to generate BSI at key PCWG2 landmarks: 2+2 criteria for early PD and post flare PD criteria with the appearance of 1 and ≥2 new lesions. Median (M) and Interquartile range (IQR) of the relative change in BSI were calculated to quantify the increase in total tumor burden. Results: A total of 257 pts were assessed, of whom 169 had two or more FU bone scans at 8 or 12 week intervals. Of the total 169 pts, 86 (51%, 95%CI 43-58) met PD by PCWG criteria. 35 (41%, 95%CI 31-51) of 86 pts met the early PD criteria, the remaining 51 (59%, 95%CI 49-69) met PD at subsequent time points after flare period. The ability of the automated platform to reproduce a BSI value, retrieved from the same scan, was highly consistent (100%). The relative BSI increase during the course of meeting PD by PCWG2 is shown in the Table. Conclusions: This is the first quantitative assessment of changes in total tumor burden in pts meeting PCWG2 criteria. Relative changes in BSI can be substantial in meeting the criteria. These data build on the PCWG2 criteria by quantitating the increase both of existing lesions and the contribution of new lesions. We are now assessing the associations with survival that these incremental increases represent. [Table: see text]
Association of Wnt pathway activation with prechemotherapy abiraterone acetate resistance in metastatic castration-resistant prostate cancer (mCRPC) by genome-wide analysis of metastases.
Authors: Kohli Manish , Wang Liguo , Dehm Scott , Hillman David W. , Sicotte Hugues , Gormley Michael , Bhargava Vipul , Ricci Deborah S. , Li Weimin , Tan Winston , Costello Brian Addis , Pitot Henry C. , Dronca Roxana Stefania , Ho Thai Huu , Bryce Alan Haruo , Zhenqing Ye , Vedell Peter T , Barman Poulami , Carlson Rachel , Wang Liewei 
Published: March 2017

175 Background: Genome and transcriptome aberrations associated with primary resistance to abiraterone acetate/prednisone (AA/P) in mCRPC are not known. In a prospective trial (NCT#01953640) we assessed whole-exome and RNA-seq based aberrations in metastases of CRPC stage patients (pts) for identifying markers associated with primary resistance to AA/P. Methods: Whole-exome and RNA-seq of biopsies from metastases was performed followed by analyses for association between genomic aberrations & primary resistance. Primary resistance was defined by progression on AA/P after 12-weeks of therapy(non-responders) using PSA, RECIST, bone scan and symptom criteria (per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders, and also in genes that were differentially expressed between non-responders and responders and a “risk ratio” (RR) was calculated thereof. Results: Between 6/2013 & 8/2015, 92 pts were enrolled of which 82 had complete whole-exome, RNA-seq and 12-week outcome data available for analysis. Median age was 72.5 yrs (IQR: 68.5-78); median PSA-18 ng/ml (IQR: 8.1- 46.6). At 12-weeks 33/82 had progressed. Using the RR of 2 as threshold, we identified 113 and 292 genes that were more frequently mutated in non-responders & responders respectively. Among the 113 genes, OBSCN, ADAM21, LPHN3, DOCK10 ( P = 0.08, RR= inf) & USP42 ( P = 0.16, RR = 5.71) were the top candidates.Gene network analysis revealed that in non-responders, genes involved in the Wnt/β-catenin pathway were frequently mutated and negative regulators of Wnt pathway ( DKK4, SFRP2 & LRP6) were also frequently deleted. Gene expression analyses revealed the expression levels of Wnt/β-catenin pathway inhibitors were significantly reduced while expression levels of cell cycle regulatory genes were significantly increased in non-responders. Conclusions: In this study we observed Wnt/β-catenin pathway activation to be associated with primary AA/P resistance. This finding offers a potential for the development of predictive biomarkers and modulation of targeted pathways to overcome AA/P resistance. Clinical trial information: NCT# 01953640.
Inherited pathologic mutations and family history in patients with prostate cancer.
Authors: Lin Shuwen , Ledet Elisa M. , Schiff Joshua , Ernst Emma M. , Garvey Cathryn E. , Lewis Brian E. , Sartor Oliver 
Published: March 2017

185 Background: In prostate cancer (PCa), germline pathogenic variants have previously been underestimated. PCa patients (pts) with DNA repair defects have a higher percentage of non-PCa family history (FH) with the most common cancers being derived from the breast, GI tract, ovary, pancreas, lymphoma/leukemia. The goal of this study was to evaluate and characterize pathogenic variants detected in PCa patients undergoing both enhanced FH screening and genetic testing. Methods: In this single-institution study, 535 PCa pts from Tulane Cancer Center over the last year underwent enhanced FH screening, and FH of PCa and other cancers were collected. 124 PCa pts including those with both localized and metastatic disease were identified to have a FH that met NCCN guidelines for genetic testing. Genetic testing was done using a commercially available panel (Invitae, San Francisco, CA) of 25-79 cancer-related genes for mutations and selected exonic deletions/duplications. Results: Of the 124 tested pts, 21 pts (16.9%) had ≥ 1 germline pathogenic variant (PV) and 47 pts (37.9%) had ≥ 1 germline variant of unknown significance (VUS). PVs included: BRCA2 (n = 4), BRCA1 (n = 3), CHEK2 (n = 3), MUTYH (n = 3), ATM (n = 2), TP53 (n = 2), MITF (n = 1), NBN (n = 1), PMS2 (n = 1), and (RAD51D (n = 1). Of the 124 tested pts, 68 pts (54.8%) had PCa FH, 68 (54.8%) had breast cancer FH, 22 (17.7%) had pancreatic cancer FH, 16 (12.9%) had ovarian cancer FH, and 37 (29.8%) had both breast and PCa FH. Between the pt groups (those with PVs, VUSs and negative results), there were no differences in FH rates of PCa, breast, pancreatic, or ovarian cancer. There was no significant difference in the age at diagnosis (dx) between the groups or between pts with PCa FH and those without. The median ages at dx were 65 for PV pts, 60 for VUS pts, and 59 for negative result pts. There were no statistically significant differences in initial Gleason score or metastatic disease status in these three groups (p = 0.35 and p = 0.66). Conclusions: In this dataset, FH cannot discriminate between those with and without inherited PV using a broad panel of genes that include those that alter DNA repair. The implications of these findings are broad. [Table: see text]
Evaluation of a multimodal strategy to accelerate drug evaluations in early-stage metastatic prostate cancer.
Authors: O'Shaughnessy Matthew , McBride Sean Matthew , Vargas Hebert Alberto , Touijer Karim A. , Morris Michael J. , Danila Daniel Costin , Laudone Vincent Paul , Bochner Bernard H. , Sheinfeld Joel , Teo MinYuen , Dayan Erica Simone , Bellomo Lawrence P. , Sjoberg Daniel , Heller Glenn , Zelefsky Michael J. , Eastham James Andrew , Scardino Peter T. , Scher Howard I. 
Published: March 2017

187 Background: The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with “high-risk” tumors is no longer practical now that 6 life-prolonging systemic therapies in metastatic castration-resistant prostate cancer are available. New strategies are needed to rapidly evaluate and prioritize regimens for large-scale phase 3 testing. Methods: We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of “no evidence of disease” (NED) was defined by an undetectable PSA with noncastrate levels of testosterone at 20 months. Results: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation. Conclusions: Treatment directed at all sites can eliminate detectable disease in selected patients with metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.
Race, demographics, and socioeconomics as they relate to newly diagnosed metastatic prostate cancer in the United States.
Authors: Matulewicz Richard , Weiner Adam Benjamin , Tosoian Jeffrey J. , Delancey John Oliver , Feinglass Joseph , Eggener Scott E. , Schaeffer Edward M. 
Published: March 2017

195 Background: As screening practices evolve, understanding the influence race, demographics, and socioeconomic status have on the presentation of metastatic prostate cancer (mPCa) can lead to improved diagnostic strategies in high-risk populations. Methods: Men diagnosed with prostate cancer in the National Cancer Data Base from 2004-2013 were identified. Characteristics of men presenting with and without metastatic disease were compared. A four-level composite metric of SES was created using census-based income and education data. Multivariable logistic regression analysis evaluated the association of age, SES, race/ethnicity, insurance status and other relevant covariates with the likelihood of presenting with mPCa. Results: Of the 1,034,754 PCa patients identified, 4% presented with mPCa. Compared to the highest SES group, odds of mPCa increased continuously with decreasing SES. A total of 24% of White men were in the lowest SES while more than half of Black and Hispanic men were in lowest SES category. Black and Hispanic men had higher overall rates of metastases (5.9% and 6.2%; OR 1.47, 95% CI 1.43-1.51 and OR 1.22, 95% CI 1.17-1.28, respectively) compared to Whites (3.6%). Having Medicaid or no insurance increased the odds of being diagnosed with mPCa compared to having other insurance (13% vs 4%; OR 3.91, 95% 3.78-4.05) with all other variables held constant, including SES. Among men in the lowest SES, the effect of SES appeared to be additive to race: OR 1.34 (95% CI 1.29-1.39), OR 2.09 (95% CI 2.00-1.78), and OR 1.66 (95% CI 1.56-1.77), for White, Black, and Hispanic ethnicity all in the lowest SES group, respectively. Across each race, men aged 75 and older had the highest rates of mPCa. Overall, Black men over age 74 had a higher rate of mPCa (14%) relative to Whites (9%) and Hispanics (11%). Conclusions: There is an inverse relationship between SES and odds of presenting with mPCa. Having no insurance or Medicaid increased the odds of mPCa, even when accounting for SES. Black and Hispanic race was associated with increased odds of mPCa, and the effects of race and SES appeared to be additive.
IsoPSA: Interim clinical performance evaluation of a novel structure-based biomarker for prostate cancer in a multicenter prospective trial for Gleason ≥ 7.
Authors: Klein Eric A. , Di Loreto Robert , Hafron Jason , Kernan Kenneth , Manickam Kannan , Stovsky Mark 
Published: March 2017

20 Background: We report results from an interim evaluation of IsoPSA, a novel structure-focused protein assay to assess potential discrimination of high-grade (Gleason≥7) from benign or low-grade (Gleason=6) patients. The assay produces a single quantitative parameter, K, describing the overall composition of complex PSA (cPSA) isoforms, using step partitioning of proteins into two aqueous phases. The ratio of the overall complex PSA concentrations in the two phases differentiates between the two patient cohorts. In this multicenter prospective trial we provide performance data compared with biopsy reports. Methods: 217 plasma samples were obtained from multiple clinical sites, collected within 30 days prior to prostate biopsy from patients with blood PSA between 2 and 44 ng/ml (mean 7.5) and frozen at -80 degC. IsoPSA was evaluated within 90 days following collection against 12 core TRUS biopsy results as the ‘gold standard’ comparator. The prevalence of high-grade patients in the sample cohort was 33%. Results: IsoPSA results are reported as risk probability using a logistic regression model combining IsoPSA, K and age as input parameters, calibrated with 118 samples. We denote two possible regions signifying cohorts with low and high risk for aggressive cancer. These results could effectively reduce the number of unnecessary biopsies by 53%, while identifying high risk patients who could benefit from biopsy. Conclusions: This study provides further supporting analysis for IsoPSA, a novel structure-focused assay for prostate cancer. A simple parsimonious statistical model further enhances clinical performance using the test parameter IsoPSA K, and age only. [Table: see text]
Immune evaluation study of sipuleucel-T (Sip-T) in African-American and European-American men with castration-resistant prostate cancer.
Authors: Thakur Archana , Lum Lawrence G. , Hwang Clara , Paller Channing Judith , Schalk Dana , Kondadasula Vidya , Heilbrun Lance K. , Heath Elisabeth I. 
Published: March 2017

206 Background: Sipuleucel-T (Sip-T) is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients and targets the prostate antigen, prostatic acid phosphatase (PAP). In Phase 3 trials of Sip-T, there was a suggestion that AA men treated with Sip-T had enhanced OS benefit compared to the general population. This study was designed to evaluate the peripheral immune parameters in African American (AA) and European American (EA) prostate cancer patients receiving Sip-T treatment. Methods: Peripheral blood mononuclear cell and serum samples were evaluated for T- and B cell responses in 10 AA and 20 EA men with mCRPC. Antigen-specific T cell response was measured by IFN-γ Elispots, antigen-specific IgG and IgM responses to PA2024, PAP, PSMA, and PSA by ELISA, cytokine and chemokine levels by luminex and immune cell phenotyping by flow cytometry in the PBMC at baseline, 6-, and 10-week time points after completion of Sip-T treatment. Results: IFN-γ EliSpots were ≥ 2-fold higher when stimulated with PA2024 and PAP antigens in AA compared to EA patients post treatment. Humoral immune responses (IgM) to PA2024 and PAP was ≥ 100-fold higher at 6 and 10 weeks after completion of the 3rd infusion in both groups, however, there were no appreciable differences in antibody levels between AA and EA patients. Interestingly, there were ≥ 2-fold higher IgM titers for non-targeted PSA and PSMA at 6 and 10 weeks post treatment compared to baseline levels in both groups suggesting epitope spreading. Humoral responses (IgM) to PAP, PSA and PSMA at baseline were higher in AA patients compared to EA patients. The Th1 and Th2 cytokine and chemokine profiles showed no difference between AA and EA men except for inflammatory chemokine IL-8 which gradually decreased at 6 and 10 weeks from the baseline in AA patients compared to the transient decreases in EA patients. Conclusions: Our preliminary results are suggestive of slightly increased IFN-γ EliSpot responses in AA patients compared to EA patients. Both, AA and EA showed potent IgM antibody response to PA2024 and PAP antigens post treatment compared to the baseline levels. Clinical trial information: NCT01727154.
The association of BMI and PSA density on survival among patients with metastatic or castration-resistant prostate cancer.
Authors: Glaser Zachary A , Avulova Svetlana , Stocks Blair , Penson David F. , Moses Kelvin A. 
Published: March 2017

207 Background: The majority of deaths from prostate cancer are among men with metastatic (mPCa) or castration-resistant prostate cancer (CRPC). Long-term outcomes of these patients are generally not well characterized as data from most randomized trials were censored at interim analysis. The objective of our study is to investigate factors associated with survival in a dedicated outpatient clinic. Variables of interest included body mass index (BMI) and PSA density (PSAD) at diagnosis, as well as initial treatment. Methods: All patients with mPCa or CRPC seen in the Vanderbilt Comprehensive Prostate Cancer Clinic were eligible. Demographic and pathologic information were extracted from the electronic record under IRB-protocol. Overall survival (OS) was estimated using the Kaplan-Meier method. Multivariate analyses using Cox proportional hazard models were also performed. Results: Clinicopathological data was available for 65 patients at interim analysis of a total of 198 patients. Median follow-up was 7.4 years and median BMI was 28.5 kg/m2. Disease characteristics included 31/65 (47.5%) with Gleason 8 or greater on biopsy, median PSAD of 0.34, and 14 (23.3%) presenting with M1 disease. Patients underwent surgery (53%), radiation (20%) or androgen deprivation (ADT, 24.6%) initial therapy. BMI > 30 kg/m2 was associated with lower 5-year mortality (6.5% vs. 13.3% BMI < 30 kg/m2, p = 0.042). In addition, PSAD above median was associated with worse 5-year mortality (37.7% vs 6.1% PSAD < 0.34, p = 0.048). Initial treatment was also associated with 5-year mortality (10% surgery vs 0% radiation vs 100% ADT, p < 0.01). Multivariate analysis showed BMI is independently associated with OS (HR 0.807 (95% CI 0.70-0.93), p < 0.01) correcting for age and stage. Conclusions: We show BMI, PSAD and initial treatment are associated with survival for patients who develop advanced prostate cancer. Furthermore, BMI is significantly associated with survival in this cohort. The survival benefit of surgery likely reflects the higher percentage of M1 disease among patients who receive ADT only. Our findings should prompt further analysis of the impact of clincopathlogic factors and treatment type in a larger cohort.
High-resolution peripheral quantitative computed tomography (HR-pQCT) to detect compartmental bone loss on androgen deprivation therapy (ADT): A feasibility study.
Authors: Aggarwal Rahul Raj , Rodvelt Tammy J. , Tao Dora , Hough Jeffrey , Thomas Miles , Ma Brian , Zhang Li , Majumdar Sharmila 
Published: March 2017

209 Background: ADT causes bone loss, yet standard bone density (DXA) measurements do not distinguish cortical vs. trabecular bone loss and are falsely elevated in patients (pts) with sclerotic metastases, potentially underestimating fracture risk. HR-pQCT of the tibia and radius is a validated method to assess compartmental bone density and architecture that may overcome these limitations. Methods: Cross-sectional study of prostate cancer pts who underwent HR-pQCT (Scanco XtremeCT) of the radius and tibia and DXA scans within 6 months of initiating ADT. The relationship between HR-pQCT and relevant clinical variables was assessed using Spearman’s rank correlation method. Results: 22 pts were enrolled. Median baseline characteristics included: age = 64.5 (range 53-90), serum testosterone (T) level = 17 ng/dL (6-978), and interval between ADT start and HR-pQCT = 1.6 months (0-5.7). 5 pts (23%) were osteopenic as assessed by DXA. The correlation between HR-pQCT and clinical variables in shown in the Table. Of 12 pts with bone metastases, 7 (58%) had DXA L-spine and/or hip t-scores > 2 standard deviations above mean for 30 year-old male. In contrast, all 7 pts had HR-pQCT measurements within the expected range based on age, sex, and serum T. Conclusions: HR-pQCT to assess bone loss in prostate cancer pts on ADT is feasible. Radial trabecular bone volume and density are correlated with relevant clinical variables including ADT duration and serum T. In pts with bone metastases, HR-pQCT may provide more accurate means to estimate BMD and determine fracture risk. Longitudinal studies in pts on ADT with paired HR-pQCT scans are ongoing. Clinical trial information: NCT02168062. [Table: see text]
A comparison of surrogate endpoints for all cause mortality in men with localized unfavorable-risk prostate cancer.
Authors: Royce Trevor Joseph , Chen Ming-Hui , Wu Jing , Loffredo Marian , Renshaw Andrew A. , Kantoff Philip W. , D'Amico Anthony Victor 
Published: March 2017

21 Background: Several surrogates for prostate cancer-specific mortality exist, but whether these are surrogates for all cause mortality (ACM), and how their performance compares, is unknown. We investigated the relative efficacy of 4 candidate surrogates for ACM using the proportion of treatment effect (PTE) metric. Methods: Two-hundred and six men with localized unfavorable-risk prostate cancer were randomized to radiation therapy (RT) or RT and 6 months of androgen-deprivation therapy (ADT) from 1995 to 2001 and followed for a median of 16.62 years. Among the 159 men with no or minimal comorbidity, a significant reduction in the risk of death was observed in those randomized to RT and ADT versus RT alone; these 159 men formed the study cohort. In order to assess whether the candidate surrogated satisfied Prentice’s criteria for surrogacy, Cox regression analyses were performed to assess the risk of death for each of the candidate surrogates and treatment before and after adjusting for prostate-specific antigen (PSA), age at randomization, T category, and Gleason score. Results: PSA nadir > 0.5 ng/mL, PSA doubling time < 9 months and interval to PSA failure < 30 months met Prentice’s criteria for surrogacy (P = 0.01, 0.003, and 0.03 for the surrogate covariate in the multivariable model, respectively) for ACM, while PSA failure did not (P = 0.10). For the three surrogates, the PTE values were 103.86%, 43.09%, and 41.26%, respectively. Conclusions: A PSA nadir value of > 0.5 ng/mL following RT and ADT identified men prior to PSA failure who were at high-risk for death and therefore could be used to select men for entry, at the time of PSA nadir and before PSA failure, onto randomized trials evaluating the impact on survival of salvage ADT with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer. By enriching study cohorts with men who have achieved a surrogate endpoint for ACM, one can enhance the likelihood that the study will be able to observe whether survival is prolonged when novel treatment is added to ADT, as compared to ADT alone, in an abbreviated time period. Clinical Trial Number: NCT00116220