bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of elderly patients (pts) treated with docetaxel (DOC) for metastatic castration-sensitive prostate cancer (mCSPC): Results from ECHOS, a multicenter Italian observational study.
Authors: Caffo Orazio , Maruzzo Marco , Pravisano Federico , ButtIgliero Consuelo , Sorarù Mariella , Masini Cristina , Gori Stefania , Sabbatini Roberto , Pappalardo Annalisa , Cattrini Carlo , Fornarini Giuseppe , Vittimberga Isabella , Rametta Alessandro , Zucali Paolo Andrea , Fantinel Emanuela , Grillone Francesco , Fratino Lucia , Galli Luca , Giordano Monica , Basso Umberto ,   on behalf of ECHOS trial group
Published: January 2024

153 Background: ECHOS trial is a large real-world study which is collecting data on mCSPC patients treated in the daily clinical practice in Italy from 2015. To date, > 1500 pts were included in the study, most of them treated with DOC, according to the availability of the active agents over the time in Italy. In the present analysis, we assessed the outcomes of pts ≥75 yrs old who received DOC for mCSPC. Methods: We retrospectively and prospectively reviewed the clinical records of a consecutive series of mCSPC pts treated with DOC in the daily clinical practice in 69 Italian Hospitals. The treatment mostly consisted of DOC at the standard dose of 75 mg/sqm every 3 wks for six courses. For each pt we recorded the pre and post-DOC clinical history, the baseline characteristics of the pts, the treatment details and clinical outcomes. For the purpose of the present study, we considered only pts who ended chemotherapy by September 2022. Results: Among 920 mCSPC pts treated with DOC, 132 (14.4%) were ≥ 75 yrs old. Most of them (76%) presented de novo disease with high-volume features. Their baseline characteristics were similar to those of younger pts excepting for baseline hemoglobin levels which were significantly lower in older pts (median 12.6 vs 13.5; p = 0.001). Older pts received either a reduced dose (16.7%) or a modified schedule (8.4%) more frequently than younger one (p < 0.0001). Thirty-six pts experienced a grade 3-4 toxicity, which was mainly hematological (75% of the cases). The median progression-free survival (PFS) was 12.6 mos in older pts compared to 14.9 mos observed in younger ones (p 0.2). The median number of life prolonging agents administered after DOC progression was 1 in pts ≥75 yrs as well as in pts < 75 yrs. The median overall survival (OS) was 27.9 mos and 42.4 mos in older and younger pts, respectively (p < 0.0001). Conclusions: Our data suggest that DOC was efficacious and well-tolerated in mCSPC pts ≥75 yrs although the treatment was administered with either dose or schedule modifications in about 25% of the cases. No differences were observed in terms of PFS between pts ≥75 and ones < 75 yrs. Nevertheless, the median OS of older pts was significantly worse compared to that of younger ones.
Novel dual inhibitors of AR/AR variants and AKR1C3: Preclinical activities for advanced prostate cancer therapy.
Authors: Gao Allen , Ning Shu , Armstrong Cameron , Xing Enming , Lou Wei , Li Pui-Kai , Evans Christopher P. 
Published: January 2024

169 Background: AR/AR-variants and AKR1C3 play critical roles in prostate cancer progression and driving resistance to antiandrogens, and are attractive targets for therapeutic intervention for advanced prostate cancer. However, there are currently no clinically available therapies that simultaneously target both AR/AR variants and AKR1C3. We have developed the novel small molecule inhibitors, LX-1 and its analog LX-1S, which target both the AR-V7 splice variant and the enzyme AKR1C3. Methods: A library of the LX compounds was designed and synthesized according to structure based computer modeling. The effects of the lead LXs on the expression and activity of AR/AR-variants and AKR1C3 were evaluated. RNA-seq was performed on the lead LXs. Resistant cell sublines generated from C4-2B cells resistant to enzalutamide (MDVR), apalutamide (ApalR), darolutamide (DaroR), or abiraterone (AbiR) were treated with LX-1 or their respective antiandrogen. Mice bearing VCaP xenograft tumors and LuCaP35CR PDX tumors were treated with LX-1/LX-1s and effects on tumor growth were assessed. Results: Molecular docking studies and in vitro experiments demonstrated that LX compounds effectively bind to the AKR1C3 active site and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and inhibit their target gene signaling, induce G0/G1 arrest in anti-androgen resistant cell lines. LX-1/LX-1S treatment resulted in reduced tumor volumes and decreased intratumoral testosterone in both xenograft tumor and PDX models. LX-1 effectively inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. Moreover, LX-1 synergized with enzalutamide and abiraterone as well as docetaxel, suggesting its potential to enhance the anti-tumor activity of these standard therapies in resistant prostate cancer. Furthermore, LX-1/LX-1S improved enzalutamide treatment in resistant prostate cancer tumor models. Notably, LX-1S demonstrates significantly better bioavailability and efficacy than LX-1 in reducing resistant cell growth in both in vitro and in vivo animal models. Conclusions: Our study unveils the potential of LX compounds, especially LX-1 and its analog LX-1S, as promising therapeutic agents for advanced prostate cancer. These compounds not only inhibit AR and AKR1C3 signaling but also suppress resistant tumor growth and synergize with antiandrogens to enhance their therapeutic efficacy.
Outcomes for patients with mCRPC and liver metastasis receiving 177-Lu-PSMA-617 treatment.
Authors: Muniz Miguel , Sartor A. Oliver , Mahmoud Ahmed M. , Orme Jacob , Kwon John Y. , Andrews Jack R. , Kase Adam McLain , Mosalem Osama M , Bryce Alan Haruo , Riaz Irbaz Bin , Thorpe Matthew , Kendi Ayse T. , Johnson Geoffrey , Ravi Praful , Kwon Eugene D. , Childs Daniel S 
Published: January 2024

175 Background: It is well-known that patients with liver metastases from metastatic castration resistant prostate cancer (mCRPC) have poorer or transient responses to many forms of systemic therapy. Data on outcomes following treatment with Lutetium-177–PSMA-617 is scarce. The VISION trial reports hazard ratios for overall survival in the subgroup of patients with liver metastases without disclosing the absolute duration of survival. Using real-world clinical data, we examine this important subgroup of patients, describing their PSA response rates and survival. Methods: A single institution database was assembled to include all patients receiving 177-Lu-PSMA-617 at Mayo Clinic Rochester, MN, and starting treatment in the interval of March 2022 to March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were categorized based on the presence or absence of measurable liver metastases on their baseline PSMA PET scan. Best PSA response while on treatment was annotated and reported as percent decline from baseline. Survival was calculated from date of first cycle of 177-Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (liver metastases versus no liver metastases) were compared using Chi square test and Kaplan-Meier method, respectively. Those with available pre-treatment circulating tumor DNA (ctDNA) genomic profiling, performed by Guardant (83 gene panel), were assessed for the presence of pathogenic and likely pathogenic alterations. Findings are summarized using descriptive statistics. Results: The overall cohort consisted of 212 patients, including 29 (14%) with liver metastases on pre-treatment PSMA PET/CT. The median number of cycles received was 4 (range, 1-6) for patients with liver metastases and 6 (range, 1-6) for those without hepatic involvement. The observed PSA50 response trended lower for those with liver metastases (34.5% [10/29] versus 51% [94/183], p= 0.091). At median (IQR) follow-up of 10 (8-12) months, there was a numerical but not statistically significant difference in median OS (11.28 months versus NR, p=0.066). In the exploratory analysis of baseline ctDNA, BRCA2 copy number loss was relatively enriched among patients with liver metastases (4 of 19, 21%) versus patients without liver disease (5.7%, 9/158). Conclusions: Our data suggest that the presence of liver metastases predict poorer outcomes in patients receiving Lutetium-177–PSMA-617 treatment, which is similar to data reported with other forms of systemic therapy for mCRPC. To maximize the anti-tumor activity of radioligand therapy in the liver, combination approaches should be explored.
Men with adrenal-permissive HSD3B1 genotype and prostate cancer mortality: Results from the Veterans Affairs Health System Million Veteran Program.
Authors: McKay Rana R. , Nelson Tyler J. , Pagadala Meghana , Teerlink Craig , Gao Anthony , Bryant Alex , Agiri Fatai , Guram Kripa , Pridgen Kathryn , Seibert Tyler M , Lee Kyung Min , Carter Hannah , Lynch Julie Ann , Hauger Richard , Rose Brent S. 
Published: January 2024

207 Background: The 3β-HSD1 protein, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary of non-testicular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding 3β-HSD1 protein with decreased susceptibility to degradation resulting in increased of extragonadal androgen synthesis. Retrospective studies have suggested an association with the HSD3B1 CC genotype and resistance in prostate cancer. Methods: We conducted a cohort analysis of patients with a diagnosis of prostate cancer enrolled in the Million Veteran Program with genotyping and phenotyping information available through Veterans Health Administration. The primary endpoint was to evaluate prostate cancer-specific mortality (PCSM) in the overall cohort. PCSM was defined as the time from diagnosis to death from prostate cancer, censored at the date of last VA follow-up. Secondary endpoints included incidence of metastases and PCSM in predefined subgroups. HSD3B1 genotype status was categorized as AA (wild type), AC (heterozygous), CC (homozygous). Results: The study included 5287 men with prostate cancer; 402 (7.6%) HSD3B1 CC, 1970 (37.3%) HSD3B1 AC, and 2915 (55.1%) HSD3B1 AA. The cohort included 29.6% (n=1567) Black men of whom 1.2% (n=19) were HSD3B1 CC. Cumulative incidence of PCSM at five years after prostate cancer diagnosis was higher among men homozygote for HSD3B1 variant genotype CC compared to heterozygotes AC and wild-type homozygotes AA (1.9% for AA vs. 2.1% for AC vs. 4.0% for CC, p<0.017). While the cumulative incidence of metastases was similar in between HSD3B1 genotype groups (12.3% for AA, 11.8% for AC, 13.2% for CC, p=0.789), in patients who developed metastatic disease (n=619), the cumulative incidence of PCSM at five years was higher in the HSD3B1 CC group compared to AC and CC (19.2% for AA vs. 17.6% for AC vs. 37.3% for CC, p<0.005). Conclusions: Among men with prostate cancer, HSD3B1 CC genotype is associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-HSD1 and the androgen-signaling axis.
11-Ketotestosterone and time to castration resistance in patients with recurrent non-metastatic prostate cancer receiving androgen deprivation therapy.
Authors: Guillemette Chantal , Dahmani Cylia , Caron Patrick , Simonyan David , Lacombe Louis , Aprikian Armen G. , Saad Fred , Carmel Michel , Chevalier Simone , Levesque Eric 
Published: January 2024

209 Background: The contribution of 11-oxygenated androgens to disease progression in men receiving androgen deprivation therapy (ADT) for recurrent non-metastatic prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the potent androgen receptor (AR) agonist 11-ketotestosterone (11KT), could serve as a potential predictor for the onset of castration resistance (CRPC). Methods: The multi-institutional prospective PROCURE cohort involves 2,026 patients who underwent radical prostatectomy for localized PCa. In this cohort, a subset of 145 patients who received ADT therapy for recurrent disease and had available plasma samples post-surgery were included in this study. The effect of therapy on steroid levels was assessed in paired samples obtained before and after the initiation of ADT (n=50), and samples from patients under combined ADT with AR pathway inhibitors, enzalutamide (n=10) and abiraterone (n =15). 11-oxygenated androgens (n=7) and canonical steroids, such as testosterone (T) and dihydrotestosterone (DHT), were quantified by mass spectrometry. Kaplan-Meier survival analyses were used to investigate relationships of androgen levels with the occurrence of CRPC. Results: 11-oxygenated androgens remained unaffected by ADT, which stands in contrast to the observed changes in T, DHT and other steroids. In men with castrated T levels, 11KT was the most abundant androgen. Elevated 11KT was associated with a sooner time to CRPC ( P=0.023). The 10-year CRPC event-free rate was 63% vs. 84% for 11KT levels above and below the median, respectively. The initiation of enzalutamide had no impact on 11-oxygenated androgen levels, whereas abiraterone significantly reduced 11KT levels owing to the adrenal origin of its precursor. Conclusions: Our findings indicate that 11KT is a significant component of the hormonal profile predictive of an earlier onset of CRPC and inhibition of its production by the CYP17A1 inhibitor abiraterone.
Estimating median overall survival of apalutamide compared to placebo in metastatic hormone-sensitive prostate cancer (mHSPC) populations: Statistical extrapolations of the TITAN study.
Authors: Agarwal Neeraj , Bjartell Anders , Juárez Álvaro , Kerßenboom Ronja , Perualila Nolen , Wigfield Peter , Chi Kim N. 
Published: January 2024

223 Background: Apalutamide plus ADT (APA) demonstrated significantly improved overall survival (OS) compared to placebo plus ADT (PBO) for patients with mHSPC in the TITAN study (HR, 0.65; 95% CI, 0.53 to 0.79; P < .0001). At the time of final analysis, the median OS was not reached in the APA arm or subgroups after a median follow up of 44 months. This work aimed to estimate OS medians for APA and PBO arms beyond the TITAN follow-up by fitting validated survival models. Methods: OS was predicted for the overall population treated with APA or PBO, with or without Inverse probability of censoring weighting (IPCW) crossover adjustment, and for the low and high-volume (LVD, HVD), HVD synchronous and HVD metachronous subgroups. General population mortality adjusted TITAN patient-level data was fitted to six parametric models (Weibull, exponential, log-normal, log-logistic, generalized gamma, and Gompertz) using the individual fits approach. Best fit was determined by statistical and visual fits, along with the Akaike Information Criterion (AIC)/Bayesian Information Criterion (BIC) ranking, according to the recommendations of the National Institute for Health and Care Excellence Decision Support Unit 14. Results: Best fit extrapolation estimated median OS of 71.8 months for the overall mHSPC population treated with APA (Table), leading to an estimated median improvement of up to 32 months versus PBO. Median OS values predicted by the other five models ranged from 62.4 to 78.1 months. Across subgroups, best fit models estimated median OS of 113.7 months for APA in LVD and a consistent median OS of 52 months for HVD subgroups. Conclusions: While results of this extrapolation study should not be equated to those of a clinical trial, this analysis meets an evidence gap by predicting median OS in the APA arm of the TITAN study for the overall mHSPC population as well as for various subgroups of this heterogeneous population, strengthening the evidence supporting early treatment with APA across the broad mHSPC population. [Table: see text]
A novel blood-based mRNA genomic test for screening, early detection, prognosis, and monitoring of prostate cancer: A multicenter study.
Authors: Hashimoto Yutaka , Verma Shiv , Deng Guoren , Chauhan Dharam P , Nair Sujit , Yoshino Hirofumi , Arima Junya , Liu Yutong , Hatano Koji , Shivakumar Yogesh , Krishnappa Raghunath S. , Chandran Chitra , Ragavan Narasimhan , Enokida Hideki , Nonomura Norio , Balaji K C , Rawal Sudhir K , Tewari Ashutosh K. , Dahiya Rajvir , Gupta Sanjay 
Published: January 2024

271 Background: Current screening tools, including prostate-specific antigen (PSA) and clinicopathologic parameters, have limitations in the diagnosis and prognosis of prostate cancer. This study examined whether genomic biomarkers can improve screening and monitoring of prostate cancer. Methods: We identified a panel of 25 prostate cancer-related genes through rigorous bioinformatics, computational analyses and genetic testing. These tests, developed by Geneverify Inc. (Hayward, CA; U.S. patent # 10801072 and 10822661) were utilized and optimized by qRT-PCR to determine the diagnostic and prognostic ability of prostate cancer using blood and tissues. The log2-fold increase in gene expression was used to assign the risk score to individual patients. ROC (receiver operator characteristic), AUC (area under ROC curve), and calibration curves were generated to display the overall performance and discrimination ability to separate cancer and non-cancer specimens. Results: A total of 419 prostate cancer patients (135 blood and 284 tissue samples) and 130 normal samples were analyzed in this study. The eligibility criteria were to collect blood and surgical specimens from patients with prostate cancer from 9 hospitals. The study endpoints were to analyze mRNA genomic profiling and correlate with clinicopathologic parameters of the patients. In the blood, a 25-panel gene-set separated prostate cancer patients (n=135) from non-cancer (n=30), AUC = 0.906 [sensitivity = 90% and specificity = 91%]. Assessment of tissue specimens from benign (n=100) and cancer patients (n=284) showed similar results with AUC = 0.9514 [sensitivity = 95% and specificity = 94%]. Interestingly, patients with Gleason grades (GS) >7 showed higher expression of these genes compared to GS <7, suggesting the prognostic ability of the gene-set. When we compared the gene expression in blood verses tissues, there were similar patterns, suggesting that blood can be used for screening, diagnosis and risk assessment of prostate cancer. Conclusions: To our knowledge, this is the first study to investigate the role of mRNA-based genomic signatures for screening, early diagnosis and prognosis of prostate cancer using blood samples. Our data suggest that blood mRNA-genomic profiling developed by Geneverify has the ability to diagnose prostate cancer and stratify patients into distinct prognostic groups, which in turn help in making better treatment strategies.
A novel cardiovascular disease risk score for prediction of atherosclerotic disease events in men with prostate cancer.
Authors: Stabellini Nickolas , Tan Min Choon , Cullen Jennifer , Weintraub Neal L , Shanahan John , Agarwal Neeraj , Patel Sagar A. , Montero Alberto J. , Guha Avirup 
Published: January 2024

314 Background: Prostate cancer patients (PC) face an elevated risk of both developing atherosclerotic cardiovascular disease (ASCVD). The American College of Cardiology Pooled Cohort Equations (PCE) for ASCVD predictions may lack accuracy. Methods: Males ≥18 years, diagnosed with PC between 2005-2012 at a hybrid academic-community practice were included. Using XGBoost algorithm we developed using a training subset of the cohort (50% train + 25% test), ranked 33 covariates (including demographic, treatment-related and social determinants of health (SDOH) information) for ASCVD prediction using SHAP (Shapley additive explanations) values. The top 10 predictors were transformed in a predictive equation using logistic regression models. This equation was tested in the cohort validation subset (25%), and subsequently compared to the PCE risk score. Results: We included 1,506 patients, with a median age of 67 (IQR 60-74) years, 13.8% had advanced stage disease (TNM III-IV), 1.5% had high risk PC (Gleason 8-10), and 20.5% received androgen deprivation therapy (ADT). Of those, 10.4% had a 10-year ASCVD risk. The PCE had an area under the curve (AUC)=0.61 and underestimated ASCVD in 0.9% (mean risk=20.1% [95% CI 17.2-23.0] vs. mean predicted risk=19.2% [95% CI 18.6-19.8]). The equation pooled from the top-10 predictors of the ML algorithm (C-index=0.78 [95% CI 0.75-0.81]) achieved an AUC=0.71 (Table). Conclusions: Conventional PCE tend to underestimate ASCVD risk in males with PC. A cancer-specific model inclusive of SDOH exhibits good performance for predicting ASCVD risk in this population. [Table: see text]
Post radical prostatectomy (RP) PSA outcomes following 6 versus 18 months of perioperative androgen receptor signaling inhibitors (ARSI) in men with localized high-risk prostate cancer: Results of Part 2 of a randomized phase 2 trial.
Authors: McKay Rana R. , Xie Wanling , Yang Xiaoyu , Acosta Andres , Rathkopf Dana E. , Laudone Vincent Paul , Bubley Glenn , Einstein David Johnson , Chang Peter , Wagner Andrew , Kane Christopher J. , Preston Mark A. , Kilbridge Kerry L. , Chang Steven Lee , Choudhury Atish Dipankar , Pomerantz Mark , Trinh Quoc-Dien , Kibel Adam S. , Taplin Mary-Ellen 
Published: January 2024

326 Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, abiraterone acetate, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. We demonstrated favorable pathologic responses (tumor ≤5 mm) in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant AAPL. Methods: At Part 2, patients were randomized 1:1 to AAPL for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (<ypT3 or ≥ypT3). The primary endpoint was biochemical progression-free survival (bPFS) at 3 years post-RP. Secondary endpoints included safety and time to testosterone recovery (>200 ng/dL). Results: Overall, 69% (n=82/118) of patients enrolled to Part 1 were randomized to Part 2, of whom 58.5% (n=48) had ≥ ypT3 disease at RP. Patient preference was the main reason for non-randomization in Part 2. Of patients not randomized to Part 2, 32.3% (n=10) had a pathologic complete response or minimum residual disease (tumor ≤5 mm) at RP. In the intent-to-treat analysis, 3-year bPFS was 81% for Arm 2A and 72% for Arm 2B; the difference was not statistically significant (HR 0.81 90% CI 0.43-1.49). In a post-hoc per-protocol analysis, the 3-year bPFS was 83% for AAPL treated patients and 69% for patients on observation (HR 0.50 90% CI 0.26-0.97). Of patients randomized to Part 2, 81% of patients had testosterone recovery in the AAPL treated group compared to 95% in the observation group with median to recovery of 8.7 months compared to 4.0 months, respectively. Of the 37 patients receiving AAPL on Arm 2A, 28 (75.7%) experienced any grade treatment-related adverse event (TRAE) and 4 (10.8%) had grade 3-4 TRAE. The most common any grade TRAE were fatigue (27%) and hypertension (16%). Conclusions: Neoadjuvant ADT in localized high-risk prostate cancer resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, Part B of the study was underpowered to detect a difference between treatment arms. Subsequent studies will evaluate clinical and molecular predictors of bPFS. Clinical trial information: NCT02903368 .