bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-Year result of single-institute cohort study in single-fraction HDR monotherapy for localised prostate cancer.
Authors: Ahmed Imtiaz , Tun Khin Sandar , Shibuthomas Sharon , Cain Alex , Mahar Sadia , Yoganayagam Nicola , Cyriac Abby , Choudhury Mahbuba , Dawam Daben 
Published: March 2023

362 Background: The aim if this single institute UK-based study was to look at 3-year and 5-year bRFS and toxicity profiles. Methods: It is a prospective data study with a total number of 174 patients who were treated with single-fraction HDR monotherapy between July 2014 and February 2017. Biochemical recurrence is defined using Phoenix criteria. Results: The median age was 67.5 years with the median presenting PSA of 8. Majority of patients were lower risk group with 55% for combined low and favourable intermediate risks. 81 patients had Gleason score 6(3+3) and 77 patients had GS 7(3+4). Total hormone duration was 8 months and median duration of hormone prior to HDR monotherapy was 4 months. Overall bRFS at 3 years was 96% and 5 years was 88%. 5-year bRFS as per risk stratification was 100% in low risk, 92% in favourable intermediate risk, 83% in unfavourable intermediate risk and 79% in high-risk groups. This study had better 5-year overall bRFS compared to published data in single fraction HDR monotherapy (88% vs 73.5%, p value 0.001) (Morton et al., 2020). Despite inferior 5-year overall bRFS in compared to 2-fractionated HDR monotherapy (88% vs 95%) (p value 0.001), no difference in 5-year bRFS noted in low and favourable intermediate risk groups (100% vs 100% and 92% vs 93% respectively) (Morton et al., 2020). Two-thirds (71%) of biochemically recurred patients found to have local recurrence disease. The median time of biochemical recurrence was 47 months. Higher risk groups had higher 5-year biochemical recurrence risk. Acute and late toxicity profiles were minimum with acute G2 GU toxicity (2%) and GI toxicity (1%); late G2 GU toxicity (2%) and GI toxicity (0%) with no G3, G4 GU or GI toxicities. Conclusions: This prospective study had shown better overall 5-year bRFS especially in low and favourable intermediate risk groups with minimal toxicities. Therefore, single-fraction HDR monotherapy could be considered for elderly or patients with significant co-morbidities who are more suitable for single treatment rather than 2 fractions in these risk groups. Further randomised multicentre studies in these risk groups are suggested.
A phase II study of rucaparib monotherapy in nonmetastatic, hormone-sensitive prostate cancer (nmHSPC) with “BCRAness” genotype (ROAR).
Authors: Sahu Kamal Kant Kant , Li Haoran , Mathew Thomas Vinay , Benson Mallory , Hawaks Josiah , Brown Julian , Thorne Kelli , Sherwin Kathy , Cheney Jackson , Boucher Kenneth M. , Gupta Sumati , Kohli Manish , Swami Umang , Agarwal Neeraj , Maughan Benjamin L. 
Published: March 2023

364 Background: Prostate cancer (PCa) patients (pts) with DNA repair defects (aka “BRCAness”) generally have more aggressive disease and a worse overall prognosis compared to men without BRCAness (PMID: 33781305). Biochemical recurrence (BCR) develops in almost one-third of men with PCa after treatment with local therapy. We hypothesized that treatment with rucaparib monotherapy in men with systemic treatment naïve high-risk nmHSPC would result in acceptable disease control, allow a delay of androgen deprivation therapy (ADT) and the onset of metastasis. Methods: This is a single-arm, open-label, phase II trial; eligibility criteria: (1) Histologically proven prostate adenocarcinoma, presence of one of the following alterations in (by soft tissue or liquid biopsy): BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, NBN, PALB2, RAD51C, RAD51D, RAD51, RAD51B, (2) No radiographic evidence of metastatic disease by conventional scans (3) PSA doubling time of ≤10 months. The primary endpoint: PSA progression-free survival (PSA-PFS). Secondary endpoints: safety, the proportion of pts with a PSA 50% response (PSA50), and an undetectable PSA. Results: Seven pts were enrolled in the study with the following pathogenic alterations: ATM (n=3), BRCA2 (n=2), BRCA1 (n=1), BRIP1 (n=1), RAD51(n=1), and received treatment with rucaparib at 600 mg twice daily. A 4-week treatment duration comprised one cycle. The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI: 0 - 85.11 months). 2/7 patients achieved PSA50; both had nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 pt each). No dose-limiting toxicities or severe AEs were seen. The study was prematurely terminated in June 2022 after the accrual of 7 pts because next-generation scans (e.g., PSMA-PET) became the standard of care for pts with BCR. Conclusions: Rucaparib demonstrated acceptable toxicity and preliminary efficacy in pts with PCa with BCR. Gene alteration-specific efficacy will be presented in the meeting. Limitations: Small cohort, no comparison arm. Hence results should be interpreted cautiously but generally consistent with larger prospective trials of PARP inhibitors. Clinical trial information: NCT03533946 . [Table: see text]
Germline DNA damage response (DDR) mutations in an East Asian (EA) cohort with prostate cancer (PCa).
Authors: Lua Joanne Y.H. , Chan Johan W.K. , Ong Enya H.W. , Chow Melody , Tay Kae-Jack , Tuan Jeffrey K.L. , Wang Michael L.C. , Lee Lui Shiong , Kanesvaran Ravindran , Khor Li Yan , Chua Melvin L.K. Lee Kiang 
Published: March 2023

373 Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. Additionally, germline mutations in DDR genes are linked to PCa susceptibility. Here, we report the germline DDR mutation frequencies in an EA PCa cohort, and their associations with clinicopathological indices and outcomes. Methods: We utilized a prospectively recruited cohort of 891 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline mutation profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Following joint genotyping, common variants of ≥1% were filtered, and only variants defined as pathogenic (P)/likely pathogenic (LP) in ClinVar or predicted to be P by CADD or REVEL were retained. We used a 32 DDR gene-set for tests of association with clinicopathological indices, biochemical relapse-free rate (bRFR), and distant metastasis-free survival (DMFS). Results: Median follow up was 54 (33-83) mo; median age at diagnosis was 70 (64-74) y. 741 (84%) men had localized PCa, 65 (7%) had N+M0, and 80 (9%) had M1 disease. Among those with localized PCa, 417 (56%) were stratified as NCCN high/very high. 5-year DMFS was 100%, 96%, 86%, and 74% for NCCN low, intermediate, high/very high, and N+M0 PCa, respectively. 31 (3.5%) men in our cohort harbored a P/LP variant in at least one of the 32 DDR genes; P/LP variants were most frequently observed for BRCA2 (N=11[1.2%]), ATM (N=6[0.7%]), and RAD50 (N=5[0.6%]). P/LP variants were more frequent in men with N+M0/M1 compared with those with localized PCa (29% vs 16%, P=0.05), and in men with GS 9-10 vs 6-8 tumors (43% vs 20%, P=0.002). Presence of P/LP DDR variants were significantly associated with bRFR (HR 2.44 [95% CI:1.0-6.1], P=0.049) in M0 patients treated with RT+/-hormonal therapy on univariable and multivariable analyses. Conclusions: Herein, we observed lower frequencies of germline DDR P/LP mutations in our EA PCa cohort than other published Chinese cohorts (Wei, et al. 2018; Wei, et al. 2020). Nonetheless, there was a strong trend for increased incidence of DDR mutations with more advanced PCa. Men with DDR mutations were more likely to fail treatment than men without. [Table: see text]
Comparative transcriptomic analysis of DNA-damage response and androgen receptor pathway activity between biopsy and radical prostatectomy specimens before and after pre-operative real-time MRI-guided stereotactic body radiotherapy.
Authors: Nagar Himanshu , Dillard Alicia , Hakansson Alexander K. , Liu Yang , Davicioni Elai , Wolfe Sydney , Hu Jim C. , Scherr Douglas , Khani Francesca , Marciscano Ariel E. E. , Barbieri Christopher 
Published: March 2023

375 Background: Pre-Prostatectomy MRI-Guided Stereotactic Body Radiotherapy for High-Risk Prostate Cancer Trial (PREPARE SBRT; NCT03663218) is an ongoing clinical trial testing the safety of preoperative MRI-guided SBRT for men with clinically localized high-risk prostate cancer. We sought to compare transcriptomic profiles of biopsy (Bx) specimens to acutely irradiated radical prostatectomy (RP) specimens. Methods: Biopsy and post-irradiated RP specimens from 10 subjects were examined. The median interval between the end of RT and the date of RP was 5 days. Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before irradiation and RP samples post-irradiation using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for effects in tissue preservation from the procedure different of Bx vs RP. Linear regression model with the interaction effect of cohort (SBRT vs control) by procedure (Bx vs RP) to select signatures impacted by radiation treatment. Results: Transcriptomic signatures associated with Androgen Receptor (AR) activity were significantly downregulated (p=0.002) in irradiated RP specimens compared with pre-treatment biopsies. Analysis of DNA damage repair (DDR) pathways demonstrated that nucleotide excision repair (NER) and non-homologous end joining (NHEJ) signatures were increased (p=0.002 and p=0.02, respectively) after pre-operative RT whereas homologous recombination (p=0.06) and mismatch repair (p=0.08) were not significantly different between pre-treatment and irradiated tissues. Several metabolic-associated pathways were impacted by pre-operative RT including increased glycogen metabolism (p=0.008) and a NADH-NADPH conversion (p=0.001) signature indicative of RT-induced oxidative damage. Consistent upregulation of transcriptomic features associated with increased angiogenesis (p=0.0012) and stromal remodeling (p=0.0008) was observed in irradiated samples. Conclusions: Paired transcriptomic analysis following pre-operative RT demonstrated differential upregulation of specific DDR pathways including NHEJ and NER and metabolic alterations related to oxidative stress and glycogen metabolism. AR activity signatures were decreased in response to pre-operative RT.
Metformin for biochemical recurrence of prostate cancer: Immune data from a phase 2 study.
Authors: Bilusic Marijo , Toney NIcole J , Donahue Renee Nicole , Karzai Fatima , Madan Ravi Amrit , Schlom Jeffrey , Gulley James L. , Rai Priyamvada , Due Cassie , Gregory Philip , Mateo-Victoriano Beatriz , Plimack Elizabeth R. , Geynisman Daniel M. 
Published: March 2023

377 Background: Metformin impacts immune response in several ways. It protects CD8 TILs from apoptotic death, downregulates CD39 and CD73, reduces MDSC activity and suppresses the transcription of PD1 thus enhancing CD8+ T cell antitumor activity (Ma et al, 2000, Nature). There is limited data on the immunologic impact of metformin treatment in hormone sensitive prostate cancer. Methods: We conducted an open label, randomized, phase II trial of bicalutamide with or without metformin of patients with high risk, biochemically recurrent prostate cancer (NCT02614859). Patients were randomized 1:2 to observation for an initial 8 weeks or metformin 1000 mg twice daily. Bicalutamide 50 mg/day was added after 8 weeks to both arms. The study discontinued accrual after interim analysis indicated no difference in PSA at 32 weeks between the two arms; however, metformin monotherapy for 8 weeks induced modest PSA declines observed in 40% of patients. Here we report immune responses in a subgroup of patients (N=12), including systemic cytokine levels and 158 circulating immune cell subsets after 8 weeks of metformin monotherapy. Results: Twelve patients treated at the NCI were analyzed. After 8 weeks, the metformin arm showed increased pDCs and lower Tregs compared to baseline. Significant differences in the percent change of immune parameters after 8 weeks of metformin monotherapy compared to 8 weeks of observation are summarized. Conclusions: Metformin has been shown to reduce markers of immune exhaustion in hormone sensitive prostate cancer which is supported by a greater reduction of PD-1+ and Tim3+ NK cells. Additional immune changes included increases in activated subpopulations of natural killer (NK) cells, which have been reported as a potential predictive biomarker of prolonged treatment response to hormone therapy in prostate cancer (Pasero et al, Oncotarget, 2015). Clinical trial information: NCT02614859 . [Table: see text]
Limited relevance of the “very low risk” prostate cancer classification in the modern era: Results from a large institutional active surveillance cohort.
Authors: Shee Kevin , Cowan Janet E. , Washington Samuel L. , Nguyen Hao G , Shinohara Katsuto , Carroll Peter , Cooperberg Matthew R. 
Published: March 2023

381 Background: Although the American Urological Association recently dropped the “very low risk” (VLR) category for prostate cancer (PCa), the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum based on number of positive biopsy cores, tumor extent in each core, and PSA density. This subdivision may be outdated in the modern era in which targeted prostate biopsies are common practice. We identified the proportion of VLR patients at our institution to determine whether an alternative classification may be more appropriate for risk-stratification in the modern era. Methods: Participants were diagnosed from 2000-2019 with cT1-2N0/xM0/x PCa, PSA <20ng/ml, biopsy Gleason grade group (GG) 1-2, and initially managed with AS. VLR PCa was defined as <3 positive cores, ≤50% cancer per core, and PSA density <0.15. UCSF-CAPRA score was calculated for each patient. The primary outcome was major upgrade (≥GG3) on subsequent biopsy. Multivariable Cox proportional hazards regression models were used to calculate associations between CAPRA score and risk of major upgrade, adjusting for age, genomic testing, and prostate MRI finding. Results: Of 1554 patients initially managed with AS, 364 (23%) met NCCN VLR criteria. 49 (3%), 781 (50%), 505 (33%), and 219 (14%) patients had CAPRA scores of 0, 1, 2, and 3, respectively. Proportion of patients deemed VLR decreased over time; among 84 patients initially managed with AS during or after 2018, only one patient (1%) met VLR criteria in 2018, while the stratification by CAPRA demonstrated that 21 (25%), 25 (30%), and 38 (45%) patients had CAPRA scores of 1, 2, and 3, respectively, over the same period. CAPRA score was significantly associated with major upgrade on biopsy on multivariable Cox proportional hazards regression modeling independent of age, genomic testing, and MRI finding (HR 1.46, 95%CI 1.22-1.74, p<0.01). Conclusions: The relevance of VLR PCa in the modern targeted biopsy era has diminished, with no cases meeting VLR criteria in a large AS cohort after 2018. CAPRA score is an option for a more contemporary risk stratification tool for men on AS.
The difference in serum testosterone recovery between Gn-RH Antagonist and LH-RH agonist among patients with prostate cancer treated with radiation therapy.
Authors: Takei Akinori , Sakamoto Shinichi , Niino Jun , Takeuchi Nobuyoshi , Kanesaka Manato , Sazuka Tomokazu , Imamura Yusuke , Akakura Koichiro , Ichikawa Tomohiko 
Published: March 2023

382 Background: Only limited data exist related to the serum testosterone (TST) recovery after discontinuation of Gn-RH antagonist (Degarelix acetate). In the present study, we investigated the difference in serum testosterone (TST) recovery between LH-RH agonist and Gn-RH antagonist among prostate cancer (Pca) patients received radiation therapy in combination with androgen deprivation therapy (ADT). Methods: We analyzed the association between TST levels after the end of endocrine therapy and clinical factors in 130 patients who underwent ADT for prostate cancer at Chiba University hospital between May 2003 and May 2020. The proportional hazards model and Kaplan-Meier methods were used for the statistical analysis. Results: The median patient age and PSA were 72 years, and 16.8ng/mL, respectively. The median initial TST and nadir TST were 457 ng/dL, and 20ng/dL, respectively. The median duration of ADT was 857 days. As factors affect the speed of recovery to the castration level (TST 50 ng/dL), univariate analysis showed that Gn-RH antagonist presented the significantly shorter TST recovery compared to those of LH-RH agonist (HR 1.9, p=0.0078), together with the duration of hormone therapy (857 days) and Nadir TST level (20 ng/dL), GS8 and PSA (16.8ng/mL). Multivariate analysis showed that Nadir TST level was an independent predictor (HR 2.0, p=0.0093). As factors affect the speed of recovery to the physiological level (TST 200 ng/dL), univariate analysis showed that Gn-RH antagonist presented the significantly shorter TST recovery compared to those of LH-RH agonist (HR 2.1, p=0.0064). Multivariate analysis showed that duration was the only independent predictor (HR0.34, p=0.0029). Kaplan-Meier curve demonstrated shorter time for the TST recovery in Gn-RH antagonist compared to the LH-RH agonist for the castration level (p=0.0064) and the physiological level (p=0.0052). Conclusions: TST recoveries were significantly shorter in Pca patients treated with Gn-RH antagonist than LH-RH agonist. Nadir TST value, duration, and a type of LH-RH drug may comprehensively suggest us the dynamics of TST recovery after ADT. [Table: see text]
Disparities in prostate cancer survival outcomes in Appalachian Kentucky.
Authors: Pandey Deepali , Chen Quan , Huang Bin , Myint Zin , Wang Peng 
Published: March 2023

39 Background: Prostate cancer (PC) is the most common male cancer in the United States and the second leading cause of cancer-related death. Our group previously reported that men from Appalachian Kentucky had worse survival outcomes compared to non-Appalachian Kentucky and general population. This survival difference could be mainly due to socio-economic disparities. However, several new treatments have been approved for metastatic PC (mPC) in the last decade and these current standard of care (SOC) therapies have significantly improved survival outcomes in mPC. Therefore, we aim to investigate whether the recent change in SOC treatments have improved overall survival (OS) in patients with Appalachian (App) Kentucky vs. Non-Appalachian (Non-App) Kentucky from 2004–2019. Methods: All male patients who were > 20 years old with primary diagnoses of prostate adenocarcinoma, listed in Kentucky cancer Registry (KCR), diagnosed between 2004 and 2019, were included in the study. Basic demographics and survival outcomes were compared for all stages of PC and between App and Non-App Kentucky. We also compared the survival difference between two time periods 2004- 2011 vs. 2012-2019. Kaplan Meir and multivariate Cox Regression were performed to compare patients’ overall survival (OS). Results: A total of 36,695 patients were included in this retrospective analysis, of which 74.3% were Non-App and 15.7% were App. Caucasians predominated in both groups (N-App 85% vs. App 97%). The majority of Kentucky patients were aged between 50-74 years (79%). App Kentucky was noted to have more poorly differentiated histology (44.4% vs 40.1%), high Gleason score (26.4% vs 20%), more distant disease at the time of diagnosis (8.3 vs 6.7%), and higher percentage of patients with smoking history (40.1% vs 34.9%) compared to Non-App, respectively. A higher proportion of Non-App Kentucky had private insurance (35%) at the time of cancer diagnosis compared to more patients enrolled in Medicare (56.6%) or Medicaid (4.7%) in App. There was a survival difference between App and Non-App Kentucky by univariate analysis (p<0.001). In multivariate Cox regression showed that Non-App patients had better OS (p<0.001; HR=0.92, 95%CI 0.87-0.96). Patients diagnosed in the years 2012- 2019 had better survival compared to patients in 2004 – 2011 group (p=0.01; HR=0.94, 95%CI 0.9-0.99). Other factors that contributed to better survival include younger age, lived in the metro area, had private insurance, being a nonsmoker, being lower stage, and receiving treatment. We got similar result for stage IV patients, but the App variable was not significant in the COX regression (p=0.2). Conclusions: Our study shows that Appalachian has worse outcomes compared than Non-Appalachian Kentucky based on population-based analysis from 2004-2019. Additional research is needed to understand the health care disparities in App Kentucky.
Inherited risk for prostate cancer (PCa): Following the natural history of men with high-risk genetics using multiparametric MRI (mpMRI).
Authors: Couvillon Anna , Turkbey Baris , Choyke Peter L. , Lee-Wisdom Katherine , McKinney Yolanda , Sidlow Robert , Mullane Michael P. , Giri Veda N. , Morgan Todd Matthew , Cheng Heather H. , Merino Maria J. , Figg William Douglas , Pinto Peter A. , Dahut William L. , Karzai Fatima 
Published: March 2023

390 Background: PCa has inherited risk factors including high genetic risk variants such as BRCA1/2, HOXB13, and DNA mismatch repair genes. mpMRI has been shown to be effective for detection and staging of localized PCa. This study follows participants (prts), born biologically male, without a diagnosis of PCa with known germline pathogenic or likely pathogenic variants (PV) in BRCA1/2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C/D, BRIP1, or FANCA-FANCM (NCT03805919). Methods: Up to 500 eligible prts 30-75 years old (yo) with a documented germline PV will enroll. Prts undergo biennial clinical exam and mpMRI, and annual PSA monitoring and are followed at 12-month intervals to determine PSA, prostate cancer diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes clinical or imaging findings. Biopsy specimens undergo molecular analyses. Results: To date, 175 prts have been enrolled: 169 (97%) White, 3 Hispanic (2%), 1 African American (1%), 1 Asian (1%), and 1 biethnic (1%). Median age is 47 yo. The most common monoallelic PV are: 48.6% BRCA2, 25.1% BRCA1, 6.3% CHEK2 and 5.7% MSH2. PVs in ATM, PALB2, HOXB13, PMS2, MLH1, MSH6, BRIP1, EPCAM and RAD51D are ≤4%. One subject carries three distinct PVs ( BRCA2, CHEK2, BRIP1). Indication for biopsy was found in 26.3% of prts with 22/46 (47.8%) with a PIRADS 4 lesion, 6/46 (13.0%) PIRADS 3 lesion, 12/46 (26.1%) elevated PSA (median=2.8 ng/mL) or 6/46 (13.0%) due to clinical discretion. Adenocarcinoma was diagnosed on 13/39 (33.3%) biopsies with median age at diagnosis=59 yo. 9/13 (69%) prts had a PSA <3 ng/ml at diagnosis. Nine prts were diagnosed with ISUP Grade Group (GG) 1, 3 with GG2, and 1 with GG3. Eight prts opted for active surveillance (AS), 2 for radiation therapy (RT), and 3 for prostatectomy (RP). Two prts on AS converted to definitive treatment (one RP and one RT) due to progression in GG on the year 1 AS biopsy. Conclusions: mpMRI screening in men with germline PV can be used for diagnosis and monitoring of PCa and facilitates detection below conventional PSA thresholds in a high genetic risk setting. Access to genetic testing and other variables need to be addressed in underrepresented minorities. Correlative studies, including cfDNA and PBMCs, are ongoing. Clinical trial information: NCT03805919 . [Table: see text]