bluuebunny/crossref_metadata_2025_split huggingface dataset:
KEYNOTE-365 cohort B: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—New data after an additional 1 year of follow-up.
Authors: Appleman Leonard Joseph , Kolinsky Michael Paul , Berry William R. , Retz Margitta , Mourey Loic , Piulats Josep M. , Romano Emanuela , Gravis Gwenaelle , Gurney Howard , De Bono Johann S. , Boegemann Martin , Emmenegger Urban , Joshua Anthony M. , Massard Christophe , Sridhar Srikala S. , Conter Henry Jacob , Li Xin Tong , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y. 
Published: March 2021

10 Background: For men with mCRPC, systemic therapies such as docetaxel and cabazitaxel improve survival, but more effective treatments are needed. KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to examine the safety and efficacy of pembro in combination with 4 different study medications (cohorts A, B, C, D) in mCRPC. Previous data from cohort B with a median of 20 months of follow-up showed that pembro + docetaxel and prednisone was well tolerated and had antitumor activity in patients (pts) with mCRPC previously treated with abi or enza. New efficacy and safety data after an additional year of follow-up are presented. Methods: Cohort B enrolled pts who did not respond to or were intolerant to ≥4 weeks of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 months of screening (determined by PSA progression or radiologic bone/soft tissue progression). Pts received pembro 200 mg IV every 3 weeks (Q3W), docetaxel 75 mg/m2 IV Q3W, and oral prednisone 5 mg twice daily. Primary end points were safety, PSA response rate (PSA decrease >50% from baseline), and ORR per RECIST v1.1 by blinded independent central review. Efficacy and safety were assessed in all pts as treated. Results: Of the 104 treated pts, median age was 68.0 years (range, 50-86), 23.1% had PD-L1–positive tumors (combined positive score ≥1), 25.0% had visceral disease, and 50.0% had measurable disease. Median time from enrollment to data cutoff was 32.4 months (range 13.9-40.3); 101 pts discontinued, primarily because of disease progression (77.9%). Efficacy outcomes are reported in the table below. Treatment-related adverse events (TRAEs) occurred in 100 pts (96.2%); the most frequent (≥30%) were diarrhea (41.3%), fatigue (41.3%), and alopecia (40.4%). Grade 3-5 TRAEs occurred in 46 pts (44.2%). Five pts (4.8%) died of AEs; 2 were treatment-related pneumonitis. Conclusions: After another year of follow-up, pembro + docetaxel and prednisone showed improved ORR and PSA response rates compared to the prior dataset in pts with mCRPC previously treated with abi or enza. Safety was consistent with known profiles of each agent and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]
Clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving radium-223 (Ra-223) early versus late in the treatment sequence.
Authors: Mbuagbaw Lawrence , Lowther Jennifer , Lee-Ying Richard M. 
Published: March 2021

136 Background: Ra-223 is the only targeted alpha therapy shown to prolong overall survival (OS) in men with mCRPC. The purpose of this real-world study is to evaluate clinical outcomes of patients (pts) when Ra-223 is used early (second-line) or late (third or later lines) for mCRPC. Methods: We used administrative databases in Ontario (2012-2017) to estimate OS from start of second-line life prolonging therapy (LPT), event free survival (EFS; time from start of second-line LPT to start of fourth-line or death) using counting process models, comparing 2 cohorts of patients: Early Ra-223 (2nd line) vs Late Ra-223 (3rd or later line). All models are adjusted for relevant fixed and time-varying covariates, including age, prostate specific antigen, hemoglobin, Charlson Comorbidity Index (CCI), use of bone health agents, prior systemic treatments, Gleason score, TNM score, Androgen Deprivation Therapy (ADT) and standardized pain score. Results: Data from 598 men in Ontario with mCRPC who received at least 2 lines of LPT, including Ra-223 in second line or later were analyzed (Early Ra-223=253; 42.3%; Late Ra-223=345; 57.7%). The mean age (standard deviation) at the start of first-line LPT was 72.2 years (8.8). Patients in the early Ra-223 cohort had a longer time from diagnosis of prostate cancer to receiving first-line LPT, a longer time from start of first-line to start of second-line LPT, and were less likely to receive docetaxel. The median number of Ra-223 cycles was 5 (range 3-6) and 4 (range 3-6) and the mean number lines of total LPT was 2.7 ± 0.9 (2.0 - 7.0) and 3.8 ± 0.9 (3.0 - 7.0) in the early and late Ra-223 cohorts, respectively. OS was better in the Early Ra-223 cohort compared to the Late Ra-223 cohort (Hazard Ratio [HR] 0.79; 95% Confidence Interval [CI] 0.66-0.95). EFS was better in the Early Ra-223 cohort compared to the Late Ra-223 cohort (HR 0.71; 95% CI 0.58-0.86). Time to first hospitalization and time to first emergency department visit was longer in the early Ra-223 cohort. Conclusions: Real-world data from Ontario, suggests that patients who received Ra-223 in second-line versus third-line or later had better outcomes. Patients who received Ra-223 early received less chemotherapy, but had better survival. The selection of patients who may benefit the most from Ra-223, and the optimal timing of the Ra-223 in the sequence of treatments, are being evaluated in a larger Canadian study including data from four Canadian provinces (REACTIVATE NCT04281147 ).
ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.
Authors: Jaeger Ellen , Ledet Elisa Marie , Moses Marcus W. , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Barata Pedro C. , Sartor A. Oliver 
Published: March 2021

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.
Comprehensive genomic profiling of matched primary prostate cancer tissue and cell-free DNA (cfDNA) to assess ontogeny of BRCA1/BRCA2 mutations.
Authors: McFarland Taylor Ryan , Nussenzveig Roberto , Swami Umang , Sayegh Nicolas , Kessel Adam , Sharma Prayushi , Li Haoran , Kohli Manish , Maughan Benjamin Louis , Pal Sumanta K. , Agarwal Neeraj 
Published: March 2021

166 Background: Both olaparib and rucaparib have recently been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with BRCA1/2 mutations (BRCAm). In the PROFOUND trial, 36.9% of men had either no tissue or tissue that was inadequate for genomic profiling (PMID: 32343890). A recent report suggests BRCAm may be an early event in the evolution of prostate cancer (PMID: 29662167). This suggests comprehensive genomic profiling (CGP) of primary prostate tissue may suffice to guide treatment selection, even years after tissue collection. Herein, we investigate the ontogeny of BRCAm by comparing CGP of matched primary prostate cancer tissue to CGP of cfDNA. Methods: Eligibility criteria included men diagnosed with metastatic prostate cancer that had matched CGP of both primary prostate cancer tissue and cfDNA. Genomic profiling was performed by CLIA certified laboratories. Only somatic mutations detectable by both platforms were used for concordance analysis. Results: We identified 198 patients that had matched CGP of primary prostate tissue and cfDNA. Thirteen men had a pathogenic BRCAm in at least one test. Of these 13 positive test for BRCAm, 2 were rearrangements, 1 copy number loss, and 5 were germline mutations. Both platforms tend to filter out germline alterations therefore, they were not included in the estimation of concordance. Overall somatic BRCAm concordance between primary prostate tissue and cfDNA was 196/198 (98%). Notably, no new BRCAm were identified in cfDNA with a median difference of 23.62 (0.1 - 232.2) months between prostate cancer tissue and cfDNA collection. Conclusions: There were no BRCAm detected only in cfDNA, suggesting that BRCAm is an early event in the ontogeny of prostate cancer. Based on this, it is unlikely that delaying sequencing would benefit patients with advanced prostate cancer. In the event that tissue is unavailable or inadequate for CGP, profiling of cfDNA is a valuable alternative for detection of BRCAm.
Addressing financial toxicity in urologic oncology patients.
Authors: Parikh Divya Ahuja , Srinivas Sandy , Kerr Elizabeth , Patel Manali I. 
Published: March 2021

170 Background: Financial toxicity, or the financial burden related to cancer care, is a source of distress for urologic oncology patients. This study aimed to address financial toxicity among prostate, kidney and bladder cancer patients and test the feasibility of a lay-health worker (LHW) and social work (SW) driven intervention. Methods: LHW assessed financial burden in urologic oncology patients with advanced cancer who presented for return visits at a single academic center. The LHW collected responses to three statements on a Likert scale – “I worry about the financial problems I will have in the future because of my illness or treatment”, “My cancer or treatment has reduced satisfaction with my present financial situation”, and “I feel financially stressed”. Patients who responded, “Very much” (4) or “Quite a bit” (3) to all statements were offered a one-on-one consultation with a trained SW. The SW provided personalized recommendations after review of patients' financial information, insurance status, and out of pocket costs. SW referred patients to appropriate support services including those offered by the hospital, government, nonprofits and private corporations. Pre-specified outcomes included pre/post-intervention financial toxicity and patient satisfaction with the intervention. Results: 145 patients (67%) agreed to be screened for financial toxicity by the LHW. Most participants were White (n = 100, 69%), male (n = 130, 90%), married (n = 104, 72%) and with incomes > $100,000 (n = 111, 77%). The majority had prostate cancer (n = 87, 60%), followed by kidney cancer (n = 36, 25%) and bladder cancer (n = 22, 15%). 12% (n = 26) responded “I worry about the financial problems I will have in the future because of my illness or treatment”, “Very much” or “Quite a bit”. 14% (n = 20) responded “My cancer or treatment has reduced satisfaction with my present financial situation”, “Very much” or “Quite a bit”. 12% (n = 17) reported “I feel financially stressed”, “Very much” or “Quite a bit”. A total of 14 patients were eligible for the intervention and were referred for a one-on-one SW consultation. Post-intervention results indicated excellent patient satisfaction with the intervention and a significant improvement in financial toxicity. 100% of patients reported the SW “provided financial resources that were beneficial to me”, and 78% (n = 11) had a decrease in financial toxicity score post-intervention (average decrease = -1, p = 0.05038). Conclusions: In this single institution study of prostate, kidney and bladder cancer patients with overall low baseline financial burden a LHW and SW driven intervention was feasible and effective in reducing financial toxicity.
Understanding racial disparities in survival among U.S. veterans with localized high-risk prostate cancer, 2004-2019.
Authors: Parikh Ravi Bharat , Chhatre Sumedha , Talwar Ruchika , Medvedeva Elina , Cashy John , Malkowicz S. Bruce , Narayan Vivek , Mamtani Ronac , Robinson Kyle William , Jayadevappa Ravishankar 
Published: March 2021

202 Background: Known racial disparities in prostate cancer outcomes between African-American (AA) and non-Hispanic White (W) men may be ameliorated in the Veterans Health Administration (VA), a large national equal-access health system. We examined factors contributing to racial disparities in mortality among men with high-risk localized prostate cancer diagnosed in the VA. Methods: In this retrospective cohort study, we used linked administrative, survey, and electronic health record data from the Veterans Health Administration (VA) Corporate Data Warehouse to identify AA and W Veterans who were diagnosed with high-risk localized PC, as defined by D’Amico criteria, between January 1, 2004 and December 31, 2013. Patients were followed through December 31, 2019. The primary outcome was all-cause mortality. We used hierarchical Cox regression models, sequentially adjusting for covariates related to social determinants of health (e.g. travel time, marital status), clinical factors at diagnosis (e.g. PSA, Gleason, comorbidity), diagnosing facility, and prostate cancer treatment and adherence to American Cancer Society survivorship care guidelines. Results: Among 21,338 Veterans receiving continuous VA-based care (median age at diagnosis 66 years [interquartile range [IQR] 61-74]), 7,472 (28.7%) were AA, 9,404 (44.1%) died, and median follow-up was 8.4 years (IQR 6.1-11.1). After adjusting for all covariates, AA Veterans (adjusted hazard ratio [aHR] 0.84, 95% confidence interval [CI] 0.83-0.91) had improved overall survival compared to W Veterans. This association persisted in all hierarchical regressions (see Table), was present in all pre-specified subgroups, and was strongest among Veterans living in rural domiciles (aHR 0.70, 95% CI 0.64-0.77). Conclusions: AA Veterans with high-risk localized prostate cancer had improved long-term survival compared to W Veterans, which stands in contrast to prior studies among non-Veterans. Equal access to care may improve racial disparities in prostate cancer, although future studies should clarify mechanisms of improved survival for AA Veterans with prostate cancer in order to provide insights for ameliorating outcome disparities in non-Veterans with prostate cancer. [Table: see text]
Multimodal biomarkers overcome sampling bias to predict presence of aggressive localized prostate cancer.
Authors: Berman David Monty , Lee Anna YW , Lesurf Robert , Patel Palak , Ebrahimizadeh Walead , Bayani Jane , Boufaied Nadia , Jamaspishvili Tamara , Guerard Karl-Philippe , Dion Dan , Lee Laura A , Venkateswaran Vasundara , Chevalier Simone , Brimo Fadi , Buttyan Ralph , Thomson Axel A , Park Paul C , Lapointe Jacques , Boutros Paul Christopher , Bartlett John 
Published: March 2021

209 Background: Histopathologic investigation of diagnostic prostate biopsies both confirms the presence of disease and estimates its potential for distal spread via tumour grade. The accuracy of biopsy grading is limited by intra-tumoral heterogeneity, inter-observer variability, and other factors. To improve risk stratification at the time of diagnosis, we sought to create objective molecular biomarkers of radical prostatectomy grade that are resistant to sampling error and should be useful when applied to biopsy tissue. Methods: We developed and validated a robust objective biomarker of prostate cancer grade using pathologic grading of prostatectomy tissues as the gold standard. We created training (333 patients) and validation (202 patients) cohorts of Cancer of the Prostate Risk Assessment (CAPRA) low- and intermediate-risk prostate cancer patients. To address intra-tumoral heterogeneity, each tumor was sampled at two locations. We profiled the abundance of 342 mRNAs complemented by 100 canonical DNA copy number aberration loci (CNAs) and 14 hypermethylation events. Using the training cohort with cross-validation, we evaluated models for training classifiers of pathologic Grade Group ≥2, Restricting to strategies resulting in true negative rates ≥0.5, true positive (TP) rates ≥0.8, we selected two strategies to train classifiers, PRONTO-e and PRONTO-m. Results: The PRONTO-e classifier comprises 353 mRNA and CNA features, while the PRONTO-m classifier comprises 94 mRNA, CNA, methylation and clinical features. Both classifiers (PRONTO-e, PRONTO-m) validated in the independent cohort, with respective TP rates of 0.809 and 0.760, false positive rates of 0.429 and 0.262, F1 scores of 0.709 and 0.724, and AUCs of 0.792 and 0.818. Conclusions: Two classifiers were developed and validated in separate cohorts, each achieved excellent performance by integrating different types of molecular data. Implementation of classifiers with these performance characteristics could markedly improve current active surveillance approaches without increasing patient morbidity and may help better inform patients on their individual need for definitive therapy versus active surveillance.
Clinical significance of the sonazoid-enhanced ultrasound for prostate cancer.
Authors: Akatsuka Jun , Kimura Go , Toyama Yuka , Hasegawa Hiroya , Mikami Hikaru , Endo Yuki , Takeda Hayato , Hayashi Tatsuro , Kondo Yukihiro 
Published: March 2021

212 Background: This was a prospective study to evaluate the diagnostic accuracy of the Sonazoid-enhanced ultrasound (SEU) for prostate cancer. The primary end-point was accuracy of SEU to detect prostate cancer. The exploratory end-point was to analyze the prognostic significance of SEU positibity after radical prostatectomy (RP) in patients diagnosed as prostate cancer. Methods: In all cases locations of suspected prostate cancer were examined with SEU, digital rectal examination (DRE), B-mode (B), and power-doppler ultrasound (PDU) before prostate biopsy. We compared the sensitivity, specificity, PPV, NPV, and accuracy of SEU, RE, B, and PD. Among prostate cancer cases, effect of SEU positivity on biochemical recurrence (BCR) after radical prostatectomy was compared with that of DRE, B, and PDU. Results: Of 687 cases 416 cases (60.6%) were prostate cancer. The sensitivity, specificity, PPV, NPV, and accuracy were 52.9%, 63.5%, 69.0%, 46.7%, and 57.1% by DRE, 69.2%, 43.9%, 65.5%, 48.2%, and 59.2% by B, 66.6%, 59.0%, 71.4%, 53.5%, and 63.6% by PDU, and 66.1%, 70.1%, 77.2%, 57.4%, and 67.7% by SEU, respectively. SEU was the highest in specificity, PPV, NPV, and accuracy rate. Eighty three patients underwent radical prostatectomy. The SEU + group (69.3%) had a significantly poor prognosis compared to the SEU− group (88.7%) on the five-year BCR-free survival rate (p < 0.05). Univariate analysis showed SEU+ (HR 3.5; p = 0.02), DRE+ (HR 2.7; p = 0.04), PDU+ (HR2.6; p = 0.09), and B+ (HR 2.0; p = 0.21). SEU was the highest prognostic factor on BCR after radical prostatectomy. Conclusions: Sonazoid was able to visualize even small blood vessels in the prostate. SEU showed the highest accuracy for cancer detection and was the highest prognostic factor on BCR in the univariate analysis. To obtain the maximum benefit of Sonazoid, further examinations are needed.
Analysis of rectal dose during prostate stereotactic body radiotherapy in MR-guided radiotherapy.
Authors: Sritharan Kobika , Dunlop Alex , Mitchell Adam , Mohajer Jonathan , Smith Gillian , Tree Alison 
Published: March 2021

242 Background: The Unity MR-Linac combines a 7-MV Linac with 1.5T magnetic resonance (MR) imaging capability and it enables adaptive radiotherapy, whereby the target and organs at risk are recontoured and a plan is optimised daily. During treatment a session MR image is taken first, on which the target and organs-at-risk are contoured, and a plan created. A verification image is taken prior to dose delivery to identify intra-fractional changes. If present, the daily treatment plan is shifted to reflect the anatomy. A post-treatment image is acquired at the end of treatment. This study evaluates the dosimetric changes to the rectum caused by intra-fractional changes during treatment delivery for prostate stereotactic body radiotherapy (SBRT) calculated on the verification and post-treatment images. Methods: The first five patients treated on the MR-Linac with 5-fraction SBRT to the prostate are included in this study. For each patient, the rectum was contoured on the verification and post-treatment MR images for each of the five fractions. The dose delivered to the rectum with the original treatment plan was then calculated on each image and the V36Gy rectal dose constraint was noted. Results: Out of the 25 fractions, a post treatment image was not performed in one fraction; 24 fractions were therefore analysed in total. The rectal V36Gy dose constraint exceeded the mandatory target of 2cc on 50% of the verification images and 46% of the post-treatment images. In 6 fractions the rectal V36Gy was greater than 2cc on both the verification and post-treatment images suggesting this rectal constraint was exceeded throughout treatment. In 17% of patients, the volume of rectum receiving 36Gy increased at each timepoint an image was taken during the treatment workflow. Conclusions: The rectal V36Gy dose constraint is susceptible to minor changes in rectal filling, which may often lead to higher than the accepted dose constraint. Thus, a single planning CT scan is unlikely to be representative of dose delivered. Adaptive radiotherapy can reduce this uncertainty somewhat, but intra-fraction dose re-optimisation would be required to ensure the rectal V36Gy remains acceptable at all times.