bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood-based tumor mutational burden from circulating tumor DNA and immune checkpoint inhibitors in advanced prostate cancer.
Authors: Rauterkus Grant , Hadadi Agreen , Barnett Reagan , Weipert Caroline , Drusbosky Leylah , Gao Xin , Lilly Michael B. , Bryce Alan Haruo , Naqvi Syed Arsalan Ahmed , Barata Pedro C. , Bilen Mehmet Asim 
Published: February 2022

165 Background: A prior study of patients with advanced cancers treated with immune checkpoint inhibitors (ICI) associated improved overall survival with tissue tumor mutational burden above the 80th percentile in each histology (tTMB-H). TMB can also reliably be calculated via liquid biopsy (bTMB), and trends higher than tTMB in analogous tumors. Here, we generate a plasma-informed benchmark for bTMB-H in advanced prostate cancer and report preliminary data from an ongoing multi-institutional case series of patients treated with ICI. Methods: Circulating tumor DNA (ctDNA) next generation sequencing (NGS) results from 3,504 patients with advanced prostate cancer who received a Guardant360 liquid biopsy within a 12-month period were analyzed. The 80th percentile of TMB was defined as the benchmark for bTMB-H in this cohort, and prevalence of microsatellite instability (MSI-H) was determined. Subsequently, clinical data were collected from patients across five institutions who received pembrolizumab based on bTMB scores or other tumor characteristics (i.e. CDK12 mutation). Results: Overall, mean and median bTMB were calculated as 12.34 mut/Mb and 8.61 mut/Mb, respectively (range: 0 – 1164.75 mut/Mb). The 80th percentile of bTMB was 13.4 mut/Mb and the 90th percentile was 16.6 mut/Mb. 2.6% of patients were both MSI-H and bTMB-H. No patients with bTMB < 13.4 mut/Mb (TMB-L) were found to be MSI-H. Ten patients from five institutions received pembrolizumab (8 monotherapy) after a median of 4.5 lines of prior therapy (Table). Four patients were MSI-H. The 3 patients in the cohort with PSA decreases > 50% had both MSI-H and bTMB ≥ 13.4 mut/Mb. Per RECIST criteria, disease was controlled (CR, PR, SD) in 6 of 7 (86%) patients with bTMB scores ≥ 13.4 mut/Mb. Conclusions: These data continue to affirm that ctDNA NGS is a practical and cost-effective means of assessing potential predictors of ICI activity in patients with advanced prostate cancer. Preliminary data from this growing cohort of patients who have received ICI guided by bTMB scores and other molecular parameters identified via ctDNA NGS, including MSI-H, demonstrate a clinical benefit from therapy. Further studies are warranted for contextualizing individual tumor bTMB scores with established, pathology-specific benchmarks.[Table: see text]
ADAM: A multicenter, non-interventional, prospective cohort study for determination of prevalence of homologous recombination repair genes mutations (HRRm) in metastatic castrate-resistant prostate cancer (mCRPC)—Interim analysis.
Authors: Alexeev Boris , Lyubchenko Liudmila , Gordiev Marat , Filipenko Maxim , Anzhiganova Yulia , Sultanbaev Alexander , Bystrov Alexander , Orlov Alexander , Gopp Galina , Kopyltsov Evgeny , Lykov Alexander , Atduev Vagif , Alekseeva Galina , Mailyan Ovsep , Semenov Vladislav , Vedrova Olga , Perevoschikov Alexander , Andreev Sergei , Evgenia Logacheva 
Published: February 2022

169 Background: The HRRm detection is used to prescribe PARP inhibitors in mCRPC patients. The frequency of HRR alterations has been investigated in several clinical studies, but the prevalence of HRRm in real clinical practice remains unclear. We conducted the first study to evaluate prevalence of HRRm in mCRPC patients in Russia. This interim analysis is aimed to provide HRRm rate in real practice in Russian population. Methods: Patients with mCRPC and available tumor tissue samples (FFPEs) were enrolled from October 2020 till May 2021. Samples were analyzed in 3 labs. Target enrichment using multiplex PCR and library preparation of genes involved in HRR (BRCA2, BRCA1, RAD54L, FANCL, BARD1, ATM, CHEK1, RAD51B, PALB2, RAD51D, CDK12, RAD51C, BRIP1, CHEK2) was performed using three different techniques: GeneReader NGS System (QIAGEN), KAPA HyperPlus and SeqCap EZ Choice (Roche) and in-house targeted NGS-panel. For last 2 sequencing was performed using MiSeq (Illumina). Results: In this interim analysis we included 331 mCRPC patients from 20 sites with median age 67 years, 86,7% caucasian. Family or personal history of oncological diseases had 66 (20%) of pts 300 FFPEs were analyzed by NGS, 31 (9%) were not valid (poor quality/not enough DNA). HRRm rate is 19,7% (59/300). Most frequently mutated genes ( > 1%) listed in the table below. Other mutations (RAD51B, RAD51C, BARD1, FANCL, RAD51D, RAD54L) were detected in 1-2 cases per gene. Conclusions: This first systematic analysis of HRRm in Russian population of mCRPC patients showed general consistency with previously reported HRRm data (19,7% in our trial in comparison with 27.9% in PROfound trial). Lab approach using different techniques in real practice has to be established.[Table: see text]
Frequencies of actionable alterations found by somatic tumor sequencing in veterans with metastatic prostate cancer.
Authors: Nickols Nicholas George , Maxwell Kara Noelle , Lee Kyung Min , Hausler Ryan , Anglin-Foote Tori , Garraway Isla , Lynch Julie Ann 
Published: February 2022

178 Background: Prostate cancer comprises one third of male Veteran cancers and is their second leading cause of cancer death. Metastatic prostate cancer is lethal. Next Generation Sequencing (NGS) of somatic tumors is recommended for metastatic prostate to identify actionable alterations targeted with approved therapies. Veterans with prostate cancers harboring alterations in genes involved in the DNA damage response (e.g. BRCA1/2) or high microsatellite instability (MSI-High) may be eligible for PARP inhibitors or checkpoint blockade immunotherapy, respectively. Potential candidates may be identified for ongoing clinical trials of novel precision oncology approaches. Methods: This is a retrospective analysis of clinical, genomic, demographic data from Veterans with metastatic prostate cancer who underwent somatic NGS using the Foundation Medicine NGS platform from 2019-February 2021. To be included, prostate cancer was submitted diagnosis for the NGS testing and metastatic disease determined by the VINCI natural language processing tool. Variables included demographic, clinical, and pathological characteristics (self-identified race/ethnicity, age, rurality of residence, Gleason score, specimen site, other cancer diagnosis, mutation frequency). Primary outcome was mutation rates in homologous recombination (HR) genes under current FDA approval for olaparib (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L) or MSI-High. Raw variant data, submitted diagnosis, and clinical data were extracted from the NGS reports and harmonized for further variant annotation. Variant data included chromosome, position, reference and alternate allele, total depth, variant allele depth, and quality scores. Variants were annotated using ANNOVAR. Likely oncogenic and oncogenic mutations were identified using OncoKB. Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, 78.6% of cases from >60 years. Of the 1,597 who underwent blood or tumor testing, at least one likely oncogenic mutation in an HR gene under FDA approval for olaparib was found in 369 (23.1%) of Veterans (19% of tissue-based tests, 32.9% of blood-based tests). Of 651 liquid biopsy tests with at least one HR gene mutation, 125 of 214 (52%) had mutations at a variant allele frequency (VAF) <0.5% or were found in an MSI-High sample that could indicate a spurious mutation due to clonal hematopoiesis. 33 patients (2.1%) were MSI-High, (21 tissue-based and 12 blood-based). Frequencies of alterations in ATM (3.6%), CDK12 (5.6%), and BRCA2 (4%) in tissue-based tests were not significantly different from those reported in other series. Conclusions: NGS of somatic tumors from Veterans with metastatic prostate cancer identifies alterations that impact management and clinical outcomes.
Putative germline findings in tumor-only and liquid biopsy sequencing in veterans with aggressive prostate cancer.
Authors: Maxwell Kara Noelle , Hausler Ryan , Garraway Isla , Nickols Nicholas George , Lee Kyung Min , Lynch Julie Ann 
Published: February 2022

179 Background: Tumor-only and/or liquid-biopsy based Next Generation Sequencing (NGS)-based tests, which are routinely performed in metastatic prostate cancer patients, may identify putative germline mutations. The European Society of Medical Oncology (ESMO) made recommendations on findings which should be referred for germline genetic testing; however, it is unknown the burden of genetic testing referrals that may result from implementation of these recommendations. We therefore determined the frequency of putative germline findings in Veterans with metastatic prostate cancer who have undergone NGS-based sequencing of tumor and/or cell-free DNA (cfDNA) on the Foundation Medicine (FMI) platform. Methods: This is a retrospective analysis of Veterans with FMI NGS testing results reported from January 2019-February 2021 who had prostate cancer as the submitted diagnosis and metastatic diagnosis according to a VINCI natural language processing tool. Raw variant data were extracted from FMI reports and harmonized for variant annotation. Variants were annotated using ANNOVAR. Putative germline mutations were defined as 1) likely pathogenic or pathogenic (LP/P) by Clinvar annotation and VAF> 30%. Mutation rates are reported in genes recommended by ESMO to trigger referral for germline testing in all tumor types and all ages of diagnosis and proposed prostate cancer susceptibility genes ( ATM, BARD1, CHEK2). Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, with 78.6% of cases from men >60 years. Of 1,597 prostate cancer patients who underwent blood or tumor testing, n=85 (5.3%) had an LP/P mutation in an ESMO-guideline gene. When mutations in ATM, BARD1 and CHEK2 were added, n=133 (8.3%) of patients had an LP/P mutation. The most commonly identified putative germline findings were in BRCA2 (n=49 patients, 3.1%). 18 patients (1.1%) had mutations in other prostate cancer risk genes on the ESMO list ( BRCA1, MLH1, MSH2, MSH6, PMS2). 18 (1.1%) of patients had putative incidental germline findings, which included mutations in PALB2, BRIP1, RAD51C, RAD51D, SDHC. No putative incidental germline mutations were identified in RET, SDHA, SDHB, SDHD, TSC2, VHL. Comparing self-identified White versus self-identified Black patients, putative germline mutation rates were nearly the same in all ESMO-referral genes combined (8.2% vs 8.5%), BRCA2 (2.9% vs 3.0%), and ATM (2.4% vs 2.1%). Conclusions: While guidelines recommend that all veterans with metastatic prostate cancer undergo germline genetic testing, significant patient and system-level barriers continue to limit access to germline genetic testing for many Veterans. Tumor-only NGS testing, with a low rate of putative incidental findings, can help to prioritize which Veterans should be referred for germline genetic testing.
3JC48-3: Novel MYC inhibition in advanced prostate cancer.
Authors: Chalfant Victor , Riveros Carlos , Shukla Sanjeev , Osumi Teruko , Balaji KC 
Published: February 2022

181 Background: The proto-oncogene c-Myc is a transcription factor that is upregulated in several human cancers. Despite its key role, therapeutic targeting of c-Myc remains a challenge because of a disordered protein tertiary structure. The basic helical structure and zipper protein of c-Myc forms an obligate heterodimer with its partner MAX to function as a transcription factor. An attractive strategy is to inhibit MYC/MAX dimerization to decrease c-Myc transcriptional function. Several methods have been described to inhibit MYC/MAX dimerization including small molecular inhibitors and proteomimetics. Methods: We used NOD SCID gamma mice (NGS mice) that are immunodeficient, non-obese diabetic laboratory mice (Jackson Laboratories, Cat #J000077451) carrying patient-derived xenograft (PDX) following implantation of grade IV adenocarcinoma of the prostate from a patient into the flanks of each mouse. For maximum tolerable dose studies, we used C57BL/6 wild type mice (Jackson Laboratories, Cat #J000664). We performed a maximum dose tolerability study with the drug 3JC48-3 up to 100 mg/kg to determine limiting toxicity. We monitored the rate of growth for 2 weeks and measured the final volume of the tumors. Immunoprecipitation studies were performed using the prostate cancer cell line, PC-3, that were treated with the drug 3JC48-3 at different doses (0, 5, 10, and 20uM) for 24 hours and subsequently lysed. Results: We found 3JC48-3 decreases prostate cancer growth and viability in a dose-dependent fashion in vitro. We confirmed the inhibition of MYC/MAX dimerization by 3JC48-3 using immunoprecipitation experiments. Normal mice and mice with patient-derived prostate cancer xenografts (PDX) tolerated intraperitoneal injections of 3JC48-3 up to 100 mg/kg body weight without dose-limiting toxicity. Preliminary results in these PDX mouse models suggest that 3JC48-3 may be effective in decreasing the rate of tumor growth. Conclusions: Our study demonstrates that 3JC48-3 is a potent MYC/MAX heterodimerization inhibitor that decreases prostate cancer growth and viability in association with upregulation of both PrKD1 expression and kinase activity. In addition, 3JC48-3 is well tolerated in prostate cancer PDX mice models and may be a candidate drug for further preclinical development.
Extracellular vesicle-based assay for detecting metastases and dynamic monitoring of prostate cancer.
Authors: Wang Jasmine Jiemei , Sun Na , Lee Yi-Te , Kim Minhyung , You Sungyong , Tseng Hsian-Rong , Zhu Yazhen , Posadas Edwin Melencio 
Published: February 2022

182 Background: There is an unmet need to develop a noninvasive assay to detect the metastatic progression of prostate cancer (PCa) patients for timely treatment. We aim to optimize an extracellular vesicle (EV)-based Digital Scoring Assay to reflect the disease status of PCa. Methods: PCa EV Digital Scoring Assay integrated a PCa-derived EV purification device (i.e., EV Click Chip) and downstream reverse-transcription droplet digital PCR for transcriptomic profiling of PCa-derived EVs. The performance of the Assay for purifying PCa-derived EVs was assessed using artificial plasma samples with spiked EVs. In parallel, a panel of 11 PCa-relevant mRNA markers were selected and validated. PCa EV Digital Scoring Assay in conjugation with the 11-gene panel was tested using plasma from 20 localized, 20 metastatic PCa patients, and serial plasma from three PCa patients. mRNA expressions were computed using weighted Z score method. ROC analysis was utilized to distinguish localized from metastatic PCa. Results: After optimization, the capability of purifying PCa-derived EVs from artificial plasma samples by EV Click Chips (92.5 ± 5.4%) outperformed ultracentrifugation or precipitation methods (41.0 ± 3.2%; 34.9± 2.2%; P < 0.001). Eleven genes, i.e., ACP3, FOLH1, HOXB13, KLK2, KLK3, KLK4, MSMB, RLN1, SLC45A3, STEAP2, and TMPRSS, were selected using The Tissue Atlas and a gene set from a blood-based study as our panel. Strong signals of the panel were detected from three PCa cells (LNCaP, C4-2B, and 22Rv1) and their derived EVs, while rare signals were detected in either WBCs or EVs purified from male healthy donor. In the clinical study, the Z scores calculated from the selected 11-gene panel, were significantly higher in 20 metastatic PCa than 20 localized PCa with an area under the ROC curve of 0.88 (95% CI = 0.78-0.98). Lastly, longitudinal analyses of three PCa patients showed that the Z scores can reflect the clinical progression, response, and stable status, even when disease is undetectable by imaging. Conclusions: We develop a sensitive PCa EV Digital Scoring Assay to distinguish metastatic PCa and reveal the dynamic disease states in a noninvasive manner. This assay holds the potential to augment current imaging tools and tests for timely detection of PCa progression and improve care for patients.
Low-value prostate cancer screening among young men with private insurance.
Authors: Vehawn Jeffrey , Lange Suzanne , Choudry Mouneeb , Ambrose Jacob P. , Haaland Benjamin , Paudel Niraj , Hanson Heidi A. , O Neil Brock 
Published: February 2022

240 Background: Debate remains about the value of Prostate-specific antigen (PSA) based prostate cancer screening among men aged 55-69 (USPSTF Grade C). However, no professional society or guideline recommends PSA based prostate cancer screening in men younger than age 40. This study aims to understand the risk of PSA testing exposure in young men, and we hypothesize that substantial low-value testing occurs in this population. Methods: We performed a retrospective analysis of claims data from the MarketScan database to identify men aged 18 to 39 without prostate cancer who received a PSA test from 2008 to 2017. For the primary analysis, men were required to be continuously in the database for least 5 years. Age groups were stratified to include: men less than 25, 25-29, 30-34, and 35-39 years. Secondary analysis did not limit subjects to those with 5 years of continuous data and explored the association of Charlson Comorbidity Index (CCI), lower urinary tract symptoms, erectile dysfunction, depression/anxiety, prostate cancer screening, infertility, and hypogonadism with PSA testing in young men. We used logistic regression to determine which of the factors were associated with PSA testing in young men. Results: We identified claims for 40,164,773 adult men who met study criteria. Of these men, 3,230,748 were continuously in the Marketscan database for at least 5 years. The cumulative risk for receiving a PSA over 5 years for men under 40 is 2.5%. Stratified by age, men aged 35-39 are at highest risk (Table). Logistic multivariable regression showed that, relative to all men between 18 and 40, patients in this age group who received a PSA were more likely to be diagnosed with hypogonadism (OR 20.55, 95% CI 20.39-20.71) or lower urinary tract symptoms (OR 9.34, 95% CI 9.26-9.41). Higher CCIs appeared to correlate with a decreased rate of PSA testing. This population was not significantly more likely to be diagnosed with infertility, depression, or anxiety. Conclusions: PSA screening for men under 40 is not uncommon, especially when associated with concomitant genitourinary symptoms. At a population level, this represents substantial low-value testing. Interventions aimed at clarifying the relationship between common urologic conditions and prostate cancer, the extremely low incidence of prostate cancer in this age group, and the lack of guidelines supporting this practice may help decrease low-value PSA testing. Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA234431. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.[Table: see text]
Immunotherapy to prevent progression on active surveillance study (IPASS): A phase II, randomized, double-blind, controlled trial of PROSTVAC in prostate cancer patients who are candidates for active surveillance.
Authors: Parsons J Kellogg , Pinto Peter A. , Parnes Howard L. , Pavlovich Christian P. , Uchio Edward M. , Nguyen Mike Minh , Kim Hyung Lae , Gulley James L. , Sater Houssein Abdul , Jamieson Christina , Hsu Chiu-Hsieh , Wojtowicz Malgorzata E. , Schlom Jeffrey , Donahue Renee Nicole , Centuori Sara , Bailey Shania , Bauman Julie E. , Chow H H 
Published: February 2022

249 Background: Immunotherapy could potentially prevent disease progression for early-stage prostate cancer. In this randomized Phase 2 clinical trial, we evaluated the clinical effects of PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy that contains PSA and three T-cell costimulatory molecules, in patients with localized prostate cancer. Methods:154 patients with clinically localized, low- or favorable intermediate-risk prostate cancer active surveillance were randomized (2:1) to receive 7 doses of subcutaneous PROSTVAC or placebo (empty fowlpox vector) over 140 days. Post-intervention prostate biopsy was performed 7-14 days after the last dose. Participants were followed for 6 months post-treatment. The primary outcome was change from baseline to post-vaccination in CD4 and CD8 T cell infiltration in biopsy tumor tissue. Secondary outcomes included changes in prostate biopsy Gleason grade (Grade Group) and serum PSA. Results: There were no differences in CD4 and CD8 densities (count of cells/mm2) in post-treatment biopsy tumor tissue between groups ( p = 0.63 and p = 0.75, respectively). Compared to placebo, patients who received PROSTVAC were less likely to demonstrate upgrading at follow-up biopsy, but this difference did not attain significance (22% vs. 40%, p= 0.08). There was no difference in the change of PSA from baseline to 6 months post-treatment between arms ( p= 0.30). Conclusions: In this first-of-kind trial of immunotherapy for localized prostate cancer, PROSTVAC was well tolerated but did not elicit significant prostate tissue T-cell responses compared to placebo. The favorable post-treatment biopsy grade findings in PROSTVAC patients merit further evaluation and longer-term clinical follow-up. Clinical trial information: NCT02326805.