tbuckley/cabot-search huggingface dataset:
Beyond survival: Understanding the social dimensions of prostate cancer.
Authors: Karan Jatwani, Philip Ma, Seyedeh Azadeh Miran, Atulya Aman Khosla, Michael Joseph Whalen, Maneesh Rajiv Jain
Journal: Journal of Clinical Oncology (2025)

28 Background: Prostate cancer carries one of the highest burdens of racial disparities in outcomes in oncology. Understanding social determinants of health (SDOH), which measure inequities in healthcare, could give us insight into quality improvement strategies. We aimed to study the impact of key SDOH measures (everyday discrimination, supportive relationships, neighborhood characteristics, and food and housing security) on the perception of overall health in prostate cancer survivors using a publicly available database. Methods: A cross-sectional study was conducted using overall health and SDOH survey data collected by the National Institutes of Health All of Us Research Program from June 2017 to June 2022. Ordinal logistic regression was utilized to assess associations between overall perception of health and each specific SDOH survey domain. All statistical tests were two-sided, and a p-value less than 0.05 was statistically significant; multiplicity adjustments were not made. The Statistical package (0.13.5) of Python (Version 3.1) was used for all statistical analyses. Results: 5,909 male participants with prostate cancer met the inclusion criteria. 2,280 (38.58%) had completed the SDOH surveys and were considered for analysis. Of those, 1,966 (86%) were White, 5.88% Black or African American, and 3.55% Hispanic in ethnicity. In the ordinal logistic regression models, for every unit increase in the SDOH neighborhood characteristics score, the odds of having a higher perception of general health increased by 3% (OR 1.03, 95% CI = [1.02, 1.04], p &lt; 0.0001). For every unit increase in the SDOH day-to-day discrimination score, the odds of having a higher perception of general health increased by 3% (OR 1.03, 95% CI = [1.02, 1.04], p &lt; 0.0001). For every unit increase in the score of the supportive relationships SDOH domain, participants were 4% (OR = 1.04, 95% CI = [1.035, 1.053]) more likely to have a higher perception of general health. Controlling for all other variables, Black race, Hispanic ethnicity, a history of mental health disorders, smokers, and age less than 65 years were independently significant for poor perception of overall health (p &lt; 0.05). Conclusions: While SDOH have been linked with prostate cancer-specific mortality, this is one of the first studies evaluating the role of each component of SDOH on the perception of overall health. We highlighted that factors including neighborhood, discrimination, and supportive relationships have a quantifiable impact on health. Our study provides objective predictive changes in the overall perception of health. Using our variables as a model to predict the effect of changes in these determinants and tailor support to individual needs could ultimately improve quality of life.
Targeting highly aggressive ductal prostate tumours with poly ADP ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) combination therapy.
Authors: Weranja Ranasinghe, Mahsa Delavar, Mitchell G. Lawrence, Nicholas Choo, Birunthi Niranjan, Melissa Papagiris, Jenna Kraska, Hong Wang, Shivakumar Keerthikumar, Ganiraju C. Manyam, Patricia Troncoso, Peter S Shephard, Timothy C. Thompson, Renea Taylor, Brian Francis Chapin, Gail Risbridger
Journal: Journal of Clinical Oncology (2025)

420 Background: Prostatic ductal adenocarcinoma (DAC) is an aggressive prostate cancer variant, prone to early metastasis at low PSA levels and showing poor response to androgen blockade despite androgen receptor expression. Although DACs do not have any efficacious therapies, DACs frequently harbour DNA damage repair (DDR) mutations. We investigate the efficacy of combined PARP inhibitor (PARPi) and androgen signalling inhibitor (ARSi) therapy in DDR-proficient DAC tumours. Methods: To model DAC, organoids were developed in Matrigel from patient-derived xenografts (PDXs) originating from DDR-proficient radical prostatectomy (287R, 275R) and BRCA2 heterozygous mutant metastatic (201.1) tumours, retaining key histologic and genomic features. These organoids were exposed to different PARP inhibitors (Talazoparib, Saruparib) and androgen signalling inhibitors (Enzalutamide, Apalutamide, Darolutamide) for up to 11 days. Cell viability and growth responses were assessed using PrestoBlue and CellTiter-Glo assays and automated imaging analysis. SynergyFinder software calculated synergy scores for each treatment combination. Results were further validated in vivo using DDR-proficient 287R PDXs. Mechanistic insights were explored through RNA sequencing of 20 DAC and ten acinar radical prostatectomy samples, and four matched DAC and acinar PDXs, with γH2AX immunohistochemistry to examine DNA damage response. Results: Overall, PARPi/ARSi combination treatment significantly reduced organoid viability compared to PARPi alone or ARSi in DDR-proficient and heterozygous BRCA2 -mutant DAC tumours. The levels of synergy were comparable regardless of which PARPi and ARSi agents were combined. In vivo results using DDR-proficient PDX 287R confirmed the efficacy of PARPi + ARSi combination by reducing tumour volume by 58% compared to control ( p =0.0198) and by 40% versus PARPi alone ( p = 0.0326). Mechanistically, RNA sequencing demonstrated upregulation of multiple DDR pathways in DACs compared to acinar prostate tumours, regardless of the DDR status. After treatment with PARPi + ARSI combination, there was an increase in γH2AX compared to the control in the DDR-proficient PDX 287R (mean 1.42 vs 0.5, p=0.0056), suggesting enhanced DNA damage may contribute to the efficacy of the combination treatment. Conclusions: Our results show that PARPi increases the efficacy of ARSi in DAC. This is notable given the poor response of DAC to AR-directed treatments and provides the rationale for a pre-planned phase 1/2 study.
Association between molecular changes and perioperative immunotherapy in patients with advanced clear cell renal cell carcinoma undergoing cytoreductive nephrectomy.
Authors: Wadih Issa, Navneet Kaur, Andrew DeVilbiss, Ze Yu, Qinhan Zhou, Damla Gunenc, Chao Xing, Andrew Zhuang Wang, Tian Zhang
Journal: Journal of Clinical Oncology (2025)

573 Background: Immunotherapy (IO) combinations are standard first-line treatments for advanced clear cell renal cell carcinoma (ccRCC). However, identifying patients who will respond to IO remains a challenge, complicating treatment selection. Previous studies on biomarkers for IO response or resistance often used unmatched biopsies, limiting insights into therapy-induced changes due to patient heterogeneity. This study aims to evaluate transcriptomic changes in matched pre- and post-IO patient samples to detect treatment-induced gene and pathway alterations. Methods: A retrospective analysis was performed on patients with advanced ccRCC receiving IO-based therapies who underwent cytoreductive nephrectomy (Nx) at UT Southwestern/Simmons Comprehensive Cancer Center (SCCC). Patient-level data were extracted from an IRB-approved registry, and samples were collected from the SCCC biorepository. The primary endpoint was to identify IO-induced transcriptomic changes using paired pre- and post-treatment tissue sections. Regions of interest (ROIs) were selected based on pan-cytokeratin (PanCK) expression using the GeoMx Digital Spatial Profiler (DSP, NanoString). Whole-transcriptome analysis was performed, and data were analyzed using a two-sample t-test. Results: We identified 58 patients with advanced ccRCC who received perioperative IO regimens and deferred Nx. Of these, 7 patients had paired pre- and post-treatment samples sequenced (3 received ipilimumab/nivolumab, 3 nivolumab, and 1 pembrolizumab/axitinib). Individual analysis of each matched pair revealed an average of 92 DE genes (log fold-change &gt;1.3, p&lt;0.01). Gene set enrichment analysis (GSEA) showed differential enrichment in pathways such as immune response (interleukin signaling, JAK/STAT signaling, innate immune system activation), translational machinery, MHC-mediated tumor antigen presentation, axon guidance, and cell death pathways. Notably, a key post-IO downregulated pathway was GPCR signaling, which is implicated in tumor growth and metastasis. Taken in aggregate, bulk analysis revealed only 9 differentially expressed (DE) genes in PanCK+ tumor regions, and GSEA did not identify commonly enriched pathways. Conclusions: While bulk analysis detected few changes, individual pair analysis highlighted significant transcriptomic shifts in RCC tumors post-IO. These RCC tumors upregulated gene expression in several immune pathways, including interleukin, JAK/STAT, and innate immune pathways. This study underscores the importance of matched samples to capture patient-specific changes after IO combinations.
Nectin-4 and Trop-2 expression as potential therapeutic target in collecting duct carcinoma: Preliminary results from the CICERONE trial (NCT05372302).
Authors: Giuseppe Procopio, Alessandro Rametta, Marco Stellato, Filippo Guglielmo Maria de Braud, Katia Todoerti, Luca Agnelli, Veronica Huber, Licia Rivoltini, Luisa Rollo, Chiara Vela, Melanie Claps, Valentina Guadalupi, Eleonora Gusmaroli, Simone Rota, Anna Caliò, Guido Martignoni, Elena Verzoni, Matteo Brunelli
Journal: Journal of Clinical Oncology (2025)

587 Background: Collecting Duct Carcinoma (CDC) represents 1% of all renal cell carcinomas (RCC) and is characterized by aggressive clinical behavior and a particularly dismal prognosis. Cabozantinib and platinum-based chemotherapy are active therapeutic options, but survival remains poor with no novel agents approved for the treatment of metastatic disease. Antibody-Drug Conjugate (ADC) targeting Nectin-4 and TROP-2 are dramatically changing the therapeutic landscape of Urothelial Carcinoma (UC). Given the biological and clinical similarities between CDC and UC, we evaluated Nectin-4 and TROP-2 expression in CDC. Methods: CDC tissue samples were collected from patients enrolled in the CICERONE study (NCT05372302), a multicentric trial that aims to define the transcriptomic profile of CDC with the goal of changing the paradigm of CDC management by using biology-driven treatments. Nectin-4 and TROP-2 are surface proteins involved in cell adhesion and proliferation. Their expression was assessed by immunohistochemistry (IHC) using a validated assay with a Nectin-4 antibody (clone M22-321b41.1) and a TROP-2 antibody (Ab227689 by Abcam).Staining area was quantified as a percentage (0–100%) and considered positive if &gt;10% of the tumor surface was stained. Staining intensity was dichotomized into positive and weakly positive, based on a clear distinction from the negative control. Results: 59 tissue samples from patients with diagnosis of CDC were considered eligible after centralized histological review. Fresh or archival tumor tissue was collected from either primary lesion or metastatic sites biopsies at baseline before the start of systemic therapy. Preliminary results demonstrated that Nectin-4 was expressed in 24 out of 59 samples (41%), while TROP-2 positivity was observed in 58/59 cases (98%). Conclusions: CDC appears to be a unique kidney tumor, which lies between UC and RCC clinically and biologically. Here we report for the first time the expression of two potential therapeutic targets in metastatic CDC, Nectin-4 and TROP-2, confirming the similarities between CDC and UC.Based on this encouraging data, along with the interesting results from EV-302 trial, we hypothesize that pembrolizumab in combination with Antibody-Drug Conjugate (ADC) could be active in mCDC and this combo will be assessed in the phase II RePRINT trial (NCT06302569). Clinical trial information: NCT05372302 .
Clinical outcomes of stage IIA/IIB seminoma treated with radiotherapy and chemotherapy: Should regional therapy be considered the preferred treatment approach?
Authors: Rachel Glicksman, Di Maria Jiang, Philippe Bedard, Xiang Y Ye, Lynn Anson-Cartwright, Astrid Billfalk-Kelly, Satheesh Krishna, Martin O'Malley, Carol C Cheung, Abigail Shin, Robert James Hamilton, Padraig Warde, Peter Chung
Journal: Journal of Clinical Oncology (2025)

629 Background: With the publication of the Surgery in Early Metastatic Seminoma Trial there has been increasing interest in the use of regional therapy as first line treatment (reserving systemic therapy for relapse) in patients with testicular seminoma with low volume with retroperitoneal lymphadenopathy. Herein, we sought to evaluate outcomes with both management approaches. Methods: A prospectively maintained single-institutional database was retrospectively queried for patients diagnosed between 1995-2016 with de novo clinical stage IIA/B (CSIIA/B) or who relapsed on surveillance (Rel-CSIIA/B) treated with radiotherapy or chemotherapy. All patients were reviewed by the multidisciplinary team; while the preferred management policy during this period was radiotherapy, all treatment decisions were individualized at the physician/patient level. Results: The median follow-up was 7.1 years (IQR 4.3-9.9). There were 153 patients: 67 had de novo CSIIA/B (IIA-32, IIB-35) and 86 patients had Rel-CSIIA/B seminoma (IIA-51, IIB-35). One hundred and twenty patients (78%) received radiotherapy (IIA-78, IIB-42) and 33 (22%) received platinum-based chemotherapy (IIA-5, IIB-28). Eleven patients (IIA- 9/78, IIB- 2/42) relapsed following radiotherapy and 1 patient (IIB) relapsed following chemotherapy, corresponding to 5-year relapse rates of 10% for radiotherapy and 3% for chemotherapy. All 12 patients who relapsed were treated successfully with salvage chemotherapy. Conclusions: Regional therapy in patients with testicular seminoma with low volume with retroperitoneal lymphadenopathy gives excellent treatment results – recognising that a small proportion of patients will need salvage chemotherapy for cure, thereby exposing these patients to the morbidity of two treatment strategies. Our results support the view that regional therapy is a reasonable treatment option in this setting and should be discussed with all patients.
Real-world outcomes among patients with metastatic castration-resistant prostate cancer (mCRPC) receiving guideline-recommended therapies after treatment with <sup>177</sup> Lu-PSMA-617: A real-world prostate cancer disease observation (PRECISION) data platform analysis.
Authors: Xiao X. Wei, Neal D. Shore, Daniel J. George, Elisabeth I. Heath, Jennifer Nguyen, Jeetvan Patel, Amrita Sawhney, Barinder Kang, Clare Byrne, Jackson Tang, Alton Oliver Sartor
Journal: Journal of Clinical Oncology (2025)

61 Background: 177 Lu-PSMA-617 was approved in March 2022 for patients with mCRPC pretreated with an androgen receptor pathway inhibitor (ARPI) and a taxane. There are limited data on the effectiveness of treatments post- 177 Lu-PSMA-617. The aim of this study was to describe prostate-specific antigen (PSA) responses among patients with mCRPC receiving a guideline-recommended therapy as the next therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis, comprised of patient-level electronic health record and claims data that represent the US advanced prostate cancer population in the community, academic, urology, and medical oncology settings. Patients with mCRPC who received any guideline-recommended therapy at least 14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024 were included. Guideline-recommended therapies included abiraterone, enzalutamide, darolutamide, apalutamide, cabazitaxel, docetaxel, pembrolizumab, sipuleucel-T, niraparib, olaparib, talazoparib, rucaparib, and radium-223. Patients’ PSA values while on 177 Lu-PSMA-617 treatment were compared with their PSA values during the subsequent therapy course. Proportions of patients achieving reductions in PSA levels ≥50% (PSA50) and ≥80% (PSA80) were estimated. All analyses were descriptive. Results: A total of 152 patients receiving any subsequent guideline-recommended therapy after 177 Lu-PSMA-617 were identified. Mean age was 72.1 years. Most patients received an ARPI (n=93, 61.2%) – abiraterone (n=38), enzalutamide (n=37), darolutamide (n=10), or apalutamide (n=8) – as their subsequent therapy. Of patients who received a taxane (n=42, 27.6%), 24 received cabazitaxel and 18 received docetaxel. Median time to initiation of subsequent therapy was 206 days (interquartile range [IQR] 101–301 days) from 177 Lu-PSMA-617 initiation and 44 days (IQR 17–119 days) from 177 Lu-PSMA-617 discontinuation. Overall, among patients with sufficient information for PSA evaluation (n=30), 46.7% achieved PSA50 and 40.0% PSA80 post- 177 Lu-PSMA-617. Among patients receiving an ARPI, PSA50 was observed in 11/18 (61.1%) and PSA80 in 10/18 (55.6%). Among patients receiving a taxane, PSA50 and PSA80 were seen in 3/12 (25.0%) and 2/12 (16.7%), respectively. Conclusions: In this real-world analysis, the majority of patients who received guideline-recommended therapies after 177 Lu-PSMA-617 achieved at least a PSA50 response, suggesting that 177 Lu-PSMA-617 treatment does not preclude response to other subsequent therapies.
Optimizing clear cell renal cell carcinoma tumor-infiltrating lymphocytes under controlled hypoxic conditions.
Authors: Jad Chahoud, Marine Potez, Christopher Guske, Justin Miller, Johannes Ali, Michael Carter, Fatema Khambati, Jeffrey S Johnson, Adnan Nazir Fazili, Keerthi Gullapalli, Wade J. Sexton, Logan Zemp, Brandon J. Manley, Gabriel Roman Souza, Matthew Beatty, Philippe E. Spiess, Shari Pilon-Thomas
Journal: Journal of Clinical Oncology (2025)

581 Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) represents a promising approach for advanced solid tumor treatment. Historically, the success of TIL therapy in clear cell renal cell carcinoma (ccRCC) has been limited by difficulty expanding cytotoxic functional TILs. Hypoxic conditions in the ccRCC tumor microenvironment have been associated with mixed tumor characteristics, including metabolic dysregulation and tumor progression. Given the significant role of hypoxia in ccRCC progression, we investigated TIL expansion under controlled hypoxic conditions and its impact on TIL cytotoxic functions. Methods: Fragments or tumor digests from 41 ccRCC patients were cultured with high-dose (6000IU/mL) IL-2 for four weeks. TIL expansion success was defined as at least one fragment expanding to a minimum of 2 wells. Primary TIL underwent rapid expansion protocol (REP) at 20% (normoxic) or 5% (hypoxic) O 2 levels. Cells were rested in post-REP media for 3–4 days in their respective conditions (20% or 5% O 2 ) and subsequently collected for downstream analysis. Reactivity to autologous tumor, expression of activation/co-inhibitory markers, and memory phenotype were analyzed with flow cytometry and co-culture assays. Results: TILs were successfully grown in 87.8% of samples (36/41). TILs secreted IFNγ in response to autologous tumors in 88.6% (31/35) of the samples. Both TIL expansion and reactivity occurred independently of tumor stage or grade. TIL REP under hypoxic conditions (5% O2) was successful, and these conditions salvaged more CD8+ TILs compared to normoxic conditions (p=0.0382). Hypoxic REP TILs showed increased IFNγ, TNFα, and Granzyme B release in response to autologous tumor compared to normoxic conditions. Additionally, hypoxic REP TILs expressed higher LAG3 and TIM3 markers (p&lt;0.05), with significantly increased proportions of tissue-resident memory-like (TRM) CD8+ T-cells (CD69+CD103+) compared to normoxic conditions (18.2% CD69+CD103+ versus 2.6%, respectively, p&lt;0.0001). These features have been associated with clinical responders TILs in melanoma. Conclusions: This study demonstrates the feasibility of expanding tumor-reactive TILs from ccRCC despite tumors harboring exhausted CD8+ T-cells. Exposing TILs to hypoxic conditions enhanced effector functions and promoted the acquisition of a TRM T-cell phenotype. These findings suggest that ccRCC TIL expansion under controlled hypoxia is feasible and could confer improvement to the clinical efficacy of TIL therapy for ccRCC.
Evaluating disparities in prostate cancer-related mortality among diabetic adults in the United States and Texas: A 21-year observational study (1999-2020).
Authors: Sidra Naz, Hira Naz, Kashif Ali, Muhammad Hanif, Nirmit Patel
Journal: Journal of Clinical Oncology (2025)

30 Background: The prostate cancer (PCa) mortality risk with diabetes is poorly understood and understudied. We aim to study the annual trends and sociodemographic factors in prostate cancer-related mortality among diabetic individuals in the United States and its state of Texas from 1999 to 2020 to evaluate public health initiatives and offer insights for improving patient outcomes. Methods: Mortality trends in PCa among diabetic adults aged ≥25 years were analyzed using the CDC WONDER database, identifying through ICD-10 codes C61 “Prostate Malignant neoplasms” and E14 “Diabetes Mellitus”. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs, with 95% confidence intervals, were determined using joint point regression analysis across various demographic (sex, race/ethnicity, age) and geographic (state, urban-rural, regional) subgroups. Results: Between 1999 and 2020, 4477954 documented deaths were attributed to PCa associated with diabetes. The overall AAMR for PCa-related mortality in diabetic adults decreased in the US from an adjusted rate (AR) 109.8 in 1999 to (79.1) in 2018 (APC: -1.84%; 95% CI: -2.22% to -1.58%), then it increased to 100.4 in 2020 (APC: 10.4%; 95% CI: 2.97% to 13.4%). In Texas, AAMR for PCa among diabetic adults decreased from AR 125.5 in 1999 to 93.9 in 2018 (APC: -1.71%; 95% CI: -2.25% to -1.26%), after which it increased to 126.6 in 2020 (APC: 14.3%; 95% CI: 4.83% to 18.9%). The AAMR in U.S. men decreased from 166.8 in 1999 to 119.1 in 2018 (APC: -1.96%; 95%CI: -2.34% to -1.68%) and then increased to 147.7 in 2020 (APC: 9.66%; 95% CI: 2.66% to 12.7%). The non-Hispanic (NH) Black or African American (AA) population has the greatest AAMR (191.6), followed by the NH American Indian or Alaska Native (166.2) and the Hispanic or Latino population with AAMR (117.8). The lower-risk population was NH White with AAMR (87.2) and NH Asian or Pacific Islander (59.1). AAMR also varied by region (South: 116.5; Midwest: 101.2; Northeast: 95.5; West: 75.9), and non-metropolitan areas had higher AAMR (small metro: 100.6; micropolitan: 119.9; non-core areas: 124.3) than metropolitan areas (large central metropolitan: 102.2; large fringe areas: 84.8). The states in the upper 90th percentile of AAMRs were Oklahoma, Louisiana, Mississippi, Kentucky, Ohio, West Virginia, Maryland exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile i.e Nevada, Kansas, Arizona, Florida, MA, Wyoming, and Colorado. Conclusions: Mortality rates from prostate cancer among diabetic adults have risen in the United States and Texas over the past two decades. However, NH Black or AA, NH American Indian or Alaska Native, Hispanic or Latino men are at more risk than NH White and NH Asian or Pacific Islander.