bluuebunny/crossref_metadata_2025_split huggingface dataset:
SWOG S0421: Phase III study of docetaxel (D) and atrasentan (A) versus docetaxel and placebo (P) for men with advanced castrate resistant prostate cancer (CRPC).
Authors: Quinn David I. , Tangen Catherine M. , Hussain Maha , Lara Primo , Goldkorn Amir , Garzotto Mark , Mack Philip C. , Carducci Michael Anthony , Monk J. P. , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Higano Celestia S. , Vogelzang Nicholas J. , Thompson Ian Murchie 
Published: March 2020

4511 Background: The endothelin pathway has a mechanistic role in bone metastases (mets). Atrasentan (A), an endothelin receptor antagonist, has reported activity in CRPC. This trial tested the survival impact of A + docetaxel (D) vs. D+ placebo (P) in CRPC pts with bone mets. Methods: Eligible CRPC pts, stratified for progression type, baseline pain index (BPI), extraskeletal mets and bisphosphonate (BisP) use, were randomized 1:1 to D+A vs. D+P for 12 3-wk cycles. Non-progressors could continue blinded drug alone for 16 more wks. Co-primary endpoints: overall (OS) and progression-free survival (PFS). 930 pts were needed to detect a 25% increase in med OS with D+A (1-sided log-rank, α=0.025, 87% power). Results: 991/1,038 pts were eligible: med age 69, 16% non-white, 61% on BisP, 31% prior prostatectomy, 42% worst pain by BPI ≥ 4, 20% PSA only progression and 56% extraskeletal mets. Multivariate analysis of baseline prognostic factors predicting worse OS were: measurable or evaluable disease progression, high BPI and extraskeletal mets (all p<0.02). No differences in median OS, PFS, or response between arms. Toxicities were similar between arms. Most common toxicities were fatigue, dyspnea, neutropenia and anemia. Addition of A trended to worse OS in pts with visceral mets (HR=1.13 p=0.21) and better OS in those without: bone only (HR=0.86, p=0.20). 357 pts continued A or P up to 52 weeks, no OS difference was seen post-chemo for this subset (p=0.92). Conclusions: This phase III study found no benefit for the addition of A to D in CRPC. Unless specific biomarkers can stratify a population for benefit, endothelin modulators have limited future use in advanced CRPC. Further analyses will test putative surrogacy effects of PSA, serum bone markers and circulating tumor cell kinetics for OS. [Table: see text]
A validated whole-blood RNA transcript-based prognostic model that predicts survival in men with castration-resistant prostate cancer.
Authors: Oh William K. , Kantoff Philip , Scher Howard I. , Magidson Jay , Wassmann Karl , Lee Gwo-Shu Mary , Katz Leah M. , Subudhi Sumit Kumar , Anand Aseem , Fleisher Martin , Galsky Matt D. , Ross Robert W 
Published: March 2020

4516 Background: Survival for patients with castration resistant prostate cancer (CRPC) is highly variable. We developed a whole blood RNA transcript-based model as a prognostic biomarker in CRPC. Methods: Peripheral blood was collected from 62 men with CRPC in a training set and from 140 patients with CRPC in a validation set on various treatment regimens. A panel of 168 inflammation and prostate cancer-related genes was evaluated using optimized quantitative polymerase chain reaction to assess biomarkers predictive of survival. A 2-class proportional hazard model was developed from time of CRPC diagnosis and time of blood draw. Results: A 6-gene model (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, CDKN1A) separated CRPC patients into two classes: higher risk men who died within 2·2 years of developing CRPC and lower risk men who lived over 2·2 years (log rank p=0·00083). The results were similar regardless of the survival time definition (CRPC diagnosis versus blood draw) and did not depend on whether they received chemotherapy in addition to hormone treatment. The model successfully validated in an independent cohort of men with CRPC (p= 0.000001·7). Conclusions: Transcriptional profiling of whole blood yields critical prognostic information in men with CRPC independent of treatment. The 6-gene model suggests possible dysregulation of the immune system, a finding that warrants further study. This model may play an important role in patient counseling, in patient stratification for clinical trials, and potentially as a predictive biomarker for immune-based therapeutic strategies.
Neoadjuvant androgen pathway suppression prior to prostatectomy.
Authors: Mostaghel Elahe A. , Nelson Peter , Lange Paul H. , Lin Daniel W. , Taplin Mary-Ellen , Balk Steven P. , Ellis William J , Penning Trevor , Marck Brett , True Lawrence D. , Vessella Robert , Montgomery Robert B. 
Published: March 2020

4520 Background: Optimizing tissue androgen suppression may provide better local and systemic control of prostate cancer (PCa). Standard androgen deprivation therapy (ADT) has limited effect on tissue androgens which remain in a range which supports tumor survival. We determined whether targeting androgen metabolism using CYP17 and 5a-reductase (SRD5A) inhibitors would more effectively suppress tissue androgens and tumor volume. Methods: Open label, multicenter neoadjuvant study in men with localized PCa treated for 3 months prior to prostatectomy with zoladex and 1) avodart 3.5 mg QD; 2) avodart and casodex 50 mg QD; or 3) casodex, avodart and ketoconazole 200 mg TID. Serum and tissue androgens were measured by LC/MS/MS. Data were compared to men treated with standard ADT (LHRH agonist plus Casodex), and untreated prostatectomy tissue. The primary outcome measure was suppression of tissue dihydrotestosterone (DHT). Results: 35 men with intermediate/high risk PCa were enrolled. Tissue DHT was suppressed 30 fold (> 95%) in all groups vs. LHRH agonist/Casodex (0.92 ± 0.20 pg/mg vs. 0.03± 0.03 for all groups combined, p<0.0001). Tissue testosterone was 3-4 fold higher (consistent with SRD5A inhibition) in all treatment groups vs. LHRH agonist/Casodex (0.33 vs. 0.07 pg/mg, p < 0.05). Differences in DHT/T between groups 1 through 3 were not statistically significant. There was no correlation between tissue and serum androgens, or tissue androgen and tumor volume (p> 0.05). In subset analysis, total serum DHEA declined significantly in group 3, with free DHEA unchanged, suggesting differential effect on free and total DHEA. Pathologic complete response (CR) was seen in 2 men, and an additional 8 men had <0.2 cc of tumor, with the largest number of CR or near CR in the cohort treated with ADT, CYP17 and SRD5A inhibitor, 4 of 12 men (33%). Due to small cohort size, differences were not statistically significant. Conclusions: Addition of high dose SRD5A inhibition (with and without CYP17 inhibition) achieves prostate DHT levels 30 fold below standard ADT. In this relatively high risk population, CR or near CR was seen in 10 of 35 men receiving protocol therapy. Further suppressing the androgen receptor signaling axis may provide better local and systemic control of PCa.
Characteristics of long-term and short-term survivors of metastatic renal cell carcinoma (mRCC) treated with targeted therapy: Results from the International mRCC Database Consortium.
Authors: Xie Wanling , Choueiri Toni K. , Lee Jae-Lyun , Harshman Lauren Christine , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Yuasa Takeshi , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Heng Daniel Yick Chin 
Published: March 2020

4538 Background: Patients with mRCC have variable courses in terms of survival and response to targeted therapy. The patients at the two extremes of the survival spectrum need to be characterized. Methods: 2,161 patients with mRCC treated with targeted therapy were examined. 152 patients who survived 4 years or more after the initiation of targeted therapy (long-term) were compared with 218 patients who survived 6 months or less (short-term) over the same time period (2004-2007). Results: Long-term survivors had fewer poor prognostic factors (PFs) such as Karnofsky performance status (KPS) <80%, diagnosis to treatment interval<1 yr, hypercalcemia, anemia, thrombocytosis and neutrophilia (all p<0.0001). Patients with favorable prognosis who responded to targeted therapy were more likely to be long term survivors. For those in the intermediate risk group, patients who were long-term survivors were more likely to have only 1 poor prognostic factor (73% vs. 28%, p<0.0001) and KPS≥80% (88% vs. 69%, p=0.009) compared to those in the short term survivor group. On multivariable analysis adjusting for PFs, response to targeted therapy (PR or better) significantly predicted long term survivor status (odds ratio=6.3, 95% CI: 2.3,17.4, p=0.0004). Conclusions: Long term survivors had a higher response rate to targeted therapy, a longer treatment duration and more use of second-line targeted therapy. Baseline prognostic criteria may be able to discriminate between long- and short- term survivors. [Table: see text]
SWOG 0421: Prognostic and predictive value of bone metabolism biomarkers (BMB) in castration resistant prostate cancer (CRPC) patients (pts) with skeletal metastases treated with docetaxel (DOC) with or without atrasentan (ATR).
Authors: Lara Primo , Ely Benjamin , Quinn David I. , Tangen Catherine M. , Gertz Erik , Mack Philip C. , Twardowski Przemyslaw , Vogelzang Nicholas J. , Hussain Maha , Thompson Ian Murchie , Van Loan Marta 
Published: March 2020

4547 Background: S0421, a phase III study of DOC +/- the endothelin antagonist ATR in CRPC pts with bone metastases, showed no overall survival (OS) benefit for DOC+ATR. While BMB may have a prognostic role in CRPC, their predictive role vis a vis bone-targeted therapy such as ATR is unknown. We prospectively assessed pre-treatment serum BMB from S0421 pts to validate their prognostic and predictive value. Methods: BMB for resorption (N-telopeptide, NTX and Pyridinoline, PYD) and formation (C-terminal collagen propeptide, CICP and bone alkaline phosphatase, BAP) were assayed [Quidel (PYD, CICP, BAP) and Wampole (NTX)]. Cox regression models for OS based on BMB adjusted for clinical variables were developed. An adjusted Cox model was fit with main effects and BMB x Treatment interaction to assess predictive value of ATR on OS. Results: Of 1,038 pts, 855 (82%) submitted baseline serum: 778 (91%) were usable and analyzable. Pt characteristics: median age = 69 years; PS 0-1 = 91%, Bisphosphonate use = 61%; Gleason >7 = 56%; median PSA = 68; and bone mets only = 45%. BMB values (median; range): NTX (14 nM; 9.3-23.9), BAP (64.7 u/L; 35-164), CICP (9.5 ng/mL; 6.5-17.4), and PYD (2.8 nmol/L; 2.2-3.9). Table below shows prognostic role of BMB. Pts with very high BMB (upper 25 %ile, n=47) not only have poor prognosis (HR = 4.3, p<0.001) but have OS benefit from ATR (HR=0.34, median OS = 13.6 vs. 6.7 months; interaction p=0.002**). Conclusions: S0421 validates the strong independent OS prognostic value of BMB in CRPC. Very high BMB levels appear to be significantly predictive of OS benefit with ATR. Further study of endothelin antagonists in CRPC should focus on this high-risk pt subset. (5R01-CA120469) [Table: see text]
Association of metabolic syndrome with poorer prostate cancer and overall survival in men receiving androgen deprivation therapy (ADT) for biochemical relapse.
Authors: Rudman Sarah Maria , Gray Kathryn P. , Kasperzyk Julie , Giovannucci Edward , Pitt Michael , Loda Massimo F. , Mucci Lorelei , Sweeney Christopher 
Published: March 2020

4555 Background: The metabolic syndrome (MS) has been implicated in the development of prostate cancer (PC). In our previous study of a Veterans’ Administration (VA) cohort, MS was associated with a shorter duration of PC control with ADT. We report the impact of MS on overall survival (OS) and PC specific death for a cohort of patients with biochemical relapse. Methods: 273 pts (64 VA pts and 209 pts from Health Professionals Follow up Study) treated with ADT for biochemical recurrence post radiation or prostatectomy for PC were included. The modified Adult Treatment Panel III criteria for MS was used to identify patients with MS status prior to the commencement of ADT. Cox models tested for association of MS status with OS or time to PC specific death. With 42% overall death rate, 31% MS prevalence, there was 90% power to detect HR= 1.81 (type I error rate =0.05). Results: 31% pts (84/273) had MS and 15% pts (40/273) died of PC. Median follow-up was 9.5 years. The median OS with and without MS was 7.4 and 11.2 years respectively. Patients with hypertension, being African American, having diabetes and age were associated with increased risk of death from any causes, while hypertension and being African American were also associated with increased risk of PC specific death. A multivariate Cox regression model adjusted for age at diagnosis, race, definitive local therapy (RT vs. RP), PSA at diagnosis and Gleason score revealed MS was associated with a significantly increased risk of death from any cause and PC specific death (Table). Conclusions: In men receiving ADT for biochemically recurrent androgen dependent PC, the presence of MS at the commencement of ADT is associated with an increased risk of death from any cause as well as prostate cancer specifically. [Table: see text]
Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): Preliminary results of a randomized preoperative study.
Authors: Efstathiou Eleni , Davis John W. , Troncoso Patricia , Titus Mark Anton , Hoang Anh , Wen Sijin , Zurita Amado J. , Tran Namphuong , Molina Arturo , Logothetis Christopher 
Published: March 2020

4556 Background: Endocrine to “intracrine” androgen signaling transition, a milestone in the lethal progression of PCa, has not been characterized in localized high risk disease. Signaling heterogeneity under the selective pressure of castration may account for response differences. Methods: A single institution preoperative study of 12 weeks AA 1g/prednisone 5 mg + LHRHa compared to LHRHa (randomized 2:1) was conducted in patients (pts) with high risk PCa (clinical stage ≥T1c and biopsy Gleason score ≥8, or ≥T2b, Gleason ≥ 7 and PSA > 10ng/ml). Primary aim: Assess difference in down staging (≤ ypT2) and safety. Secondary aims: Assess difference in androgen biosynthesis, androgen signaling (AR, AR variants, NKX 3.1, ERG, PSA) proliferation apoptosis and candidate treatment resistance pathways. Results: We report on 37 (50 enrolled) pts who had prostatectomy. AA+LHRHa was given to 25pts, LHRHa to 12. Median age is 61 ys (46-74). Preoperative PSA was <0.1ng/ml in 17/25 (68%) AA+LHRHa vs 0/12 LHRHa (p 0.0001). ypT2N0 occurred in 15/25 (60%) AA+LHRHa treated pts vs 4/12 (33%) LHRHa (p 0.17). Near complete cytoreduction (<6mm scattered cells) occurred in 6/25 (24%) AA+LHRHa vs 1/12 (8%) LHRHa. Lymph node infiltration in 7/25 (28%) AA+LHRHa vs 6/12 (50%) LHRHa. Margin positivity in 2/25 (8%) AA+LHRHa vs 4/12 (33%) LHRHa (p 0.07). Grade 3 AA related AEs: elevated AST/ALT 4 (discontinued AA), hypertension 3. One AA+LHRHa pt had postop pulmonary embolism. Androgen signaling and proliferation suppression is more profound in AA+LHRHa treated remaining tumor cells (Table). Conclusions: Addition of AA to LHRHa results in greater cytoreduction, suppression of PSA and androgen signaling compared to LHRHa in high risk PCa. Findings support the hypothesis that intracrine androgen signaling is a therapy target in patients with untreated PCa and form the foundation for a marker driven treatment strategy. [Table: see text]
Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Goodman Oscar B. , Chi Kim N. , Molina Arturo , Logothetis Christopher , Jones Robert J. , Staffurth John , North Scott A. , Vogelzang Nicholas J. , Saad Fred , Mainwaring Paul N. , Harland Stephen John , Li Jinhui , Kheoh Thian San , Haqq Christopher M. , Scher Howard I. , Fizazi Karim 
Published: March 2020

4558 Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen production. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a randomized double blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To further evaluate primary survival result robustness, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS. Results: At randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); remainder discontinued D after completing all planned cycles (37%), due to toxicity (12%), or for other reasons (5%) per investigator. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD, or for all other reasons. Conclusions: These exploratory analyses suggest that the OS benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in AA arm of this study had a prolonged median OS of > 32 mos from time of initial D therapy. Congruity among these analyses and lack of dependence on D timing demonstrate robustness of the primary survival result. [Table: see text]
The effect of PSA frequency and duration on PSA doubling time (PSADT) calculations in men with biochemically recurrent prostate cancer (BRPC) after definitive local therapy.
Authors: Paller Channing Judith , Xie Sherlly , Olatoye Dare , Denmeade Samuel R. , Eisenberger Mario A. , Antonarakis Emmanuel S. , Carducci Michael Anthony , Rosner Gary L. 
Published: March 2020

4559 Background: The prognostic nature of PSADT in men with BRPC makes it an attractive intermediate endpoint for assessing novel therapies in these patients. Although a number of investigational agents appear to favorably modulate PSADT, slowing in PSADT has also been observed in placebo-treated men. We aimed to determine whether PSADT calculations could be influenced by the frequency and duration of PSA measurements. Methods: We performed a retrospective analysis of men with BRPC who chose to defer hormonal therapy. Eligible men were those with PSA values ≥0.2 ng/mL and at least 6 values taken on average 3 mo apart, and whose local prostate cancer therapy was completed ≥1 year prior. To examine the influence of PSA frequency and duration on PSADT, we calculated median PSADT using different subsets of available PSA values (e.g. each vs every other; and first 3 vs. remaining PSA values). Results: After a median follow-up of 58 mo (range, 6-185 mo), 213 men with BRPC had ≥6 PSA values and 127 men had ≥9 PSA values for analysis. Men (77% white, 23% black/other) had a median age of 61 y with Gleason score distribution as follows (≤6: 30%; 7: 40%; ≥8: 18%; NOS: 12%). For men with ≥6 data points: PSADT calculated using earlier values ranged from 13.2 to 16.6 mo, compared to 16.6 to 17.8 mo, respectively, for the remaining values (within-patient change range: 0.6-1.2 mo). For men with ≥9 data points: PSADT calculated using earlier values ranged from 15.3 to 19.9 mo compared to 22.1 to 22.3 mo, respectively, for the remaining values (within-patient change range: 3.5 to 4.5 mo). When we examined the frequency of PSADT by using every other value, we found little difference (22.3 vs 22.1 mo). Conclusions: These data show that PSADT appears to increase even in the absence of therapy, and may be influenced by duration of PSA follow up. This finding explains PSADT slowing on placebo arms and calls into question the utility of PSADT as a surrogate endpoint. Placebo-controlled trials and the use of standard clinical endpoints are recommended to screen novel agents in men with BRPC to mitigate bias because of natural PSADT variability.
Gene expression biomarkers to predict overall survival of prostate cancer patients.
Authors: Li Chunde , Peng Zhuochun , Skoog Lambert , Hellborg Henrik , Jonstam Gustaf , Wingmo Inga-lill , Hjelm-Eriksson Marie , Harmenberg Ulrika , Ährlund-Richter Lars , Pramana Setia , Pawitan Yudi , Nistér Monica , Nilsson Sten 
Published: March 2020

4561 Background: Current clinical parameters are not accurate in the prediction of overall survival of prostate cancer patients. Methods: Driven by cancer stem cell hypothesis and by using a simple bioinformatics analysis, we identified 641 genes with either consistently high or low level of expression in human embryonic stem cells. We showed that these 641 genes had strong power to classify cancers into different biological subtypes and named them as embryonic stem cell gene predictors (ESCGPs). Nineteen selected ESCGPs and five control genes were analyzed by multiplex quantitative PCR in prostate fine needle aspiration (FNA) samples taken at diagnosis. The cohort included 189 patients diagnosed during 1986-2001. Of these patients, 97.9% had overall and cancer specific survival data and 77.9% were treated by medical or surgical castration as the primary treatment. The cohort was divided into a discovery and two validation subsets. The univariate and multivariate Cox proportional hazards and Kaplan-Meier plots were used in the survival analysis. A published dataset was used for an external validation. Results: Ten gene markers F3, WNT5B, VGLL3, CTGF, IGFBP3, c-MAF-a, c-MAF-b, AMACR, MUC1 and EZH2, showed a significant correlation to overall or cancer specific survival. Four of these genes, F3, IGFBP3, CTGF and AMACR, were independent of all clinical parameters. An expression signature of F3, VGLL3 and IGFBP3 characterized patients into three subtypes. The median overall survival was 2.60 years in the high risk, 3.85 years in the intermediate risk and 7.98 years in the low risk subtype, corresponding to a HR of 5.86 (95% CI 2.91-11.78, p<0.001) for the high risk and 3.45 (95% CI 1.79-6.66, p<0.001) for the intermediate risk over the low risk subtype. Two gene markers, F3 and EZH2, were further verified by the external validation. Conclusions: The new ESCGP gene markers and the expression signatures can be used to predict the overall and cancer specific survival of prostate cancer patients.