bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort.
Authors: Pagadala Meghana , Lynch Julie Ann , Karunamuni Roshan , Alba Patrick , Lee Kyung Min , Agiri Fatai , Anglin-Foote Tori , Carter Hannah , Gaziano J. Michael , Jasuja Guneet Kaur , Deka Rishi , Rose Brent S. , Panizzon Matthew , Hauger Richard , Seibert Tyler 
Published: February 2022

155 Background: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man’s risk of dying from prostate cancer and thus inform screening decisions. This might be especially useful in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Our object was to determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Methods: We analyzed the Million Veteran Program (MVP), a multi-ancestry population of over 500,000 individuals participating in the VA healthcare system. Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer (first-degree relative) and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. The primary outcome studied was age at death from prostate cancer. The key secondary outcome was age at diagnosis of prostate cancer metastases. Cox regression was used to test associations. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group ( p <10-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio (HR80/20) for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer (Table). PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.[Table: see text]
Abiraterone decanoate (PRL-02): Pharmacology of a single intramuscular (IM) depot injection compared to oral abiraterone acetate (AA) in intact male rats.
Authors: Moore William R. , Sharp Matthew , Eisner Joel Robert , Bell Caroline , Freeman Stuart , Leesnitzer Tony , Schotzinger Robert 
Published: February 2022

160 Background: Oral AA is a standard of care for metastatic prostate cancer. The recommended daily AA 1000 mg dose produces high peak and low trough plasma concentrations that are associated with safety issues (e.g., hepatotoxicity) and inadequate efficacy, respectively. PRL-02 is a novel abiraterone prodrug undergoing evaluation in patients with advanced prostate cancer (NCT04729114). In chemically-castrate monkeys, single doses of PRL-02 suppressed androgens for 14 weeks at much lower plasma exposures than AA (Moore et al, ASCO GU 2021). The present study in intact male rats evaluated the systemic exposures and activity of PRL-02 compared to daily oral AA at 7 and/or 14 days post-treatment start. Methods: Sexually mature male rats (n=4 per timepoint) were administered a single IM dose of PRL-02 (90 mg/kg), daily AA (90 mg/kg) or IM/oral vehicle (VEH). Biological samples were collected on Day 7 (PRL-02/VEH; 0h) or Day 14 (PRL-02/AA/VEH; 2, 6 and 24h) post-dosing. Drug and androgen concentrations were determined by LC-MS/MS. Testicular CYP17 hydroxylase activity was measured ex vivo on Day 14. Results: The Day 14 plasma exposure from abiraterone was greater from AA (5.6 - 210 ng/mL) than from PRL-02 (1.15 – 1.37 ng/mL). However, for Day 14 tissue exposures (AUC0-24) from ‘total abiraterone equivalents’ (TAE; concentration of free abiraterone plus abiraterone from prodrug) were greater from PRL-02 in adrenal, testes, lymph node and bone target tissues than from oral AA; exposures from AA were only greater in non-target tissues such as liver and brain (Table). There was no measurable Day 14 CYP17 hydroxylase activity in testes following PRL-02 or AA dosing; inhibition appeared irreversible from PRL-02 and AA. Compared to VEH, a single IM dose of PRL-02 resulted in 81% and 75% reductions in plasma testosterone (T) on Days 7 and 14 post-dose, and an 80% reduction in testicular T on Day 14. Daily AA resulted in a 98% reduction in plasma T after 14 days. Conclusions: Single-dose IM PRL-02 blocked testicular CYP17 enzyme activity as effectively as daily AA in intact male rats and produced a durable large reduction in plasma T. The pharmacological activity, tissue and plasma distribution of TAE from IM PRL-02 in the rat model, along with results from prior monkey model studies, suggest the potential for a greater therapeutic index than from daily oral AA and support the ongoing evaluation of IM PRL-02 in patients with advanced prostate cancer.[Table: see text]
Quantifying molecular imaging patterns of treatment response or progression using a novel traffic light workflow within a prospective phase I/II trial of 177LuPSMA-617 and NOX66 (LuPIN).
Authors: Pathmanandavel Sarennya , Crumbaker Megan , Yam Andrew O. , Nguyen Andrew , Niman Remy , Wilson Peter , Sharma Shikha , Ayers Maria , Eu Peter , Stockler Martin R. , Martin Andrew James , Joshua Anthony M. , Emmett Louise 
Published: February 2022

166 Background: 177Lutetium PSMA-617 (LuPSMA) is an effective therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance may occur. We developed a quantitative workflow for serial PSMA PET/CT to optimise predictive and prognostic imaging biomarker capability for progression free (PFS) and overall survival (OS). Methods: 56 men with mCRPC previously treated with taxane chemotherapy and androgen signaling inhibitor were enrolled, receiving up to 6 doses of LuPSMA and a radiation sensitizer idronoxil (NOX66). 68Ga-PSMA-11 PET/CT was performed at study entry and exit. Traffic Light (TL) quantification workflow was developed to track changes in both tumour volume and intensity at a total body and lesional level. Lesions were classified as responding in green (>30% decline in volume), stable in yellow (<30% change in volume/intensity), progressive in red (>30% increase in volume/intensity, or new). Overall response pattern was categorised as responding ( green/yellow), low volume red (<50% progressive disease) or high volume red (>50% progressive disease). TL workflow results were correlated with PFS and OS. Results: 37/56 men underwent both entry and exit imaging. The median PSA decline was 77% (IQR 34-92%), and 70% (26/37) achieved PSA response >50%. PSA progression occurred in 54% (20/37) at exit imaging. Median PFS was 8.6 months (95%CI 5.6-11.6) and median OS 22 months (95% CI 18.6-25.6). 95% (35/37) had reduction in PSMA SUVmax (-26.1 (IQR +11.7 to -89.4)) and SUVmean (-3.3 (+2.9 to -14.2)). PSMA total tumor volume reduced in 68% (25/37) (median -0.64 liters (range +1.44 to -1.1)). On TL workflow, 24% (9/37) had responding/stable disease ( green/ yellow), 76% (28/37) had progressive disease ( red) of whom 41% (15/37) had low volume progression and 35% (13/37) high volume progression. Men with high volume progression had worse OS compared to responders (HR 0.18 (0.05-0.59), p 0.005), and low volume progression (HR 0.30 (0.11-0.80), p 0.02). 68% (19/28) had progression on both TL workflow and PSA, while 32% (9/28) had progression on TL workflow without PSA progression. In multivariable analysis, TL workflow and PSA progression at time of exit scans were independent predictors of OS (Table). Conclusions: This study demonstrates the feasibility of characterizing lesional response on molecular imaging with a quantification TL workflow. TL workflow response independently correlated with survival outcomes, indicating serial PSMA PET has prognostic biomarker potential. Clinical trial information: ACTRN12618001073291.[Table: see text]
Liquid biopsy AR/enhancer alteration detection before AR-targeted therapy and correlation with survival in metastatic castrate-resistant prostate cancer patients.
Authors: Shiang Alexander , Chauhan Pradeep S. , Dang Ha X. , Webster Jace , Ledet Elisa M. , Babbra Ramandeep K , Feng Wenjia , Harris Peter K. , Jaeger Ellen B. , Miller Patrick , Caputo Sydney , Cittolin Santos Giordano Fabricio , Pachynski Russell Kent , Sartor A. Oliver , Maher Christopher , Chaudhuri Aadel A 
Published: February 2022

171 Background: Patients with metastatic castrate-resistant prostate cancer (mCRPC) have a variety of different systemic therapy options, yet survival outcomes remain poor. To minimize the chance of rapid resistance, it is critical to be able to personalize therapy upfront. We previously developed a cell-free DNA liquid biopsy assay that tracks alterations in the androgen receptor ( AR) locus, including its upstream enhancer (EnhanceAR-Seq). This assay demonstrated the ability to stratify patients based on resistance to AR-directed agents after treatment started (Dang and Chauhan et al., JCO PO, 2020). Here we evaluated if the same approach can accurately risk-stratify patients with mCRPC prior to the initiation of first-line AR-targeted therapy. Methods: We performed EnhanceAR-Seq on plasma cell-free DNA samples from 55 mCRPC patients prior to the initiation of AR-targeted therapy. Forty-seven patients were treated with Abiraterone and eight with Enzalutamide. Five patients were excluded due to having already received AR-targeted therapy or being lost to follow-up. Kaplan-Meier analysis was performed, and progression-free survival (PFS) and overall survival (OS) were assessed in relation to AR/enhancer locus status (wild-type vs. altered). Results: Median follow-up time was 30 months. EnhanceAR-Seq noninvasively detected AR/enhancer locus alterations in 36% (18/50) of the patients in our cohort, while 64% (32/50) were determined to be wild-type. Alterations detected by the assay were AR amplification (12/18), AR nonsynonymous single nucleotide variants (4/18), AR truncation (2/18), and AR enhancer amplification (13/18). Eleven patients had both AR gene body and enhancer amplifications present. Strikingly, patients with AR/enhancer alterations detected in plasma cell-free DNA were found to have significantly worse outcomes, with median PFS of 16.3 (wild-type) vs. 10.8 months (altered) (p = 0.046; HR = 2.10), and OS trending toward significantly different with median 34.3 (wild type) vs. 24.7 months (altered) (p = 0.19; HR = 1.05). Conclusions: AR/enhancer locus alterations in patients with mCRPC, as detected noninvasively by EnhanceAR-Seq, corresponded with significantly worse PFS and trended toward significantly worse OS. Our results support the role of cell-free DNA AR/enhancer locus alterations as prognostic, and potentially predictive, biomarkers that enable more precise upfront risk stratification and treatment personalization.
Underutilization of standard of care (SOC) treatment intensification in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) by specialty.
Authors: Swami Umang , Hong Agnes , El-Chaar Nader N. , Nimke David , Ramaswamy Krishnan , Diessner Brandon , Sandin Rickard , Agarwal Neeraj 
Published: February 2022

183 Background: Intensification of androgen deprivation therapy (ADT) with docetaxel (DOC) or novel hormone therapies (NHTs) [abiraterone, enzalutamide, or apalutamide] has shown to improve survival outcomes and is SOC in men with mCSPC.1 However, recent evidence indicates that most pts still only receive ADT ± first-generation non-steroidal antiandrogens (NSAA).2-4 This is one of the first studies to assess the real-world utilization of intensified treatments as first-line (1L) therapies for pts with mCSPC by physician specialty. Methods: This retrospective study used the Optum health insurance claims database, which includes pt claims data from commercially insured and Medicare Advantage populations. Adult pts (≥18 years) had ≥2 claims for prostate cancer (PC) and ≥1 claim for metastasis (the first claim was index date) within 90 days (d) prior to, or any time after, the first claim for PC from January 2014– June 2019. 1L treatments included any systemic treatment for mCSPC within 90 d pre-index, plus any other treatment received within 180 d of the first. Physician specialty was determined from medical or pharmacy claims during 1L treatment and categorized as Urologist; Oncologist; urologists and oncologists (Both); or other specialties (Other). Treatment patterns and pt characteristics across specialties were analyzed descriptively. Results: Of 4,675 mCSPC pts identified, 16% received care from Urologists, 20% from Oncologists, 63% from Both, and 1% from Other. Pts seen by Urologists were more likely to be older and have Medicare compared to pts seen by the Oncologists or Both. Treatment intensification with NHT and/or DOC was numerically higher among Oncologists and Both compared with Urologists. However, all specialties prescribed ADT ± first-generation NSAA most frequently for 1L mCSPC treatment, even in patients with visceral metastases (Table). Conclusions: Despite evidence of improved survival with intensified treatment for pts with mCSPC, we observed its underuse by all specialties and even among pts with visceral metastases. Our results highlight a great need to advance the implementation of evidence-based medicine in mCSPC. 1. Sayegh N et al. JCO Oncol Pract 2021; OP2100206. 2. Ryan CJ et al. J Urol 2021; Online ahead of print. 3. Freedland S et al. Ann Oncol 2021; 32: S650-S651. 4. Freedland S et al. J Clin Oncol 2021; 39(Suppl 15): e5073.[Table: see text]
Genomic characterization of patients (pts) with de-novo high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) compared to those without dn-hv-mCSPC.
Authors: Sayegh Nicolas , Jo Yeonjung , Tripathi Nishita , McFarland Taylor Ryan , Kessel Adam , Nussenzveig Roberto , Chigarira Beverly , Li Haoran , Tandar Clara , Sahu Kamal Kant , Haaland Benjamin , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: February 2022

186 Background: Dn-hv-mCSPC have the poorest survival outcomes among various subsets pts with mCSPC (Fizazi, Lancet Oncol 2019). However, the molecular underpinnings behind the poor prognosis is not entirely understood. In this study, we aimed to assess the tumoral genomic characteristics in pts with dn-hv-mCSPC. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: patients with mCSPC with availability of tumor comprehensive genomic profiling (CGP) from a CLIA-certified lab before start of ADT. Clinically relevant genes previously reported to be associated with prognosis in metastatic prostate cancer were included: TP53, PTEN, RB1, BRCA2, CDK12, MYC, PIK3CA, SPOP, APC, CTNNB1, and, ATM. Variants of unknown significance and genomic aberrations present in < 5% pts were excluded. High-volume disease was defined per CHAARTED criteria. Genomic aberration prevalence was compared using a Chi-square test and was adjusted for false discovery (Benjamini-Hochberg). Results: 304 pts were eligible: dn-hv-mCSPC (N = 100) vs non-dn-hv-mCSPC (N = 204); median age 67 vs 63 years, median PSA at baseline 35 vs 14 ng/mL, median Gleason score 9 vs 9, visceral metastases 15% vs 3%. 41% and 27% of pts had ≥2 mutations in the dn-hv-mcSPC and non-dn-hv-mCSPC respectively (P = 0.01). Overall, most commonly mutated genes were TP53, TMPRSS2, and PTEN. Pts with dn-hv-mCSPC had higher frequency of TP53 (P = 0.016) and BRCA2 (P = 0.03) mutations. Conclusions: In this real-world patient population, dn-hv-mCSPC pts were shown to have a greater number of clinically relevant genomic aberrations. Detailed genomic landscape of these pts will be presented in the meeting. These hypotheses-generating data need external validation.
Randomized phase II trial of neoadjuvant abiraterone plus or minus cabazitaxel in high-risk prostate cancer: ACDC-RP.
Authors: Fleshner Neil E. , Hansen Aaron Richard , Chin Joseph , Winquist Eric , Van Der Kwast Theodorus , Lajkosz Katherine , Kenk Miran , Berlin Doron , Veloso Rosette , Sridhar Srikala S. , Hamilton Robert James , Kulkarni Girish S. , Finelli Antonio , Zlotta Alexandre R. , Joshua Anthony M. 
Published: February 2022

224 Background: High-risk prostate cancer has a significant risk of recurrence when treated with unimodal therapy. The utility of neoadjuvant therapy prior to radical prostatectomy (RP) has yet to be defined. The ACDC-RP study investigated the use of abiraterone acetate (AA) + prednisone (P) + leuprolide (LHRH) with or without cabazitaxel prior to RP in high-risk patients. Methods: This phase II trial randomized patients to Arm A (AA/P + LHRH + cabazitaxel 20 mg/m2 with peg-filgrastim 6 cycles) or Arm B (AA/P + LHRH) for 6 months prior to RP. The primary objective was to compare the rate of pathological complete response (CR) or minimal residual disease (MRD) between treatment arms. MRD was defined as ≤5% of prostate volume involved by tumor. We present RP pathological outcomes, safety signals, and early biochemical response data. Results: Out of 78 randomized participants, 70 completed the full course of study treatment and underwent RP. Across both treatment arms, 31 (44%) men achieved either CR or MRD; 5 men had CR (2 in Arm A) and an additional 26 men exhibited MRD (15 in Arm A), p = 1 between Arm A and B. Kaplan-Meier analysis demonstrated no difference in biochemical-free survival (BFS) rate between the two treatment groups. Patients who achieved a CR/MRD experienced significantly longer BFS. Conclusions: Study findings indicate significant tumor response with 44% of patients exhibiting CR/MRD, with no significant difference observed between the two treatment arms. Patients who exhibit CR/MRD experienced better BFS rates. Genomic efforts are underway to determine predictors of response. Clinical trial information: NCT02543255. [Table: see text]
The lexicon of PET/CT reports in prostate patients: Evaluating confidence.
Authors: Baumgartner Jessica , Tward Jonathan David 
Published: February 2022

232 Background: Pet/CT scans are increasingly used to evaluate prostate cancer patients with biochemical failure following surgery or radiation therapy for localized prostate cancer. We assessed the language used in report impressions to characterize the reader's confidence for lesions in various anatomic sites. Methods: Between 2015 and 2021, 419 fluciclovine PET/CT scan reports were identified in our institutional outcomes database. Thirteen phrases routinely used in the report impression section by radiologists at least once to characterize a lesion of interest were identified. The phrases were categorized in the following confidence categories: Definitive (positive, negative), Likely (consistent with, most likely, favors, probable), and Unsure (suspicious for, concerning for, non-specific, conspicuous, compatible with, borderline, unknown). The final analysis set included 353 reports where the prescan PSA value was known within the prior 90 days of the scan. Descriptive statistics, stratified by prescan PSA value, were used to characterize this language for the following anatomic regions: bone, regional lymph nodes, prostate fossa, prostate gland/seminal vesicles, other soft tissue. Results: Overall, definitive language was used between 34.6% to 87.1% of the time, depending on the anatomic context (table). The intact prostate was the least likely site to use definitive language (34.6%), whereas bone was most likely (87.1%). Intact prostates in post-radiation patients had the most uncertainty to the persistence of disease (42.3% unsure, 23.1% likely). The highest degree of definitive certainty occurred in impressions of persons with PSA <0.5 (89.2%), whereas the least definitive certainty was in patients with PSA >1 (66.2%). Overall, definitive, likely and unsure findings were reported in 68.6, 9.7%, and 21.7% of scans. Conclusions: Fluciclovine PET/CT scans routinely result in equivocal findings, which vary by anatomic site of interest and prescan PSA level. The language utilized in these reports has not been standardized. Future work aims to create a clear confidence level lexicon standard to assist radiologists and providers in reporting standardization.[Table: see text]
Bladder volume variation in hypofractionated prostate radiotherapy.
Authors: Joyce Ronan , Murphy Jake , O'Neill Eoin , Lyons Ciara A. 
Published: February 2022

234 Background: A full bladder for prostate radiotherapy treatment limits overall dose to the bladder and displaces bowel from high dose regions. There is currently no clear consensus on optimum bladder volume for prostate radiotherapy. Inconsistent bladder volumes can cause dosimetric uncertainty, distress, treatment delay and negative toxicity outcomes for patients. To identify potential ways to improve bladder filling consistency we retrospectively analysed bladder volume variation over the course of patients’ treatment and its relationship to various patient and treatment factors. Methods: We included all patients treated with 60gy in 20 fractions to the prostate only over a 1-year period. Standard fractionation, palliative, post-operative, and whole pelvis treatment regimens were excluded from our study. Patient, tumour, and treatment characteristics were collected retrospectively. We recorded patient reported IPSS scores that were completed pre and post treatment. Daily bladder volumes were recorded from cone beam CT (CBCT) retrospectively for a subset of 34 patients and included in correlative analyses with various treatment and patient factors. Results: 69 men were included in this study with a mean planning CT bladder volume of 272ml (79-574). Patients were divided into large ( > 180ml) and small subgroups (N = 46 vs 23). Smaller bladders resulted in a greater post treatment IPSS score (10.2 vs 7.7 (p = 0.2)) and greater change in IPSS (+3.3 vs +1.4 (p = 0.23). The variation of daily bladder volumes as measured by the standard deviation was positively associated with planning CT volume (p < 0.05), variation in daily treatment time (p < 0.05) and urinary symptoms (p = 0.29). Greater discordances between planning CT time and mean radiotherapy time resulted in a greater average difference between CBCT bladder volume and planning CT volume (p = 0.16). There were no appreciable seasonal or diurnal associations for all recorded bladder volumes. Conclusions: Smaller bladder volumes at planning CT are associated with increased urinary symptoms whereas larger volumes undergo more daily variation. This data suggests an optimal planning bladder volume of 200-400ml to minimise on treatment variation. This is the first study to demonstrate a relationship between variation in daily treatment times and daily bladder variation. Synchronisation of planning CT time with patient treatment time preference will enable patients to better replicate planning CT bladder volumes. This, along with several other areas for improvement highlighted by this study have formed the basis for a prospective single centre pilot study.