bluuebunny/crossref_metadata_2025 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
Prostate-specific membrane antigen (PSMA) PET-CT guided radiotherapy in oligometastatic prostate cancer.
Authors: Engels Benedikt , Guler Ozan Cem , Onal Cem , De Ridder Mark
Published: March 2017

213

Background: Metastases-directed therapy by metastasectomy or radiotherapy (RT) might delay disease progression and postpone systemic treatment in patients with oligometastatic prostate cancer. Here, we evaluated retrospectively the efficacy and toxicity of 68Ga prostate-specific membrane antigen (PSMA) PET-CT guided radiotherapy (RT) in the treatment of oligometastatic prostate cancer. Methods: A total of 23 prostate cancer patients with biochemical relapse, of which 13 castration-sensitive and 10 castration-resistant, were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤ 3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in castration-resistant patients. Local control (LC), progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Results: A total of 38 metastases were treated. Involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), para-aortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.06 ng/ml (range 0.10 – 29.0 ng/ml). A median dose of 43.5 Gy (range, 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range, 2-17 months), 19 patients (83%) are in remission. Four patients (17%) developed distant recurrence. The actuarial 1-year LC, PFS and OS rates were 100%, 51% (95% CI 8-83%) and 100%. Castration-sensitive patients displayed a statistically significantly superior PFS on univariate analysis as compared to castration-resistant patients (1-year PFS 67% vs 0%, p < 0.01). One patient experienced grade 2 acute gastro-intestinal toxicity. No grade 3 or more toxic events were observed. Conclusions: By providing optimal LC, low toxicity and a promising PFS in castration-sensitive patients, the current retrospective study illustrated that 68Ga PSMA PET-CT guided RT may be an attractive treatment option in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.
Diagnostic characteristics of men harboring lethal prostate cancer: A population-based analysis.
Authors: Thomas Helgstrand John , Klemann Nina , Toft Birgitte Grønkaer , Vainer Ben , Brasso Klaus , Iversen Peter , Røder Martin Andreas
Published: March 2017

217

Background: Prostate specific antigen (PSA) based screening increases the number of men diagnosed with early localized prostate cancer (PCa). Further, curatively intended therapies have been demonstrated to reduce PCa mortality in randomized trials. However, controversy exists, and the overall impact on PCa mortality is less clear. Men who eventually die from PCa may constitute a subgroup with either adverse histopathological characteristics and/or clinically advanced disease at diagnosis. However, the clinical characteristics at diagnosis for men who eventually die from PCa are largely unknown. We retrieved clinical characteristics of all men dying from PCa in Denmark in an 18-year period. Methods: All men who died of PCa during the period 1995 to 2013 were identified in the Danish Causes of Death Registry. Age, Gleason score (GS), tumor stage classification, and PSA were retrieved from the Danish Prostate Cancer Registry (DaPCaR). For validation, manual revision of patient charts was performed. Patients were divided into three clinical phenotypes: distant metastatic disease, locally advanced/N+ disease, and localized disease. Patients with localized disease were further grouped according to GS and PSA. Results: A total of 19,487 men died of PCa in the period 1995-2013. In total, 46.7%, 16.8% and 25.1% of men presented with distant metastatic disease, locally advanced/N+ disease or localized disease, respectively. Among men with localized disease, 85.1% had GS ≥ 7 and only 2.1% (0.5% of all men dying from PCa) only, presented with low risk (PSA < 20 and GS ≤ 6) localized disease at the time of diagnosis. Conclusions: The majority of men (63.5%) who died from PCa had either locally advanced/N+ or M+ disease at diagnosis. Among men with localized PCa at diagnosis, the majority of men subsequently dying from PCa had either PSA > 20 ng/ml and/or adverse histopathological characteristics with Gleason score ≥ 7. A total of 94.5% of patients dying from PCa had either metastatic, locally advanced/N+, and/or GS ≥ 7 disease. Patients with localized disease, PSA < 20 ng/ml and GS ≤ 6 amounted for only 0.5% of all patients dying from PCa.
Prior therapy and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based database.
Authors: Francini Edoardo , Gray Kathryn P. , Xie Wanling , Kantoff Philip W. , Harshman Lauren Christine , Taplin Mary-Ellen , Sweeney Christopher
Published: March 2017

221

Background: Recent reports have shown that patients (pts) with low volume (LV) mHSPC and those who relapse after prior local therapy (PLT) have median overall survival (OS) longer than 5 years with androgen deprivation therapy (ADT) alone. Using data from our prospectively collected hospital-based database, we aimed to detail the outcomes of pts with mHSPC by combining PLT or de novo (DN) and LV or high volume (HV) of disease. Methods: A cohort of mHSPCpts treated with ADT between 1990 and 2013 was identified in the Dana-Farber Cancer Institute IRB approved database and categorized as DN or PLT and HV or LV, at time of ADT start. HV was defined as visceral metastases and/or ≥ 4 bone metastases (BM) with at least 1 BM beyond the pelvis and axis. The analysis endpoints included OS, defined as time from ADT start to death from all causes. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Cox proportional hazards model evaluated patient and disease volume groups on disease outcomes and provided estimates of hazard ratio (95% CI) for the comparison by groups. Results: Of the 354 pts included and classified as LV or HV, 202 (57%) had PLT, while 152 (43%) presented with DN metastases. The distributions of the 4 groups are 38% (PLT/LV), 19% (PLT/HV), 14% (DN/LV) and 29% (DN/HV). Compared to pts in PLT/LV group, those in the other 3 cohorts had a significantly higher risk of death. In particular, a statistically significant gradient in OS was noted (Trend test P < 0.001) within the groups in favor of PLT, primarily, and LV, secondarily. Conclusions: Consistent with the results seen in clinical trials, our hospital database informs us that disease volume and history of PLT define 4 distinct subgroups with different outcomes. This classification can be routinely used for counseling pts and future clinical trial design including oligometastatic disease. [Table: see text]
Impact of resistance exercise on metabolic syndrome (MetS) parameters in men receiving androgen deprivation therapy (ADT) for prostate cancer.
Authors: Dorff Tanya B. , Gross Mitchell E. , Quinn David I. , Pinski Jacek K. , Schroeder E. Todd , Groshen Susan G. , Dieli-Conwright Christina Marie , Kiwata Jacqueline
Published: March 2017

223

Background: Cardiovascular disease is the leading cause of death in men with prostate cancer. ADT is effective treatment, but can induce loss of skeletal muscle, plus increase central fat, lipids, and insulin resistance. These changes in MetS components may contribute to excess cardiac risk. We tested whether a resistance exercise program, designed to increase skeletal muscle mass, could offset adverse changes in MetS parameters during ADT. Methods: Men on ADT for at least 12 weeks were randomized to exercise (EX) or no exercise (NOEX). EX was supervised, periodized resistance training followed by stretching 3x/week for 12 weeks, 45 min/session. NOEX did home-based stretching 3x/week. Baseline and post-intervention measurements included weight, waist circumference, lean body mass, lipids, insulin, glucose, hsCRP. Quality of life (QOL) was evaluated with FACT-P and BFI, and muscle biopsies were obtained pre- and post-intervention. Mean of changes from baseline were compared between groups using ANCOVA. Results: 24 men (mean age 65; range 49-81) completed protocol with 100% compliance (n = 12 EX, n = 12 NOEX). Baseline PSA ranged from 0 – 8.1 ng/mL and did not change; subjects had been on ADT for a mean of 17 months (range 3-84). In multivariable analysis controlling for baseline muscle mass, age, and ADT duration, the mean change in waist circumference after 12 weeks was significantly different between EX (-2.05 cm +/- 2.82) and NOEX (+0.69 cm +/- 2.01) groups (p = 0.011, t-test). There were no significant differences for other parameters. However, consistent patterns were noted in: mean fasting glucose -4.59 mg/dL in EX compared with +1.12 mg/dL in NOEX (p = 0.21, t-test) and diastolic blood pressure -2.17 mmHg in EX vs +2.0 mmHg in NOEX (p = 0.27, t-test). In the EX group 5/12 had MetS at baseline which remained stable while the NOEX group increased from 2/12 with MetS at baseline to 3/12 post intervention. Analysis of QOL and muscle biopsies are ongoing. Conclusions: Supervised resistance exercise for 12 weeks is feasible and decreases waist circumference in men receiving ADT for prostate cancer. Longer follow-up may reveal additional impacts of resistance training on MetS. Clinical trial information: NCT01909440.
Contribution of mouse adrenal glands to intratumor androgens and growth of castration-resistant prostate cancer xenografts.
Authors: Mostaghel Elahe A. , Biehl Heather , Hernandez Susanna , Zhang Ailin , Bartlett Jon , Corey Eva , Penning Trevor M. , Oksala Riikka , True Lawrence D. , Nelson Peter
Published: March 2017

224

Background: Historical studies using radioimmunoassay did not detect adrenal androgens in serum from castrate mice, and it is widely held that rodent adrenal glands do not make adrenal androgens due to lack of CYP17A expression. This contrasts with the clinical setting in which circulating adrenal androgens are significant and inhibition of adrenal CYP17A markedly decreases tissue androgens. Methods: We evaluated CYP17A (by methylation, transcript and protein) and androgens (by mass spectrometry) in adrenal glands of CB17-NOD/SCID mice. We determined the impact of adrenalectomy (ADX) on suppressing tumor androgens and growth in two patient derived xenografts (PDX) models of castration resistant prostate cancer (CRPC). Results: CYP17A is unmethylated, and transcript and protein are present in adrenals from intact and castrate mice. In castrate mice adrenal levels of DHEA (0.75 pg/mg), androstenedione (AED; 44pg/mg), T (12.5pg/mg) and DHT (4.7 pg/mg) are detectable and nearly 2 orders of magnitude higher than in kidney, liver or muscle (p < 0.05 for all). In castrate mice bearing LuCaP35 and LuCaP96 tumors, ADX suppressed tumor steroids at 21-30 days after ADX vs castration alone (LuCaP35: AED 0.05 vs 0.02 pg/mg, p = 0.005; T 0.64 vs 0.03 pg/mg p < 0.001; DHT 2.3 vs 0.23 pg/mg, p = 0.0003; LuCaP96: AED 0.06 vs 0.02 pg/mg p = 0.08; T 0.81 vs 0.03 pg/mg, p < 0.0001; DHT 1.3 vs 0.04 pg/mg, p = 0.002), and delayed time to tumor re-growth (median survival: LuCaP35 33 vs 179 days, p = 0.006; LuCaP96 25 vs 301 days, p = 0.0012). Whereas tumor recurrence in LuCaP96 was uniformly delayed, a subset of tumors in LuCaP35 showed more rapid regrowth after ADX (66 days vs undefined, p = 0.008), with a trend toward increased levels of tumor steroids (progesterone 0.25 vs 0.02 pg/mg, p = 0.07; T 0.14 vs 0.02, p = 0.04; DHT 0.36 vs 0.21, p = 0.17). Recurrent tumors variably showed induction of full length and truncated AR variants and/or induction of steroidogenic enzymes as potential mechanisms of resistance. Conclusions: Adrenally-derived steroids are produced in mice and contribute to tumor androgen levels and growth in PDX models. Mice are an appropriate model for evaluation of steroidogenesis inhibitors in CRPC xenograft studies
Family history, race, and prostate cancer.
Authors: Schiff Joshua , Ledet Elisa M. , Ernst Emma M. , Garvey Cathryn E. , Cotogno Patrick , Sartor Oliver
Published: March 2017

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Background: African American (AA) race and family history (FH) of prostate cancer (PCa) increase the incidence and mortality of PCa. The goal of this study was to assess and compare FH in AA and Caucasian (C) men. Methods: During June 2015 through September 2016, 338 men with prostate cancer had FH collected at Tulane Cancer Center (C = 266 and AA = 72). A FH was defined as ≥ 1 1st degree relative with PCa and/or ≥ 2 affected 2nd/3rddegree relatives. Documented clinical factors were age at diagnosis (dx), Gleason score, incidence of radical prostatectomy (RP), and presence of metastases (at any time). Chi-square and Mann-Whitney U tests were performed to identify potential clinical correlates with regard to FH and race. Results: For demographics see table below. On average, men with a FH of PCa (n = 110) had a median age at dx of 59.6 as compared to those without a FH of PCa (n = 151) (median age at dx = 63.0). Overall FH patients (pts) were younger at dx (p = 0.00046). FH had a particularly impactful influence upon the age at dx for C men (p = 0.00086, 58 [n = 88] vs. 62.5 [n = 112]); statistics were limited for AA men. Gleason scores were not different between pts with or without a FH, and there was no relationship between Gleason score and race. Metastatic disease (mets) was detected in 23.97% of men (n = 93). C men with a FH of PCa (n = 40) were 1.55 times more likely to develop mets (p = 0.0352). AA data were limited so no comment can be made. No relationship was detected between the pts having undergone a RP and race, but pts with a FH of PCa (n = 61) were 1.39 times more likely to have undergone surgery (p = 0.016). Data by racial subsets were too limited to be conclusive. Conclusions: The study highlighted the significant impact that FH of PCa has upon age at dx and presence of mets. More AA data are needed to be conclusive. [Table: see text]
5-year patient-reported outcomes of bowel and urinary bother in the CHHiP trial (CRUK/06/016).
Authors: Dearnaley David P. , Mossop Helen , Syndikus Isabel , Khoo Vincent , Bloomfield DJ , Parker Chris C. , Logue John , Scrase Christopher D , Birtle Alison J. , Staffurth John , Malik Zafar , Panades Miguel , Eswar Chinnamani , Graham John , Russell J. Martin , Gao Annie , Wilkins Anna , Cruickshank Clare , Griffin Clare , Hall Emma
Published: March 2017

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Background: Hypofractionated radiotherapy (hRT) has been shown to be non-inferior to conventional fractionation (cRT) in the CHHiP trial. Clinician reported toxicity was low across all fractionation schedules at 5 years (y), as were patient reported outcomes (PRO) to 2y. Here we aim to confirm these findings with PRO data at 5y. Methods: The CHHiP trial randomised patients (pts) in a 1:1:1 ratio to cRT: 74Gy/37 fractions (f) or hRT: 60Gy/20f or 57Gy/19f. Overall bowel bother (BB) and urinary bother (UB) were assessed as single items of the UCLA-PCI and EPIC-50 instruments. PRO were completed before hormone therapy and RT (pRT). Late symptoms were assessed 6 monthly from 6-24 months and yearly to 5y. Differences in the distribution of scores were assessed using a chi2 trend test. Odds of an increase in bother were modelled using ordered logistic regression. Kaplan-Meier methods were used to estimate time to “small” or worse bother, with RT schedules compared using the log-rank test. Results: Between Oct, 2002 and Nov, 2009 2100 pts were recruited into the PRO sub-study (696 74Gy, 698 60Gy and 706 57Gy). Return rates at 5y were 355 (51%), 388 (56%) and 402 (57%) for the 74, 60 and 57Gy schedules respectively. Cross-sectional analyses at 5y showed no difference between groups (Table 1). The odds of an increase in BB from pRT to 5y for hRT compared to cRT were (Odds Ratio (OR) (99% CI), p-value): 60Gy: 0.78 (0.52-1.18), 0.12; 57Gy: 0.75 (0.50-1.12), 0.06, and for UB were: 60Gy: 1.00 (0.67-1.50), 1.00; 57Gy: 1.08 (0.72-1.61), 0.62. Time to first late “small” or worse BB was also similar across groups (Hazard ratio (HR) (99% CI), p-value): 60Gy: 1.08 (0.85-1.37), 0.42; 57Gy: 0.92 (0.71-1.18), 0.36 or UB: 60Gy: 0.93 (0.73-1.20), 0.48; 57Gy: 0.91 (0.71, 1.17), 0.34. Conclusions: After 5 years follow-up, cRT and hRT showed a similar low level of patient reported BB and UB. Clinical trial information: ISRCTN97182923. [Table: see text]
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in pts with metastatic castration-resistant prostate cancer (mCRPC) receiving a new agent (NA)- based third-line treatment: Final results from a multicenter Italian study.
Authors: Caffo Orazio , Bria Emilio , De Giorgi Ugo , Tucci Marcello , Galli Luca , Fratino Lucia , Rossetti Sabrina , Iacovelli Roberto , Lo Re Giovanni , Mosillo Claudia , Gasparro Donatello , Guglielmini Pamela , Damiani Azzurra , Procopio Giuseppe , De Lisi Delia , Ortega Cinzia , Scagliarini Sarah , Donini Maddalena , Sperduti Isabella , Basso Umberto
Published: March 2017

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Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS . In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P < 0.0001) in pts with NLR ≤ 3.66 and > 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.
Association of cfDNA androgen receptor amplifications with BRAF alterations in mCRPC.
Authors: Ledet Elisa M. , Schiff Joshua , Cotogno Patrick , Manogue Charlotte , Ernst Emma M. , Lewis Brian E. , Sartor Oliver
Published: March 2017

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Background: Cell free DNA (cfDNA) present in plasma of cancer pts can reflect tumoral alterations. Genomic alterations in cfDNA alter prognosis and abiraterone/enzalutamide resistance in mCRPC. The goal of this evaluation was to characterize AR amplifications (Amps) and various somatic point mutations (Muts) detected in mCRPC cfDNA and to relate those changes to other common alterations in the cfDNA landscape. Methods: A heterogenous group of 46 mCRPC patients (pts) with evidence of clinical progression from Tulane Cancer Center underwent cfDNA analysis using Guardant360 test (Guardant Health, Redwood City, CA). This evaluation included full exonic coverage of 70 genes and amplifications in 18 genes. Mutations reported herein include both known pathogenic mutations as well as mutations uncharacterized for functional importance. Results: 69.5% (n = 32) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 46.8% (n = 16) had AR Amps, 43.7% (n = 14) had AR Muts, and only 6.25% (n = 2) had both. In this cohort, AR alterations were the most commonly observed aberration. In addition to amplifications, 12 different AR Muts were detected. AR Muts included: T878A (n = 9), H875Y (n = 5), W742C (n = 4), AR L702H (n = 3), and others. To better understand the relationship between AR alteration and other commonly detected cfDNA aberrations, association between BRAF (35.5%), TP53 (46.7%), and MYC (22.2%) alterations and AR were assessed. Among these genes, TP53 alterations were all Muts and MYC alterations were all Amps. BRAF alterations were predominantly Amps (N = 15) though Muts were also detected (N = 6). Neither TP53 Muts or MYC Amps were significantly associated with AR alterations. On the other hand, BRAF alterations were significantly associated with AR Amps (p = 0.041); 60% (9/15) pts with AR Amps also had BRAF alteration (Odds ratio = 7.71, 95% CI 1.284- 46.366). Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR and BRAF alterations may have significant prognostic and therapeutic implications. Further research and larger sample size is needed to further elucidate associations between the common somatic alterations detected in mCRPC.
Tissue-based analytics provide the next generation of prostate cancer risk models.
Authors: Donovan Michael , Scott Richard , Khan Faisal m , Zeineh Jack , Koll Giovanni , Gladoun Nataliya , Charytonowicz Elizabeth , Fernandez Gerardo
Published: March 2017

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Background: Quantitative analysis of formalin-fixed paraffin-embedded (FFPE) prostate samples post radical-prostatectomy (RP) can help guide management of post-operative prostate cancer (PCa) patients. We have previously published on the results of our systems (precise) pathology platform which includes integration of clinical data with immunofluorescent (IF) morphology and biomarkers to predict disease progression in post-RP patients. We extended this approach by developing quantitative image features that further refine risk discrimination by directly competing with Gleason through the incorporation of biological attributes. Methods: Tissue microarrays representing a 892 RP population from Roswell Park Cancer Institute and the Henry Ford Hospital, with median 8 years follow-up were stained with a multiplex IF assay incorporating CK18 (epithelial cells), CK5/6 (basal cells), AMACR, the Androgen Receptor (AR), and Ki67. Images were captured with a Nikon i90 microscope / CRI multiplex camera and a Bayesian probabilistic approach was used to derive micro-anatomic quantitative image attributes. We generated a 50:50 balanced training / test cohort and optimized feature construction using clinical variables. Multivariate models were produced on the 324 training set to predict disease progression (i.e. clinical failure) which included a PSA rise post-adjuvant therapy, metastasis or death from PCa. The concordance index (CI), sensitivity and specificity were used to assess performance of the model. Results: A multivariate training model yielded a CI of 0.80, sensitivity 85% and specificity 74% with a hazard ratio of 9.8. By comparison a clinical only model produced a CI of 0.77, sensitivity 80% and specificity 73%, with a hazard ratio of 6. The IF model consisted of 3 features including pathologic stage and two imaging features that combine morphometry integrated with levels of AR and Ki67. Neither the Gleason score nor PSA were selected. Conclusions: Tissue-based models which incorporate objective and biological attributes accurately predict disease progression. Once validated, such approaches may replace the subjective Gleason grading system and provide an additional tool for pathologists when assigning risk.