bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal trends and predictors in diagnosing pathologic node-positive prostate cancer in clinically node-negative patients.
Authors: Hutten Ryan , Parsons Matthew , Weil Christopher , Tward Jonathan David , Lester-Coll Nataniel Hernan , Johnson Skyler B 
Published: March 2021

128 Background: The management of men with pathologically node positive (pN+) prostate cancer (PCa) is controversial. Here, we describe the temporal patterns and predictors of incidental pN+ PCa men with clinically node negative (cN0) PCa. Methods: We performed a retrospective analysis of men with nonmetastatic, cN0, PCa from the National Cancer Database from 2010 to 2017. Clinical factors included in analysis were pretreatment PSA, pre-surgical International Society of Urological Pathology (ISUP) grade group (GG), clinical T-stage, margin status, and number of nodes sampled. Patient demographic factors included in analysis were age, comorbidity index, race, insurance status, and treatment facility type. We performed univariable and multivariable logistic regression to evaluate temporal trends in the rates of cN0,pN+ prostate cancer diagnosed over time. Two-level hierarchical logistic regression was used to identify covariates associated with pN+ disease. Patients were clustered within treatment facilities to account for individual facility practice patterns. Results: We identified 304,234 men with cN0 PCa who underwent radical prostatectomy (RP) between 2010 and 2017. Within this group 10,919 (3.59%) were found to have pN+ disease. During this period, the annual rate of pN+ PCa increased from 2.02% (n=822) in 2010 to 5.12% (n=2,072) in 2017 (p<0.001). On multivariable logistic regression, ISUP GG was most strongly associated with detection of pN+ PCa. Compared to ISUP GG1, GG2 (OR 3.5, p <0.001), GG3 (OR 8.8, p <0.001), GG4 (OR 12.6, p <0.001) and GG 5 (OR 26.5, p <0.001 ) were all significantly associated with pN+ PCa. Over the study period, the rates of pN+ identification increased from 5.5% to 9.4% in men with GG4, and from 13.4% to 19.5% in men with GG5 (p <0.001). Between 2010 and 2017, the rates of RP in GG4 and GG5 similarly increased by 12% and 16%, respectively (p <0.001). Other significant covariates are depicted in Table. 22% of the total variance was explained by inter-facility variation. Conclusions: The proportion of men with cN0 found to have pN+ PCa is increasing over time, with pN+ incidentally found in nearly 1 in 10 men with GG4 and 1 in 5 men with GG5 PCa. GG4 and GG5 are the strongest independent predictors of pN+ disease, while controlling for clinical and demographic factors. As incidental pN+ results in upstaging, often requiring adjuvant treatment with radiation and systemic therapies, these data are useful for informing discussions prior to RP. [Table: see text]
Abiraterone acetate in patients with metastatic castration-resistant prostate cancer, chemo-naive, who received a prior diethylstilbestrol therapy.
Authors: Bastos Diogo Assed , Pioner Giovani Thomaz , Panhoca Renato , Perez Marjo Deninson Cardenuto , Damião Ronaldo , Werutsky Gustavo , Vacari Estela Vacari , Ferreira Amanda Yaeza , Fabricio Vanessa Carvalho , Gidekel Rosemarie 
Published: March 2021

130 Background: The use of diethylstilbestrol (DES) for the treatment of metastatic castration resistant prostate cancer (mCRPC) is very common in developing countries. Retrospective data suggests that abiraterone acetate (AA) is active in patients that progressed to DES. This phase II study evaluated the efficacy and safety of abiraterone acetate in chemotherapy-naïve patients with metastatic CRPC who have progressed to DES. Methods: Patients with DES−refractory metastatic CRPC with ongoing ADT, serum testosterone level < 50 ng/dL and ECOG of 0-2 were included. All patients received AA 1,000 mg with prednisone 5 mg once daily in a 28 days cycles. The primary endpoint was the time to PSA progression (PSAP) by PCWG2 and was previously reported. We present here secondary endpoints: overall survival, PSA response, maximum PSA change from baseline and safety. Results: A total of 46 patients were enrolled, median age was 69.8 years, 76% had gleason > = 7 at diagnosis, median time from metastatic disease to DES discontinuation was 25.9 months, and a median duration of prior DES of 7.2 months. AA treatment resulted in median time to PSA progression of 7.3 months. PSA response rate (³ 50%) was 47.5% (95% CI: 36,1% to 68,5%) at 12 weeks and 57.5% (95% CI: 27.0% to 59.1%) at any time. 93.4% received chemotherapy after progression to AA. The median overall survival was 29.6 months. Substantial declines in serum androgens from baseline to week 12 occurred and in this group a higher proportion of PSA responses occurred. The incidence of adverse events (AEs) related to AA was 74% and prednisone 59%. Hypertension (21.7%), fatigue (19.6%) and oedema peripheral (13.0%) were the most frequent AA related AEs. The most frequent prednisone related AEs were hyperglycaemia (15.2%) hypertension (10.9%). Serious AEs occurred in 23.9% of subjects and 3 subjects (6.5%) died of AEs not related to study drugs. Conclusions: AA is well tolerated and demonstrated activity in mCRPC patients previously treated with DES, therefore it should be considered an option in chemo-naïve patients. Serum androgens levels tend to decrease with AA treatment and are associated with PSA responses. Clinical trial information: NCT02217566.
Gut microbiota-associated compounds increase lethal prostate cancer risk.
Authors: Naelitz Bryan Douglas , Reichard Chad A. , Wang Zeneng , Jia Xun , Li Jianbo , Stampfer Meir J. , Klein Eric A. , Hazen Stanley L. , Sharifi Nima 
Published: March 2021

147 Background: Gut-microbiota-mediated metabolism of trimethylamine-associated nutrients and amino acids has been linked to altered cholesterol metabolism and endothelial inflammation. However, the association between these compounds and lethal prostate cancer (PCa) remains unknown. Methods: A nested case-control study was performed using samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate the association between baseline serum levels of target metabolites (choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide, phenylacetylglutamine, hippuric acid, and p-cresol sulfate) and lethal PCa risk. Lethal cases were randomly matched to controls at a 1:3 ratio on the basis of age, race, and enrollment date. Multivariable logistic regression, conditioned on case status and adjusted for PSA and BMI, was performed to assess the association between analyte quartile (Q) with lethal PCa. Trend of increasing odd ratios (OR) was evaluated using the Cochran-Armitage test. Results: 173 lethal PCa cases and 519 controls were analyzed. Relative to those in Q1, cases with baseline levels of choline and betaine above the median exhibited increased odds of developing lethal PCa after adjusting for BMI and PSA (Table). Lethal PCa risk increased across quartiles of choline in a dose-dependent fashion ( P-trend: 0.005), but not for betaine (P-trend: 0.08). Higher serum levels of other trimethylamine-associated compounds including γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide were not consistently associated with PCa mortality. Baseline serum levels of phenylacetylglutamine, a gut-microbiota metabolite of phenylalanine, were associated with incident lethal PCa, with risk increasing across quantiles (P-trend: 0.003). Elevations in hippuric acid and p-cresol sulfate levels were not consistently associated with greater lethal PCa risk. Conclusions: Serum levels choline, betaine, and phenylacetylglutamine are associated with PCa mortality, underscoring the potential role of gut-microbiota-mediated metabolism in the biology of lethal PCa. Clinical trial information: NCT00002540. [Table: see text]
Prospective randomized trial of gene expression classifier utility following radical prostatectomy (G-MINOR).
Authors: Morgan Todd Matthew , Okoth Linda A. , Spratt Daniel Eidelberg , Dunn Rodney , Feng Felix Y , Johnson Anna M. , Lane Brian R. , Linsell Susan , Ghani Khurshid R. , Montie James E. , Mehra Rohit , Daignault-Newton Stephanie , Huang Huei-Chung , Todorovic Tamara , Davicioni Elai , Burks Frank , Rodriguez Paul , Sarle Richard , Miller David Christopher , Cher Michael L. ,   Michigan Urological Surgery Improvement Collaborative
Published: March 2021

15 Background: Decipher is a tissue-based genomic classifier (GC) developed and validated in the post-radical prostatectomy (RP) setting as a predictor of metastasis. We conducted the first prospective randomized controlled trial assessing the use of a prostate cancer GC, with a primary objective to determine the impact of test results on adjuvant treatment decisions. Methods: The Genomics in Michigan ImpactiNg Observation or Radiation (G-MINOR) randomized trial enrolled participants across 12 centers between January 2017-August 2018. Eligible patients had undergone RP within 9 months of enrollment, had pT3-4 disease and/or positive surgical margins, and a PSA < 0.1ng/mL. Patients were assigned to either the GC or Usual Care (UC) group using cluster-crossover block randomization. Patients and providers in both arms received a CAPRA-S recurrence risk score. Decipher scores were obtained on RP tissue of all patients, but patients and providers in the UC arm were blinded to the results. The primary endpoint was the impact of impact of GC test result on adjuvant treatment decisions compared to clinical factors alone within 18 months of RP. Results: 356 patients were randomized and 340 had at least 18 months of follow-up. Of these, all but 2 control (UC) patients had sufficient tissue to pass quality control for GC testing. Randomization resulted in 175 (51.5%) GC and 165 (48.5%) UC patients. There were no significant differences in clinical variables or Decipher scores between arms. At 18 months post-RP, 19 (10.9%) patients in the GC group and 12 (7.3%) patients in the UC group had received adjuvant treatment. In the primary analysis, availability of the GC score in the GC arm was significantly associated with adjuvant treatment in GC high-risk patients after controlling for CAPRA-S risk (OR 7.6, 95%CI 1.95-29.6, p = 0.009). In the GC arm, both GC score (OR 8.8, 95%CI 1.9-39.7, p = 0.005) and CAPRA-S score (OR 3.8, 95%CI 1.09-12.9, p = 0.04) were independently associated with adjuvant treatment in a multivariable logistic regression model. Conclusions: In the first ever randomized trial testing the impact of a prostate cancer genomic classifier on treatment decisions, the use of a GC post-RP impacted post-operative treatment in a manner concordant with classifier risk. Further follow-up will be necessary to assess the impact of GC testing on oncologic outcomes. Clinical trial information: NCT02783950. [Table: see text]
Identification of prognostic and predictive biomarkers of overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel, prednisone (DP) +/- bevacizumab (B) in CALGB 90401 (Alliance).
Authors: Halabi Susan , Yang Qian , Starr Mark D. , Brady John C. , Armstrong Andrew J. , George Daniel J. , Kelly William Kevin , Beltran Himisha , Morris Michael J. , Nixon Andrew B. 
Published: March 2021

154 Background: CALGB 90401 was a phase III trial of 1050 pts with mCRPC comparing DP+B versus DP alone. While this trial did not show an improvement in OS in the overall population, there were improved PSA response, objective responses and delays in progression suggesting that subsets of men may derive benefit from this combination The purpose of this analysis was to identify and validate plasma angiokines (PAs) that are prognostic or predictive of OS and PFS benefit from bevacizumab in men with mCRPC. Methods: Baseline EDTA plasma samples from 679 consenting pts were analyzed using an optimized multiplex ELISA platform for 25 PAs related to tumor growth, angiogenesis, and inflammation. The data were randomly split into training (n = 462) and testing (n = 217) sets. The proportional hazards model was utilized to test for the prognostic and predictive importance of the PAs in predicting OS and PFS, with and without adjustment for clinical risk score. Analyses were adjusted for multiplicity using false discovery rate (FDR). Results: For the prognostic analysis, 14 PAs (angiopoeitin-2, BMP9, Chromogranin A, HER3, HGF, ICAM-1, IL6, OPN, PIGF, TIMP, TSP2, VEGFA, VEGFR1, and VEGF-R3) were prognostic of OS and 8 PAs (angiopoietin-2, HER3, ICAM-1, IL6, OPN, TIMP, VEGFA and VEGF-R3) were prognostic of PFS in the training set (FDR < 0.05). None of the PAs were statistically significant for OS or PFS when adjusting by the clinical risk score, suggesting that angiokine levels associate with clinical prognostic factors. OPN was predictive of OS in the training set but no other PAs were found to be predictive of PFS improvement with DP+B. Using the testing set, we were unable to validate that OPN is predictive of OS/PFS or any of the PAs are predictive biomarkers of the OS or PFS benefits of DP+B over DP alone in men with mCRPC. Conclusions: While PAs are prognostic for OS and PFS in univariate analysis, we were unable to validate the results in the testing set. Furthermore, we did not identify any PAs that are predictive of benefit from the addition of bevacizumab to docetaxel/prednisone with ADT in this setting. Nevertheless, these remain worthy of further evaluation as potential therapeutic targets.
Plasma cell-free DNA profiling of PI3K/Akt pathway aberrations in two multi-institutional independent metastatic castration-resistant prostate cancer (mCRPC) cohorts.
Authors: Kwan Edmond Michael , Dai Chao , Fettke Heidi , Hauser Christine , Bukczynska Patricia , Ng Nicole , Foroughi Siavash , Graham Lisa-Jane K. , Mahon Kate Lynette , Tan Winston , Wang Amy , Zhao Zhixin , Zheng Tiantian , Zhou Kemin , Yu Jian-Jun , Du Peter , Horvath Lisa , Jia Shidong , Kohli Manish , Azad Arun 
Published: March 2021

159 Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p< 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p< 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]
HHV-8 positive clinically advanced castrate-resistant prostate cancer (mCRPC): A potentially distinct molecular subset.
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Spiess Philippe E. , Danziger Natalie , Lin Douglas I. , Huang Richard , Mata Douglas A , Decker Brennan James , Gjoerup Ole , Sokol Ethan , Tukachinsky Hanna , Venstrom Jeffrey Michael , Ross Jeffrey S. 
Published: March 2021

163 Background: Herpesvirus HHV-8 has been detected in normal prostate tissue and has been linked to the acquisition of androgen-independent growth of prostate cancer cells in vitro, early development of anti-androgen therapy resistance, and more aggressive disease in a subset of patients with mCRPC. We used comprehensive genomic profiling (CGP) to test the hypothesis that HHV-8 associated mCRPC is a distinct molecular subset of mCRPC featuring altered AR signaling compared to HHV-8 negative mCRPC. Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 4,918 mCRPC were sequenced to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). HHV-8 status was determined by CGP-based identification of unique viral reads. Results: Overall, 128 (2.6%) of the mCRPC cases harbored HHV-8 sequences (Table). The patient age distribution was similar in the HHV-8+ and HHV-8− groups. GAs in AR, predominantly amplifications, and RAD21 were slightly reduced in HHV-8+ mCRPC cases (P = .01 for both). The frequencies of GAs in genes associated with mCRPC including PTEN, BRCA2, ATM, CDK12, and the TMPRSS2: ERG fusion were similar in the two groups. HHV-8+ patients were less likely to be of European ancestry (P = 0.001). Putative biomarkers associated with immunotherapy response (MSI status, TMB, and PD-L1 expression) were also similar in the two groups. Conclusions: HHV-8+ mCRPC is a rare sub-type of mCRPC with lower frequency of AR GAs compared to HHV-8− mCRPC cases, suggesting a potential role of HHV-8 in inducing androgen-independent prostate cancer growth. Additional alterations associated with potentially enhanced PARP inhibitor response seen in HHV-8+ mCRPC (e.g., RAD21) suggest that early performance of CGP may inform precision treatment strategies to be tested in clinical trials. [Table: see text]
Genomic landscape of CDK12 mutated metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Spiess Philippe E. , Danziger Natalie , Huang Richard , Mata Douglas A , Decker Brennan James , Sokol Ethan , Montesion Meagan , Tukachinsky Hanna , Venstrom Jeffrey Michael , Ross Jeffrey S. 
Published: March 2021

165 Background: Identifying prostate cancer patients likely to benefit from immune checkpoint inhibitors (ICPI) remains an unmet need. Specific loss-of-function genomic alterations (GA) in CDK12 are associated with focal tandem duplications linked to fusion-induced production of neoantigens and are a promising candidate biomarker for ICPI. Using comprehensive genomic profiling (CGP) we compared the GA landscape of CDK12 altered (CDK12mut+) and unaltered (CDK12mut-) tumors. Methods: 4,918 mCRPC tumors were sequenced using a hybrid capture-based FDA-approved CGP assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining -49% and high staining ≥50% expression. Results: Overall, 315 (6.4%) of the mCRPC cases were CDK12mut+ (Table). CDKmut+ cases had significantly fewer GA in TMPRSS2: ERG (P < .0001), TP53 (P < .0001), PTEN (P < .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P < .0001) and APC (P = .002). CDK12mut+ cases featured higher frequencies only in CCND1 (P < .0001), BRAF (P = .007) and ERBB2 (P < .001) as well as in cell cycle regulatory genes including MDM2/4 (P < .0001), CDK4 (P < .0001) and CDK6 (P = .002). CDK12mut+ cases featured more frequent MSI-H status (P = .007), significantly higher median TMB (P < .001) and more frequent low positive (1-49% staining) PD-L1 expression (P = .02). High (≥50%) PD-L1 expression was rarely identified in either cohort. Conclusions: CDK12mut+ mCRPC demonstrates a unique genomic profile with significant differences compared with CDK12mut- mCRPC. Lower frequencies of GA associated with homologous recombination defect and mTOR pathway may impact the use of platinum agents, as well as PARPi and PIK3CA/Akt/mTOR inhibitors. Opportunities for targeted therapies for BRAF and ERBB2 driven mCRPC may be enriched in the CDK12mut+ tumors and raise the possibility of combination therapy strategies although the numbers of patients are small and validation is needed. The slightly higher MSI High status, median TMB and PD-L1 staining may be associated with additional benefit from ICPI and warrants further prospective investigation. [Table: see text]
Bilateral disease and risk of prostate cancer progression in an active surveillance cohort.
Authors: Khondakar Nabila , O'Connor Luke P. , Williams Cheyenne , Daneshvar Michael , Egan Jillian , Yerram Nitin , Webster Brad , Merino Maria , Choyke Peter L. , Wood Bradford , Turkbey Baris , Pinto Peter A. 
Published: March 2021

207 Background: Active surveillance (AS) is considered the standard of care for managing patients with low-risk prostate cancer. Identifying risk factors for disease progression on AS can improve risk stratification. As previously described, the presence of bilateral disease may affect disease progression. Current systematic biopsy techniques inadequately predict presence of bilateral disease. We hypothesize that combined mpMRI-guided fusion biopsy and systematic biopsy will improve detection of bilateral disease. Methods: Our institutional database of patients referred for AS from 2007-2020 was queried. All AS patients received combined 12-core systematic biopsy and mpMRI-Fusion biopsy (Cbx), and those with Gleason Grade group 1 (GG1) on confirmatory Cbx were included. Cox regression analysis identified baseline characteristics associated with AS progression, defined as progression to GG ≥ 2. The distributions of GG and National Comprehensive Cancer Network (NCCN) risk categories were also compared. Results: 103 patients with prostate cancer and at least one follow-up biopsy at our institution were included in the analysis. 30% (31/103) had bilateral disease and 70% (72/103) had unilateral disease. On univariable and multivariable analysis, both PSAD (univariable HR = 1.6; 95% CI: 1.1-2.2; multivariable HR = 1.7; CI: 1.2-2.5) and presence of bilateral disease (univariable HR = 2.2; 95% CI: 1.3-4.0; multivariable HR = 2.2; 95% CI: 1.2-4.0) at time of confirmatory biopsy were significantly associated with AS progression. On Kaplan-Meier analysis, median time from Cbx to AS progression ≥ GG2 for the whole cohort was 52 months (95% CI: 44 - 68). The median time to progression for patients with unilateral and bilateral disease was 68 months and 52 months, respectively (log-rank test, p = 0.0055). Bilateral disease was marginally associated with receiving an NCCN score of high or very high on upgraded biopsy (RR: 3.16, 95% CI: 1.004-9.932). NCCN score at time of confirmatory biopsy was not associated with progression. However, NCCNs scores and GG at time of progression were higher among patients with bilateral disease (p = 0.015 and p = 0.024). Ultimately, use of combined biopsy resulted in 16.1% more bilateral cancers detected when compared to systematic biopsy. Conclusions: Detection of bilateral disease using combined biopsy was significantly associated with disease progression in patients on AS. Notably, combined biopsy resulted in greater detection of bilateral disease than systematic biopsy alone. Identifying presence of bilateral disease using combined biopsy could ultimately contribute to management decisions in patients on AS.