bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline circulating tumor cell (CTC) count as a prognostic marker of PSA response and progression in metastatic castrate sensitive prostate cancer (mCSPC): Results from SWOG S1216, a phase III randomized trial of androgen deprivation plus orteronel (cyp17 inhibitor) or bicalutamide.
Authors: Goldkorn Amir , Tangen Catherine , Plets Melissa , Morrison Gareth , Cunha Alexander , Xu Tong , Pinski Jacek K. , Ingles Sue A. , Triche Timothy , MacVicar Gary R. , Vaena Daniel A. , Crispino Anthony W. , McConkey David James , Lara Primo , Hussain Maha H. A. , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian Murchie , Agarwal Neeraj ,   SWOG GU Committee
Published: May 2020

5506 Background: In mCSPC, androgen deprivation therapy (ADT) combined with chemotherapy or androgen receptor signaling inhibition (ARSI) is the new standard of care. Biomarkers that predict clinical outcomes with these therapies are needed. We hypothesized that CellSearch CTC count, an FDA-cleared biomarker in metastatic castrate resistant PC (mCRPC), may be a valuable biomarker in mCSPC. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline), and CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini) per standard manufacturer protocol. CTC counts were analyzed centrally for associations with 2 pre-specified trial intermediate endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. > 4.0, (intermediate endpoint for overall survival, OS); and progression-free survival (PFS) < vs. > 2 years. Because OS data have not matured, analysis was pooled and equal numbers of samples were analyzed from each treatment arm and outcome measure (7mPSA and PFS) as stipulated by the Data Safety Monitoring Committee. Results: From 2014 to 2017, 523 baseline samples were collected. In the 7mPSA analysis (n = 264), CTCs were detected in 38% of men, with a median of 4 CTCs in those with detectable CTCs. In the PFS analysis (n = 336), CTCs were detected in 37% of men, with a median of 3 CTCs in those with detectable CTCs. Adjusting for disease burden (minimal vs. extensive) and ADT status (already initiated or not) at the time of CTC measurement, men with undetectable CTCs were 6.1-fold more likely to attain 7mPSA ≤ 0.2 (OR 6.1, 95% CI 2.1-17.2, p < 0.001) and 3.7-fold more likely to achieve > 2 years PFS (OR 3.7, 95% CI 1.7-8.1, p < 0.001) compared to men with baseline CTCs ≥ 5. Other cutpoints previously validated in mCRPC studies (CTC < 5 vs. ≥5 and CTCs 0 vs. ≥1) also strongly discriminated 7mPSA and PFS with statistical significance in this mCSPC cohort. Conclusions: CTC count at the start of treatment for mCSPC was highly prognostic of 7-month PSA response (intermediate endpoint for OS) and of PFS at 2 years. To our knowledge, this is the first such strong evidence from a prospective phase 3 trial of this magnitude. Additional analyses are planned when the trial is fully reported. Baseline CTC count may serve as a valuable prognostic marker to discriminate men likely to respond favorably to hormonal therapies from those who may benefit from early alternate interventions.
Assessment and management of cardiovascular risk factors among U.S. Veterans with newly diagnosed prostate cancer.
Authors: Sun Lova , Parikh Ravi Bharat , Robinson Kyle William , Takvorian Samuel U , Vaughn David J. , Narayan Vivek , Ky Bonnie 
Published: May 2020

5510 Background: Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer (PC). Androgen deprivation therapy (ADT) is associated with increased CVD risk, and American Heart Association guidelines recommend CVD risk factor assessment and management in PC patients starting ADT. We characterized rates of guideline-concordant assessment and management of CVD risk factors for US Veterans with newly diagnosed PC, according to ADT use and prior atherosclerotic CVD diagnosis. Methods: We used cross-sectional data from VA Corporate Data Warehouse to identify Veterans with an incident diagnosis of PC from 2001-2017. Primary outcomes were guideline-concordant baseline CVD risk factor assessment (defined as ≥1 blood pressure, cholesterol, and HbA1c or fasting glucose measurement within 1 year prior to 6 months after ADT start or PC diagnosis), CVD risk factor control, and CVD risk-reducing medication use. Risk difference multivariable regression analyses adjusting for age, race, poverty, PC risk category, and year were used to evaluate the effect of ADT on study outcomes. Results: Of 191,829 Veterans with newly diagnosed PC, 27% (n = 51,419) were treated with ADT within 1 year of diagnosis, and 18% (n = 34,110) had a pre-existing diagnosis of atherosclerotic CVD. From 2001-2017, annual rates of guideline-concordant CVD risk factor assessment increased from 26% to 77%. In adjusted analyses, pre-existing atherosclerotic CVD diagnosis was associated with higher CVD risk factor assessment rate (64% vs 53%), better control of baseline LDL (94 vs 108 mg/dL), and higher rates of anti-hypertensive (90% vs 66%), lipid-lowering (83% vs 49%), and glucose-lowering (32% vs 20%) medication use. Treatment with ADT was associated with similar to minimally higher rates of CVD risk factor assessment (58% vs 54%), LDL control (104 vs 105 mg/dL), and anti-hypertensive (73% vs 69%), lipid-lowering (55% vs 55%), and glucose-lowering (25% vs 21%) medication use. Sixty percent of men starting ADT had at least one sub-optimally controlled CVD risk factor, and 1 in 4 of these men were not receiving a corresponding risk-reducing medication. One third of men starting ADT had BMI > 30 kg/m2. Conclusions: CVD risk factor assessment in Veterans with PC has increased over time. However, ADT does not appear to meaningfully impact CVD assessment or management, despite its known association with CVD risk. Over half of patients initiating ADT had elevated CVD risk factor(s). Multi-disciplinary efforts to improve CVD risk mitigation are needed among men initiating ADT.
Late toxicities and recurrences in patients with clinical stage I nonseminomatous germ cell tumor after one cycle of adjuvant BEP versus primary retroperitoneal lymph node dissection: A 13-years follow-up analysis of a phase III trial cohort.
Authors: Hiester Andreas , Fingerhut Anna , Niegisch Guenter , Siener Roswitha , Krege Susanne , Schmelz Hans U. , Dieckmann Klaus-Peter , Heidenreich Axel , Kwasny Peter , Pechoel Maik , Lehmann Jan , Kliesch Sabine , Koehrmann Kai Uwe , Fimmers Rolf , Loy Volker Volker , Wittekind Christian , Hartmann Michael , Albers Peter 
Published: May 2020

5512 Background: One cycle of adjuvant BEP has shown superiority in recurrence free survival over RPLND in patients (pts) with clinical stage (CS) I nonseminomatous germ cell tumor of the testis (NSGCT) (JCO 2008). We report recurrences and late toxicities of this randomized trial after 13 yrs of follow-up (FU). Methods: Questionnaires of 382 unselected pts with CS I NSGCT treated within a phase III trial comparing recurrence rate after 1 cycle of adjuvant BEP (arm A) vs. RPLND (arm B) were evaluated regarding recurrences and late toxicity. Overall (OS) and progression free survival (PFS) was calculated by Kaplan-Meier and arms were compared using logrank test. Categorial data were analyzed by chi-square test (PRISM v8). Results: In each arm 191 pts were analyzed as intention-to-treat with a median FU of 13.75 yrs (0-22.9 yrs); 3/191 pts (1.6 %) in arm A and 16/191 pts (8.4 %) in arm B had a recurrence. 20-yrs PFS in arm A / B was 97 % (CI 96-99 %) / 92 % (CI 90-95 %), ( p = .0049). 20-yrs OS in arm A / B was 90 % (CI 86-94 %) / 88 % (CI 86-94 %), ( p = .83). 23/382 (6 %) pts have died, 22/23 not related to testis cancer, 1/23 died of a recurrence in arm B. 8/191 pts (4.2 %) in arm A and 4/191 pts (2.1 %) in arm B showed metachronous secondary testis cancer ( p = .26). 5/191 pts (2.6 %) in arm A and 4/191 pts (2.1 %) in arm B developed other malignancies. 170/382 questionnaires were evaluable (arm A: 95; arm B: 75). 45 pts were lost to FU. There were no significant differences comparing both treatment arms regarding potentially treatment-related late toxicities. However, excluding pre-existing complaints, ototoxicity (9/95 (9 %) vs. 4/75 (5 %) pts, p = .31) was reported more frequently in arm A. Excluding pre-existing neurological conditions, peripheral neuropathy of all grades was more frequently reported in arm A (15/95 pts; 16 % vs. 9/75 pts; 12 % pts; p = .48). Retrograde ejaculation occurred more frequently after RPLND (9/95 pts; 9% vs. 18/75 pts; 24 %, p = .01). Conclusions: After more than 13 yrs of FU, recurrences in non-risk factor selected pts with CS I NSGCT remain to be significantly more frequent with RPLND. No excess mortality due to secondary malignancies was observed. Late toxicities did not differ between 1 cycle of BEP and RPLND. Only retrograde ejaculation was observed significantly more frequent after RPLND. With long-term observation, 1 cycle of BEP has not only a high efficacy to prevent recurrence but also seems to be tolerated without clinically relevant long-term toxicity.
ProCAID: A randomized double-blind phase II clinical trial of capivasertib (C) in combination with docetaxel and prednisolone chemotherapy (DP) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Crabb Simon J. , Griffiths Gareth Owen , Marwood Ellice , Dunkley Denise , Downs Nichola , Martin Karen , Light Michelle , Northey Josh , Whitehead Amy , Shaw Emily C , Birtle Alison Jane , Bahl Amit , Elliott Tony , Westbury Charlotte , Sundar Santhanam , Robinson Angus , Jagdev Satinder , Kumar Satish , Khoo Vincent , Jones Robert J. 
Published: May 2020

5520 Background: DP extends survival in mCRPC, but clinical benefit is modest. PI3K/AKT/PTEN pathway activation is common in mCRPC contributing to disease progression and DP resistance. C is a pan-AKT inhibitor. Pre-clinical data indicate activity in prostate cancer and synergism with DP. This phase II trial combined C with DP in mCRPC. Methods: Key eligibility criteria: histologically or cytologically proven measurable or evaluable mCRPC, suitable for treatment with DP for PSA and/or radiographic disease progression, ECOG performance status 0-1, no prior chemotherapy for mCRPC, not requiring insulin or > 2 oral hypoglycaemic drugs for diabetes mellitus. Treatment: up to 10 cycles of DP (D: 75 mg/m2 IV, day 1; P: 5 mg bd oral, day 1 – 21) and random assignment (1:1, double blind) to oral C (320 mg twice daily, 4 days on/3 days off, from cycle 1, day 2) or matched placebo to disease progression. Primary endpoint: progression free survival (PFS; comprising PSA, radiographic or clinical progression, new cancer therapy or death; PCWG2 criteria) in the intent to treat (ITT) population. Secondary endpoints included overall survival (OS) and safety. PFS and OS were also assessed by composite biomarker (B) subgroup for PI3K/AKT/PTEN pathway activation status (NGS/IHC on archival tumour, contemporaneous ctDNA). Statistics: designed to detect a 50% increase in median PFS (6 to 9 months (mo)) between the placebo and C arms (90% power, 20% 1-sided alpha) by Cox proportional hazards model. Registration: ISRCTN 69139368. Results: 150 patients were randomised to 01/2019. Median follow up 16.77 months (IQR 12.0-26.5). PFS and OS by ITT and B status, are shown in the table (NR, not reached; CI confidence interval). Grade 3–4 adverse events (AE) were equally common between arms (62.2%). The most common AEs were diarrhoea, fatigue and nausea. Conclusions: Adding C to DP did not extend PFS. The OS secondary endpoint was significantly increased. PFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Clinical trial information: 69139368 . [Table: see text]
A urine exosomal circRNA classifier for detection of high-grade prostate cancer at initial biopsy: A multicenter, retrospective study.
Authors: Li Liaoyuan , Tao Wen , He Yadi , He Tao , Li Qing , Wu Zhenquan , Deng Weiming , Zhang Lingxiao 
Published: May 2020

5522 Background: The low specificity of prostate-specific antigen (PSA) has resulted in the overdiagnosis and overtreatment of clinically indolent prostate cancer (PCa). We aimed to identify a urine exosomal circular RNA (circRNA) classifier that could detect high-grade (Gleason score [GS]7 or greater) PCa. Methods: We did a three-stage study that enrolled eligible participants, including PCa-free men, 45 years or older, scheduled for an initial prostate biopsy due to suspicious digital rectal examination findings and/or PSA levels (limit range, 2.0-20.0 ng/mL), from four hospitals in China. We used RNA sequencing and digital droplet polymerase chain reaction to identify 18 candidate urine exosomal circRNAs that were increased in 11 patients with high-grade PCa compared with 11 case-matched patients with benign prostatic hyperplasia. Using a training cohort of eligible participants, we built a urine exosomal circRNA classifier (Ccirc) to detect high-grade PCa. We then evaluated the classifier in discrimination of GS7 or greater from GS6 and benign disease on initial biopsy in two independent cohorts. We used the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to evaluate diagnostic performance, and compared Ccirc with standard of care (SOC) (ie, PSA level, age, race, and family history). Results: Between June 1, 2016, and July 31, 2019, we recruited 356 participants to the training cohort, and 442 and 325 participants to the two independent validation cohorts. We identified a Ccirc containing five differentially expressed circRNAs (circ_0049335, circ_0056536, circ_0004028, circ_0008475, and circ_0126027) that could detect high-grade PCa. Ccirc showed higher accuracy than SOC to distinguish individuals with high-grade PCa from controls in both the training cohort and the validation cohorts. (AUC 0.831 [95% CI 0.765-0.883] vs 0.724 [0.705-0.852], P = 0.032 in the training cohort; 0.823 [0.762-0.871] vs 0.706 [0.649-0.762], P = 0.007 in validation cohort 1; and 0.878 [0.802-0.943] vs 0.785 [0.701-0.890], P = 0.021 for validation cohort 2). In all three cohorts, Ccirc had higher sensitivity (range 71.6-87.2%) and specificity (82.3-90.7%) than did SOC (sensitivity, 42.3-68.2%; specificity, 40.1-62.3%) to detect high-grade PCa. Using a predefined cut point, 202 of 767 (26.3%) biopsies would have been avoided, missing only 6% of patients with dominant pattern 4 high-risk GS 7 disease. Conclusions: Ccirc is a potential biomarker for high-grade PCa among suspicious men.
AR enhancer and locus genomic alterations as cell-free DNA biomarkers of primary resistance to AR-directed treatment of metastatic prostate cancer.
Authors: Maher Chris , Dang Ha X. , Chauhan Pradeep S. , Ellis Haley , Feng Wenjia , Harris Peter , Smith Grace , Qiao Mark , Dienstbach Katherine , Beck Rachel , Atkocius Andrew , Qaium Faridi , Luo Jingqin , Michalski Jeff , Picus Joel , Pachynski Russell Kent , Chaudhuri Aadel 
Published: May 2020

5529 Background: Predicting primary resistance to androgen receptor (AR)-directed therapies is critical for personalizing treatment of metastatic prostate cancer (mPCa). Analyses of liquid biopsies are potential tools but remained underutilized due to limited sensitivity. We developed a cell-free DNA (cfDNA) assay (EnhanceAR-Seq) to monitor genomic alterations in mPCa including AR enhancer duplication, a resistance marker recently discovered in ~81% of mPCa patients. Here we show that applying EnhanceAR-Seq to plasma cfDNA to monitor alterations of AR gene and enhancer ( AR/enhancer) predicted primary resistance with high sensitivity and outperformed the clinically validated CTC AR-V7 assay. Methods: Forty mPCa patients were prospectively enrolled at the Washington University School of Medicine Siteman Cancer Center with plasma cfDNA analyzed by EnhanceAR-Seq. Twenty-five of them also had the Oncotype DX AR-V7 Nucleus Detect CTC assay performed at a similar timepoint at the discretion of the treating oncologist. All patients received AR-directed therapy (eg. abiraterone, enzalutamide) and underwent standard-of-care clinical and laboratory follow-up. Primary resistance was defined as PSA progression, change of treatment or death within 4 months of treatment initiation, or radiographic progression within 6 months. Results: Median clinical follow up after diagnosis was 50 months. EnhanceAR-Seq detected alterations targeting AR/enhancer in 18 patients (45%), TP53 in 8 patients (20%), and PTEN in 6 patients (15%). We found that AR/enhancer alterations (copy gain, tandem duplication, and point mutation) in cfDNA were strongly predictive of primary resistance to AR-directed therapy (PPV = 100%, Sens. = 89%). Our assay outperformed the CTC AR-V7 assay, which was positive in only two patients (PPV = 50%, Sens. = 6%). Furthermore, patients with AR/enhancer alterations had significantly worse progression-free survival (P = 0.0015; HR = 11.5) and overall survival (P = 0.0002; HR = 6.8). Finally, serial cell-free DNA analysis of 10 patients showed that AR/enhancer copy number gain was maintained or acquired in 5 of 6 AR-resistant cases, and neutrality maintained in 4 of 4 AR-sensitive cases. Conclusions: cfDNA-based AR/enhancer locus genomic alterations could potentially be used to predict primary resistance to AR-directed therapy with higher sensitivity than the clinically validated CTC AR-V7 assay, be used for serial timepoint monitoring and guiding personalized clinical decision-making.
Comparative effectiveness of systemic treatments for metastatic castration-sensitive prostate cancer: A parametric survival network meta-analysis of randomized controlled trials.
Authors: Wang Lin , Paller Channing Judith , Hong Hwanhee , De Felice Anthony , Alexander Caleb , Brawley Otis W. 
Published: May 2020

5532 Background: Treatment decision-making for metastatic castration-sensitive prostate cancer (mCSPC) is complicated by the unclear comparative effectiveness and widely varying costs of competing strategies. Objective: To compare the effectiveness and safety of systemic treatments for mCSPC. Methods: We searched bibliographic databases, regulatory documents, and trial registries for randomized controlled trials testing active drugs added to androgen deprivation therapy (ADT) for mCSPC. We used Cochrane risk-of-bias tool (version 2) to assess trial quality and Bayesian network meta-analysis (NMA) to estimate the relative effects of competing treatments. In addition to combing published time-invariant hazard ratios (HRs), we reconstructed survival data from Kaplan Meier curves to enable parametric survival NMA that allows time-varying HR. Results: Seven trials with 7,236 patients were included comparing six treatments (Table). Risk of bias is a concern for trials with open label (N=4), missing data (N=3), or unprespecified analysis (N=3). Ordered from the most to the least effective, treatments significantly improving overall survival (OS) include abiraterone acetate, apalutamide, and docetaxel; treatments significantly improving radiographic progression-free survival (rPFS) include enzalutamide, abiraterone, apalutamide, and docetaxel. (see HRs in Table) Allowing time-varying HR produced similar treatment rankings. Serious adverse events (SAE) were substantially increased for docetaxel (odds ratio [OR] 104.17, 95% credible interval [CI] 24.85-1012.32) and slightly increased for abiraterone (OR 1.42, 95% CI 1.11-1.83). Conclusions: Abiraterone provided the largest OS benefit with slightly increased risk of SAE. Apalutamide offered comparable OS benefit with abiraterone without increasing SAE risk. Although enzalutamide delayed rPFS to the greatest extent, longer follow-up is needed to examine its OS benefit. [Table: see text]
Overall survival (OS) with docetaxel (D) vs novel hormonal therapy (NHT) with abiraterone (A) or enzalutamide (E) after a prior NHT in patients (Pts) with metastatic prostate cancer (mPC): Results from a real-world dataset.
Authors: Swami Umang , Sinnott Jennifer Anne , Haaland Ben , Maughan Benjamin Louis , Rathi Nityam , McFarland Taylor Ryan , Kohli Manish , Nussenzveig Roberto , Pal Sumanta K. , Agarwal Neeraj 
Published: May 2020

5537 Background: NHT (A and E) are approved first-line (1L) treatment (Rx) for mPC. After progression on NHT, Rx include either alternate NHT or D. However, OS from a randomized trial comparing NHT vs D after progression on 1L NHT has not been reported. Methods: Pts data were extracted from the Flatiron Health EHR-derived de-identified database. Inclusion: diagnosis of mPC; 1L Rx with single agent A or E only, single-agent Rx with alternate NHT (E or A) or D in second line (2L). Exclusion: > 180 days between date of diagnosis of mPC and date of next visit to ensure Pts were actively engaged in care at data-providing site; Rx with NHT in non-metastatic setting, any prior exposure to D. OS was compared using Cox proportional hazards model stratified by Rx propensity score. Each Pts’ probability of receiving D (rather than NHT) was modeled via a random forest based on Pts and disease characteristics which may drive treatment selection. These included pre-2L Rx ECOG scores, PSA, LDH, ALPH, Hb, age, ICD codes for liver metastasis, diabetes, neuropathy, and heart failure; insurance payer, year of start of 2L Rx, time on 1 L NHT, Gleason score, PSA at the original diagnosis of mPC. Subgroup analyses included 1L Rx duration < 12 mos. Results: 1165 Pts between 2/5/2013 to 9/27/2019 were eligible. Median follow up 8 mos (range 0.1-64.5). Median OS after 1L A was higher with E as compared to D (15.7 vs. 9.4 mos). Median OS after 1L E was higher with A as compared to D (13.3 vs. 9.7 mos) (table). Propensity distributions were overlapping among Rx arms and showed only modest imbalance. In 2L, D had a worse adjusted hazard ratio of 1.29 and 1.35 as compared to E and A respectively (p < 0.05). Similar results were seen with 1L Rx duration of < 12 mos (p < 0.05). Conclusions: These hypothesis-generating data provide real-world OS estimates with 2L D & NHT in mPC. In propensity-stratified analyses, mPC Pts who progressed on NHT had a worse OS with 2L D as compared to alternate NHT. Results were consistent in unadjusted analysis & subgroup analyses of 1L Rx < 12 mos. Results are subject to residual confounding and missingness. After prospective validation these data may aid in Rx sequencing, Pts counselling, and design of future clinical trials in this setting. [Table: see text]