bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fragmentomics of cell-free DNA from targeted panels in genitourinary malignancies.
Authors: Taylor Amy K , Helzer Kyle , Sharifi Marina Nasrin , Sperger Jamie M , Shi Yue , Annala Matti , Reese Shannon , Kaufmann Katherine , Schehr Jennifer L. , Sethakorn Nan , Kosoff David , Kyriakopoulos Christos , Armstrong Andrew J. , McKay Rana R. , Feng Felix Y , Wisinski Kari Braun , Emamekhoo Hamid , Wyatt Alexander William , Lang Joshua Michael , Zhao Shuang 
Published: January 2024

199 Background: The detection of genomic alterations in cancer is critical for identifying clinically actionable alterations for treatment decisions. Tumor samples historically have been required, but obtaining tissue for molecular profiling is not always feasible, especially in the metastatic setting. The isolation and analysis of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) via blood-based “liquid” biopsies offers non-invasive sampling of the tumor. Recently, fragmentation patterns of cfDNA (i.e. “fragmentomics”) have emerged as a method for inferring epigenomic and transcriptomic information. However, these analyses use whole-genome sequencing, which lacks the necessary depth to cost-effectively assess genomic alterations, limiting the application of these techniques clinically. Methods: We developed a novel cfDNA fragmentomics machine learning approach for standard targeted cancer gene panels in order to identify genitourinary (GU) and non-GU cancers from two independent metastatic cancer cohorts: a published cohort from GRAIL (prostate cancer, non-GU cancers, normal samples, N=198) and an expanded institutional cohort from the University of Wisconsin (prostate adenocarcinoma, neuroendocrine prostate cancer (NEPC), renal cell carcinoma (RCC), bladder cancer, non-GU cancers, normal samples, n = 431). Results: In the GRAIL cohort, 10-fold cross-validation AUCs were 0.987 for identifying prostate cancer, 1.00 for normal samples, and ranged from 0.922-0.958 for the non-GU cancers. In the UW cohort, 10-fold cross-validation AUCs were 0.950 for bladder cancer, 0.982 for prostate cancer, 0.993 for NEPC, 0.925 for RCC, and 0.980 for normal samples, and ranged from 0.874-0.954 for non-GU cancers. Our assay can sensitively detect and accurately distinguish GU and non-GU malignancies despite a median ctDNA fraction of only 0.076 in the GRAIL cohort, and a median ctDNA fraction of only 0.022 in the UW cohort. Conclusions: Our enhanced machine learning approach for examining fragmentomics in standard cancer gene cfDNA panels unlocks the potential for these established assays to be utilized to answer critical clinical questions beyond somatic variant identification. The excellent performance of our innovative approach even in samples with low ctDNA fractions suggest potential applications such as multi-cancer early detection and minimal residual disease monitoring. This framework could dramatically expand the potential of already existing clinically used assays and minimizes barriers for continued biomarker development.
First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): Extended follow-up of the phase 2 KEYNOTE-B61 study.
Authors: Voss Martin H , Gurney Howard , Atduev Vagif , Suárez Cristina , Climent Miguel Ángel , Pook David William , Tomczak Piotr , Barthelemy Philippe , Lee Jae-Lyun , Nalbandian Taron , Stus Viktor , Ferguson Thomas , Wiechno Pawel , Gokmen Erhan , Lacombe Louis , Gedye Craig , Burgents Joseph E. , Sharma Manish , Cornell Jerry , Albiges Laurence 
Published: January 2024

2 Background: Pembrolizumab (pembro) + lenvatinib (lenva) is approved for first-line treatment of advanced/metastatic RCC based on results of the phase 3 KEYNOTE-581/CLEAR study. Previously reported results from the phase 2 KEYNOTE-B61 (NCT04704219) study with a median follow-up of 15 months further support the use of pembro + lenva in the first-line setting specifically across nccRCC. We now report updated results from KEYNOTE-B61 with median follow-up of 23 months. Methods: Adults with previously untreated, advanced nccRCC (histology assessed by investigator) and measurable disease per RECIST v1.1 received pembro 400 mg IV Q6W for ≤18 cycles (~2 years) + lenva 20 mg orally once daily until intolerable toxicity, progressive disease, or patient (pt) withdrawal from the study. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DCR, DOR, and PFS per RECIST v1.1 by BICR, OS, and safety. Results: A total of 158 pts received pembro + lenva. Median age was 60 years (range, 24-87), and the most common histologic variants of RCC were papillary (n = 93; 59%), chromophobe (n = 29; 18%), and unclassified (n = 20; 13%). Median time from first dose to the data cutoff date of July 5, 2023, was 22.8 months (range, 16.6-27.6). 86 pts had discontinued treatment (most commonly due to progressive disease, n = 56 [35%]). In all pts, ORR was 51% (95% CI, 43-59; 13 CRs [8%]; 67 PRs [42%]) and DCR was 82% (95% CI, 75-88). Median DOR was 19.5 months (range, 15.3-not reached [NR]). An estimated 51% of responses had a duration of ≥18 months. ORR and DCR by histology are shown in the table. In all pts, median PFS and OS were 17.9 months (95% CI, 15.1-22.1) and NR (95% CI, NR-NR); estimated 18-month PFS and OS rates were 48% and 73%. Treatment-related AEs (TRAEs) occurred in 151 pts (96%), most commonly hypertension (56%), diarrhea (46%), hypothyroidism (41%), and proteinuria (30%). Grade 3-4 TRAEs occurred in 92 pts (58%), most commonly hypertension (25%), and diarrhea, proteinuria, and decreased weight (5% each). No deaths due to TRAEs were reported. Discontinuation due to TRAEs for pembro, lenva, or both pembro and lenva occurred in 15%, 13% and 4% of pts, respectively. Conclusions: Consistent with prior reports, pembro + lenva had durable antitumor activity and a manageable safety profile in pts with advanced nccRCC. These results continue to support pembro + lenva as a first-line treatment option for pts with variant histologies of nccRCC. Clinical trial information: NCT04704219 . [Table: see text]
The opposing effects of Class 1B and Class 2 FOXA1 mutations in prostate cancer.
Authors: Hwang Justin , Deshmukh Sachin , Wu Sharon , Elliott Andrew , Gandhi Nishant , Farrell Alex Patrick , Nabhan Chadi , McKay Rana R. , Heath Elisabeth I. , Baca Sylvan , Sartor Oliver , Dehm Scott , Antonarakis Emmanuel S. 
Published: January 2024

216 Background: PCa harbors recurrent FOXA1 alterations, yet distinct alteration types may drive divergent consequences. Here, we established several classes of FOXA1 alterations and evaluated their clinical outcomes, molecular correlates, and immunologic landscape in a large cohort of primary and metastatic PCa samples from Caris Life Sciences. Methods: We interrogated the Caris DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. FOXA1 alterations were annotated based on amino acid (a.a.) location and prior functional studies (Table). Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates. Gene set enrichment analyses (GSEA) was used to estimate signaling pathway activity. Immune-cell fractions were inferred from bulk RNA-seq using quanTIseq. All comparisons are made relative to FOXA1 WT cases. Results: The overall prevalence of FOXA1 alterations was 16%, with no enrichment in metastatic PCa samples (15.5%). Class 2 mutations were enriched in histologic NEPC, were associated with a classical NEPC mRNA signature, and showed poor survival with ADT (HR 5.6, 95% CI: 2.5–12.5, p<0.001). Conversely, metastatic PCa patients with Class 1B mutations had numerically improved survival with ADT (HR 0.76, 95% CI: 0.50–1.14, p=0.18). All FOXA1 alterations (except Class 2) resulted in increased FOXA1 transcripts, with 1B and 1C having the greatest effects (q<0.0001). Class 0 and 3 alterations had 2–5 fold higher frequency of TMB-high and MSI-high status (q<0.05). Conversely, Class 1B exhibited lower TMB and markedly fewer TP53 mutations (35.7% vs 20.3%, q<0.001) and TMPRSS2-ERG fusions (34.5% vs 4.6%, q<0.001). Class 1B was depleted of AR transcriptional signatures (q=0.01) but enriched of MYC signaling in GSEA analysis (FDR<0.001), and showed reduced expression of B7-H3. On immune-cell deconvolution analysis, Class 1B showed reduced dendritic cells, but increased B cells and neutrophils (DC: 1.96% vs 0.01%, B cell: 4.27% vs 5.29%, neutrophils: 5.05% vs 8.00%, each q<0.001). Conclusions: Different FOXA1 alterations exhibit divergent molecular and clinical features, and should not be interpreted in aggregate. In particular, Class 1B mutations are associated with a unique molecular and immunological landscape with potentially better outcomes to ADT, while Class 2 mutations are associated with NEPC phenotype with inferior ADT sensitivity. [Table: see text]
Cost-effectiveness of triplet therapies in metastatic hormone-sensitive prostate cancer used in PEACE-1 and ARASENS.
Authors: Lester-Coll Nataniel Hernan , Benjamin David Joseph , Ribault Hélène , Foulon Stéphanie , Fizazi Karim , Rezazadeh Arash 
Published: January 2024

222 Background: Recent findings from the PEACE-1 and ARASENS trials have demonstrated survival benefits in men with newly diagnosed metastatic hormone-sensitive prostate cancer using different triplet therapies, including Abiraterone and Darolutamide added to Androgen Deprivation Therapy and Docetaxel. Given the rising costs of cancer care, this study aimed to assess the cost-effectiveness of these treatment regimens. Methods: Drug prices were obtained from drugs.com and assurance-maladie.ameli.fr at wholesale prices to evaluate both United States (US) and France payer perspectives. Survival and progression data were sourced from Kaplan-Meier curves of the PEACE-1 and ARASENS trials and fitted to Weibull distribution models in R. The parameters were imported into TreeAge Pro 2023 for partitioned survival analysis. Health states were classified as "Pre-Progression," "Post-Progression," and "Death," each assigned specific health utility values and costs. Outcomes including total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Uncertainty was addressed through one-way and probabilistic sensitivity analyses. The baseline willingness-to-pay (WTP) threshold was $100,000 per QALY. Euros were converted to US Dollars. Results: At the baseline WTP of 100,000, generic Abiraterone (US, France) in PEACE-1 and Darolutamide in ARASENS from the French perspective were cost-effective. Generic Abiraterone was dominant, associated with lower net costs (-1,347 to -333) and higher QALYs (0.16) and Darolutamide had an ICER of .7,001 per QALY. In contrast, other triplet therapies increased both net costs and QALYs. Abiraterone yielded ICERs of 408,074 (US) and 114,995 (France) per QALY. Darolutamide in the US had an ICER of $383,732 per QALY. On one-way sensitivity analyses, most drugs would need to be priced at less than ~4,000 a month to be cost-effective at WTP of 100,000 per QALY. On probabilistic sensitivity analyses, with WTP of 100,000 per QALY, generic Abiraterone (US) was the cost-effective drug (88% of simulations), while brand Abiraterone and Darolutamide (US) were the least cost-effective (0% of simulations). Conclusions: Cost-effectiveness of therapies in metastatic hormone-sensitive prostate cancer vary significantly based on pricing and country payer perspective. At a WTP threshold of $100,000, only generic Abiraterone (US, FRA) and Darolutamide (France) were cost-effective. [Table: see text]
Barriers and facilitators to first-line (1L) treatment intensification (TI) in metastatic castration-sensitive prostate cancer (mCSPC): The IMPLEMENT study.
Authors: Loeb Stacy , Agarwal Neeraj , El-Chaar Nader N. , de Ruiter Laura , Kim Janet , Mack Jessica , Bland Christopher S , Rich-Zendel Sarah , Joo Jin Su , Dyson Judith 
Published: January 2024

224 Background: Despite evidence of benefits and guideline recommendations for first-line treatment intensification (ie, androgen-deprivation therapy with chemotherapy, novel hormonal therapies, or both) in mCSPC, it is underutilized. We examined barriers and facilitators that US urologists and oncologists face with treatment intensification for mCSPC and identified behavior change techniques to address these through an implementation science approach. Methods: We conducted 36 double-blind, semi-structured, virtual interviews with practicing US urologists and oncologists who manage mCSPC using an interview guide based on the theoretical domains framework. Saturation was met when no new themes emerged. Physician statements were coded into 11 domains and themes to identify barriers and facilitators. To confirm codebook reliability, 10% of transcripts were double coded independently (k=0.77). Key domains and the associated barriers and facilitators were analyzed for frequency, perceived potential to impact behavior, and presence of disagreement. Top domains were cross-referenced with a taxonomy of validated behavior change techniques. Results: 36 interviewed physicians (20 low intensifiers[≤50% of patients get treatment intensification]; 16 high intensifiers [>50% of patients get treatment intensification]), 14 (39%) were from academic centers. Five impactful domains and the associated barriers and facilitators were identified along with behavior change techniques to overcome them (Table). Conclusions: Underutilization of treatment intensification in US is multifactorial. Poor knowledge, habit, anticipated regret, costs, and reserving treatment intensification for later use were prominent barriers. These can be addressed through behavior change techniques to improve mCSPC care. [Table: see text]
The utility of ChatGPT in subspecialty consultation for patients (pts) with metastatic genitourinary (GU) cancer.
Authors: Srivastava Ayana , Galarza Fortuna Gliceida , Chigarira Beverly , Dal Emre , Hage Chehade Chadi , Gebrael Georges , Narang Arshit , Agarwal Neeraj , Swami Umang , Li Haoran 
Published: January 2024

227 Background: Cancer management requires a multidisciplinary approach, often requiring medical consultation from subspecialists. With the advent of artificial intelligence (AI) technologies like ChatGPT, it is hypothesized that these tools may help expedite the consultation process. This study aimed to assess the efficacy of ChatGPT in providing guideline-based sub-speciality recommendations for managing pts with metastatic GU cancer. Methods: In this single-institution, IRB-approved, retrospective, proof-of-concept study, pts with metastatic GU cancer over the past 3 years were screened. Those with at least one consultation referral to subspecialty clinics were randomly selected. ChatGPT 3.5 was given the most recent clinic note that triggered sub-specialty consultation. The AI tool was then asked to provide an assessment and plan. Two physicians independently assessed the accuracy of diagnoses made by ChatGPT and subspecialty physicians. The primary outcome was the consistency of ChatGPT recommendations with those of subspecialty physicians. Secondary Outcomes included potential time saved by using ChatGPT and comparison of medical decision-making (MDM) complexity levels between ChatGPT and subspecialty physicians. Results: A total of 39 pts were included. Their primary diagnoses included prostate cancer (51.3%), bladder cancer (23.1%) and kidney cancer (15.4%). The referred subspecialty clinic included cardiology (33.3%), hematology (17.9%), hepatology (2.6 %), hospice (10.3%), neurology (12.8%), pulmonary (15.4 %), and rheumatology (7.7%). The average waiting time for pts to be seen in subspecialty clinics was 44.9 days (SD = 42.4). Of 39 patient’s charts reviewed by ChatGPT, 30/39 (76.9%) had the same diagnosis with consultant sub-specialties. The average diagnoses made by ChatGPT were 8.2, compared with 3.4 made by sub-specialty physicians (p < 0.0001). The accuracy of diagnoses made by ChatGPT was the same, higher, and lower than human physicians in 10 (33.3%), 3 (10%), and 17 (56.7%) cases, respectively. Consistency of treatment plans between ChatGPT and physicians was found in 18 cases (46.2%). ChatGPT recommended additional workup in 32 cases (85.1%). The average number of words written in consultation notes by ChatGPT was 362.7 (SD = 72.9), which was significantly greater than subspecialty physicians (n = 224.7, p < 0.0001). Conclusions: These hypothesis-generating data suggest the potential utility of ChatGPT to assist medical oncologists in managing increasingly complex pts with metastatic cancer. Further studies are needed to validate our findings.
ERBB3 expression in racially diverse patients with castration-sensitive prostate cancer and its association with a unique AR activity signature.
Authors: Vellky Jordan , Vander Griend Donald , Reizine Natalie Marie 
Published: January 2024

23 Background: Despite successful clinical management of castration sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer (CRPC) is only 32%. This number is even more striking in the context of racial disparities where prostate cancer mortality rates for Black/African American (AA) men are two to four times higher than those in every other racial and ethnic group in the US. Identification of molecular expression and activity patterns that vary by racial group may provide a key to addressing outcomes related to survival disparities, as current treatments have not been developed with attention to the inclusion of diverse patient populations. Developing a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide intelligent intensification of therapeutic strategies and improve survival, particularly in high-risk patient populations. Methods: Targeted deep sequencing was performed as routine care for treatment naïve patients in the UI cohort (n=30), and immunostaining was performed in racially diverse tissue microarray (n=149). Bioinformatics analyses were utilized to identify signaling pathways associated with biomarker overexpression in the UI cohort, consolidated publicly available RNA-seq datasets (n=664), and a racially diverse Gene Expression Omnibus dataset (n=68). Results: We identified ERBB3 overexpression (OE) in racially diverse CSPC patient populations, where it was associated with advanced disease at diagnosis. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/AA men. Bioinformatics analyses showed a positive correlation between ERBB3 expression and the Androgen Response pathway despite low intraprostatic androgen and stable expression of androgen receptor (AR) transcript in Black/AA men. Clinically, ERBB3 OE is associated with high pre-treatment serum PSA in Black/AA men and is positively correlated with a clinically adaptable AR signature score. Preliminary outcomes data suggest Black/AA men with ERBB3 OE have a shorter time to disease progression. Conclusions: In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling and serum PSA despite low intraprostatic androgen, suggesting ERBB3 OE as a prospective biomarker for ligand-independent AR activation. In this context, ERBB3 OE could stratify patients for intensification of therapy in castration-sensitive disease and emphasizes the importance of biomarker-directed clinical trials with diverse populations.
Evolving trends in prostate cancer: Disparities across income levels and global regions (1990-2019).
Authors: Jani Chinmay , Dudipala Harshitha , Tran Eli , McKay Rana R. 
Published: January 2024

25 Background: Prostate Cancer, the third most commonly diagnosed cancer in 2020 and the fifth leading cause of cancer mortality worldwide, has exhibited significant disparities in global prevalence and impact over recent decades. This study assesses the trends in incidence, mortality, and disability-adjusted life years from prostate cancer in the World Bank regions based on country income levels from 1990 to 2019. Methods: The Global Burden of Disease Study database was used to extract Age-standardized incidence rates (ASIR), age-standardized (ASDR), and life years (DALYs) for prostate cancer from different World Bank regions based on income levels from 1990 to 2019. Annual percentage change was also acquired. Mortality-to-incidence ratios (MIR) were then computed. Trends were assessed using Joinpoint regression. Results: Between 1990 and 2019, ASIRs increased across all income levels, with the greatest growth in the upper middle income (+64.7%). While ASDRs decreased in high income, upper middle income, and lower middle income levels, they notably increased in low income levels (+14.3%). DALYs decreased in high income and upper middle income levels, primarily in the high income (-25.7%), and increased in lower middle and low income levels, primarily in the low income (+13.8%). MIRs decreased in all countries, with the largest decrease in high income levels (-50%). In the last 30 years, high income countries have consistently observed the highest ASIR (2019: 77.5/100,000). However, in 1990 high income countries also had the highest ASDRs and DALYs. Interestingly, by 2019 this pattern shifted, with low income surpassing high income countries in both. Conclusions: Over the last 30 years, the incidence of prostate cancer has been rising regardless of income level. Despite the universal decrease of MIRs implying improved outcomes, screening, and therapeutical strategies, the contrasting trends in ASDRs and DALYs across income levels underscore the disparities in health outcomes. Higher income countries experienced highest cancer incidence but also the highest decrease in the mortality rates while lower income countries faced the opposite challenges with lower increase but higher mortality rates. [Table: see text]
Patient-provider rurality and outcomes in older men with prostate cancer.
Authors: Stabellini Nickolas , Jiang Stephanie , Patel Vraj , Datta Biplab , Nain Priyanshu , Seth Lakshya , Kunhiraman Harikrishnan Hyma , Malik Sarah , Patel Sagar A. , Rupji Manali , Ward Kevin C , Switchenko Jeffrey M. , Moore Justin , Weintraub Neal L , Guha Avirup 
Published: January 2024

265 Background: The impact of rural residence status as a social determinant of health on prostate cancer (PC) outcomes, considering both patient and provider location, remains unexplored. Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database to identify males aged ≥66 with new primary PC diagnoses (2009-2017). Patients' rurality was defined using the 2013 SEER Rural Urban Continuum Code. Provider rurality was defined by matching the provider to Core Based Statistical Area Codes with the 2013 National Center for Health Statistics Urban–Rural Classification scheme for counties. The primary outcome was All-cause mortality. Given proportional hazard violation, adjusted extended Cox models were performed for the primary outcome. Secondary outcomes were PC-specific mortality (PCSM) and cardiovascular mortality (CVDm). Adjusted Fine-Gray models, accounting for competing risks (other causes of mortality), were applied to assess PCSM and CVDm. Results: We included 75,291 PC patients, with a median age of 72 years (interquartile range 69-76), of whom 8.9% received androgen deprivation therapy (ADT). Among them, 91.7% originated from and received treatment in metropolitan areas, 7% were from urban areas but were served by metropolitan providers, 0.8% lived in rural areas and were served by metropolitan providers, and 0.5% resided in rural areas and were served by non-metropolitan providers. All-cause mortality risk was 44% higher in patients who hailed from rural areas and had a provider from a non-metropolitan area [adjusted hazards ratio = 1.44 (95% confidence interval = 1.15-1.79); Table]. Conclusions: Patients from rural areas with non-metropolitan providers face a higher risk of all-cause mortality, underscoring the role of rurality as a contributing factor to disparities in this PC outcome.[Table: see text]