tbuckley/cabot-search huggingface dataset:
Evaluating the role of cancer-associated fibroblasts in T cell–mediated proinflammatory reprogramming of tumor associated macrophages in the prostate cancer tumor microenvironment.
Authors: David Kosoff, Erika Heninger, Matthew T Breneman, Emma Recchia, Vilena Maklakova, Aaron Lebeau
Journal: Journal of Clinical Oncology (2025)

248 Background: Tumor-associated macrophages (TAMs) have been implicated as a critical mediator of T cell exclusion and inhibition within the prostate TME. However, using a microscale cell culture platform, known as Stacks, we have previously demonstrated that while prostate tumor cells induce an immunosuppressive phenotype in TAMs, activated T cells can reprogram these macrophages towards a proinflammatory phenotype that augments tumor-directed T cell responses. To investigate how other cell populations within the TME impact T cell mediated macrophage reprogramming, we expanded our models to include cancer-associated fibroblasts (CAFs), which have been previously shown to have immunosuppressive effects that regulate macrophage function in the TME. Methods: Primary T cells and autologous monocyte-derived macrophages (MDMs) were derived from the peripheral blood samples of patients receiving care at the University of Wisconsin Carbone Cancer Center and with William S Middleton Memorial Veterans Hospital in Madison, WI. MDMs were cultured with prostate tumor (22Rv1) and CAF (hPrCSC-44) cells in mono-, co-, and tri-culture models for 72h in the Stacks microfluidic cell culture platform. Activated autologous T cells were then added to each condition for an additional 24h of culture. Models were analyzed for T cell migration and surface marker expression by confocal microscopy, secreted cytokine and chemokine profiles by protein bead array, and gene expression by qRT-PCR. Results: We found that MDM-mediated augmentation of CD4 + and CD8+ T cell migration within the prostate TME models was abrogated in the presence of CAFs. Analysis of gene expression further demonstrated that the presence of CAFs in our quad culture models resulted in a decrease in expression of T cell recruitment chemokines by the MDMs, including CCL2, CCL5, CXCL9, CXCL10, and CXCL11, compared to MDM tri-culture with tumor cells and T cells. MDMs also expressed higher levels of IL-10 mRNA, a potent immune suppressive factor, when CAFs were present in the TME. Conclusions: Using microscale cell culture technologies, we provide the first direct evidence that CAFs inhibit T cell mediated proinflammatory reprogramming of MDMs in the prostate TME. Furthermore, we demonstrate that this inhibition of MDM reprogramming is associated with a decrease in tumor-directed T cell migration compared to MDM, tumor cell, and T cell tri-cultures. This data suggests that CAFs, through their effects on MDMs/TAMs, may be playing a vital role in the inhibition of tumor-directed T cell responses. The pathways that are mediating this effect therefore represent valuable therapeutic targets to augment immunotherapeutic efficacy in prostate cancer treatment.
Assessing practice gaps and challenges for immunotherapy integration in treatment of metastatic urothelial carcinoma.
Authors: Bradley Alexander McGregor, Taral H Patel, Thandiwe Chavula, Ilona Dewald, Jeffrey D. Carter, Cherilyn Heggen, Kelly McKinnon
Journal: Journal of Clinical Oncology (2025)

694 Background: The approval of pembrolizumab with enfortumab vedotin in the first-line setting has shifted the treatment paradigm for patients with metastatic urothelial carcinoma (mUC). However, integrating these novel therapies into clinical practice can be challenging for health care providers (HCPs). To better understand real-world challenges and barriers for integrating immunotherapy in routine practice, we surveyed providers across community-based oncology settings. Methods: Between 02/2024 and 04/2024, multidisciplinary (MDT) oncology team members (N = 60) across the US were surveyed to assess providers' current practices and challenges regarding biomarker testing, immunotherapy use, and multidisciplinary coordination in mUC care. Teams then participated in a network-wide workshop to develop action plans for improving mUC care. Results: HCPs reported ongoing challenges in integrating novel therapies in clinical practice, including individualizing treatment plans and sequencing (28%), keeping up with clinical evidence (24%), and differentiating available immunotherapy and combination regimens (14%). Additionally, HCPs reported challenges in providing patient-centered supportive care (12%) and engaging patients in shared decision-making (10%). Most HCPs routinely tested for PD-L1 (82%), HER2 expression (63%) and alteration (55%), and FGFR (62%) , and &lt;50% tested PIK3CA and CDKN2A alterations. While HCPs felt confident in applying the latest guidelines to treatment selection (62%), only 45% of cisplatin-ineligible patients were reported to have received approved first-line immunotherapy combination in the metastatic setting. Most HCPs felt confident recognizing and managing immune-related adverse events (64%) and reported that only 15% of patients required treatment discontinuation due to adverse events. Only 21% of HCPs were fully satisfied with MDT coordination/communication and believed that improving MDT collaboration (33%) and provider education on integrating immunotherapy and combination approaches (31%) would most improve mUC care. After participating in a network-wide workshop, teams developed action plans including improving MDT coordination, standardizing and streamlining biomarker testing, and increasing education on treatment sequencing guidelines. Following integration of these action plans, 100% of HCPs reported improved/increased alignment with evidence-based guidelines. Additionally, HCPs reported increasing provider education on integrating immunotherapy and combination therapies into practice (71%) and improving MDT collaboration (71%). Conclusions: These data and actionable insights can inform future targeted initiatives to improve integration of evidence-based immunotherapy and combination targeted agents into practice for patients with mUC.
Relationship between androgen deprivation therapy and kidney function in patients with prostate cancer: An analysis of the RADICAL-PC study.
Authors: Geethan Baskaran, Jehonathan H. Pinthus, Celestia S. Higano, Cristina Cano Garcia, Rajibul Mian, Germano Dallegrave Cavalli, Guila Delouya, Cesar O.L. Dusilek, Bobby Shayegan, Rafaela Kirchner Piccoli, Tamim Niazi, Margot K. Davis, Avirup Guha, Joseph B. Selvanayagam, Jose Enrique Cita Pardo, Patrick P. Luke, Darryl Leong
Journal: Journal of Clinical Oncology (2025)

115 Background: Androgen deprivation therapy (ADT) is an effective treatment for patients with advanced prostate cancer (PC). However, its impact on renal function remains underexplored. We evaluated the impact of ADT on kidney function in a cohort of patients with PC. Methods: We analyzed the RADICAL-PC study (Role of Androgen-Deprivation Therapy in Cardiovascular Disease—A Longitudinal Prostate Cancer study, NCT04127631), a prospective study of patients with PC in 10 countries. ADT use was assessed at baseline and follow-up visits. We quantified kidney function using glomerular filtration rate (GFR), calculated using the CKD-EPI equation and creatinine measurements obtained at annual visits. We used a linear mixed-effects regression model to analyze the association between ADT and change in GFR (ΔGFR), adjusting for age, diabetes, hypertension, renal disease, heart failure, chemotherapy, medications, alcohol use, and smoking. Using a Cox regression model, we assessed the association between ADT and acute kidney injury (AKI) as reported by sites. Results: Our analysis included 4119 participants with a median age of 68 (IQR 63-74) years. In 1791 (43%) participants using ADT at baseline, the ΔGFR over 2 years was -0.64 [95%CI -1.05 to -0.22] ml/min/1.73m 2 /year. In 2328 (57%) ADT-naïve participants at baseline, the ΔGFR was -1.00 [95%CI -1.34 to -0.64] ml/min/1.73m 2 /year. There was no significant difference in ΔGFR between the two groups (p=0.20). Age (β=-0.58, p&lt;0.001), hypertension (β=-1.98, p&lt;0.01), and anticoagulation use (β=-3.92, p&lt;0.001) were associated with GFR decline. When analyzed as a time-varying covariate, ADT use was associated with less GFR decline than no ADT use (-0.21 vs. -1.07 ml/min/1.73m 2 /year, respectively, p&lt;0.01). Duration of ADT use was not associated with ΔGFR (+0.04 [95%CI -0.02 to 0.10] ml/min/1.73m 2 /month, p=0.18). AKI developed in 91 (2.2%) participants over a median follow-up of 25 (IQR 12-36) months. Baseline ADT use was associated with an increased risk of AKI in univariate analysis (HR 2.58 [95%CI 1.67 to 3.98], p&lt;0.001), but was not significant after adjustment for covariates (HR 1.37 [95%CI 0.83 to 2.26], p=0.22). Conclusions: This analysis suggests that ADT use is not associated with GFR decline or AKI incidence in patients with PC, challenging previous literature concerning ADT-related renal dysfunction. Further studies with longer follow-up periods are needed to confirm these findings.
Genomic features of prostate cancer patients with and without ductal adenocarcinoma (DA) based on liquid biopsy.
Authors: Qiyu Zhu, Jinge Zhao, Yifu Shi, Hao Zeng
Journal: Journal of Clinical Oncology (2025)

191 Background: Ductal adenocarcinoma (DA) is relatively rare and highly co-existed with prostate adenocarcinoma (AC). This study aims to investigate the distinctive genomic profiles of patients with DA compared to those without it. Methods: Blood samples were obtained from 144 patients (36 with DA and 108 without DA) who were diagnosed with prostate cancer from 2017 to 2023 at West China Hospital. We performed cell-free DNA sequencing to investigate the genomic differences between patients with DA (DA[+]) and those without (DA[-]), and explored the potential associations between their mutational status and prognosis. Pathogenic and likely pathogenic alterations were included for analysis. Results: We identified that AR pathway (16/36 [44.4%] vs 24/108 [22.2%], p=0.017) and WNT pathway (6/36 [16.7%] vs 5/108 [4.6%], p=0.029) mutations were significantly enriched in DA(+) compared to DA(-), with AR pathway featured by FOXA1 (9/36 [25%] vs 5/108 [4.6%], p=0.0012). DDR mutation rate and the HRD scores appeared to be comparable between DA(+) and DA(-). TP53 was associated with a deteriorating prognosis for both DA(+) and DA(-) in terms of castration-free survival (CFS). Conclusions: Our findings provide further genomic insights in prostate cancer with ductal morphology and are instructive for the diagnosis and treatment of DA. Baseline characteristics of the DA (+) and DA (-) cohorts. Variable DA (-), N = 108 1 DA (+), N = 36 1 p-value 2 Treatment line 0.4 HSPC 34 (31%) 7 (19%) CRPC 18 (17%) 6 (17%) Treatment-naive 56 (52%) 23 (64%) Metastasis at detection 0.6 M0 52 (48%) 19 (53%) M1 56 (52%) 17 (47%) Visceral metastasis 8 (7.4%) 8 (22%) 0.028 Bone metastasis 0.7 &lt;5 12 (11%) 6 (17%) ≥5 38 (35%) 12 (33%) 0 55 (51%) 18 (50%) Not available 3 (2.8%) 0 (0%) ISUP 0.055 1 3 (2.8%) 0 (0%) 2 6 (5.6%) 3 (8.3%) 3 16 (15%) 11 (31%) 4 12 (11%) 7 (19%) 5 71 (66%) 15 (42%) Age 68 (61, 73) 68 (61, 73) &gt;0.9 Baseline PSA 0.007 &lt;50 41 (38%) 23 (64%) ≥50 67 (62%) 13 (36%) 1 n (%); Median (IQR). 2 Pearson's Chi-squared test; Fisher's exact test; Wilcoxon rank sum test. DA: dutal adenocarcinoma of the prostate; HSPC: hormone-sensitive prostate cancer; CRPC: castration-resistant prostate cancer; ISUP: International Society of Urological Pathology grading; PSA: prostate-specific antigen.
Comorbidity burden and effectiveness of immunotherapy in patients with metastatic renal cell carcinoma.
Authors: Emre Yekeduz, Martin Zarba, Eddy Saad, Connor Wells, Marc Machaalani, Razane El Hajj Chehade, Marc Eid, Chris Labaki, Rashad Nawfal, Renee Maria Saliby, Karl Semaan, Clara Steiner, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2025)

509 Background: Comorbidities pose a challenge in the treatment of patients with cancer and present a barrier to inclusion in clinical trials. While the effect of comorbidities on the efficacy of immunotherapy (IO) has been studied in various malignancies, it remains unclear in patients with metastatic renal cell carcinoma (mRCC) treated with IO-based combinations. Methods: Data from patients with mRCC receiving IO-based combinations (IO+IO or IO+anti-vascular endothelial growth factor (VEGF)) as first-line treatment were collected from the Dana-Farber Cancer Institute and the Tom Baker Cancer Centre-University of Calgary. The comorbidity burden was assessed at baseline using the Charlson Comorbidity Index (CCI). Patients were stratified into two groups: CCI-low (≤3) or CCI-high (&gt;3), to predict overall survival (OS) through maximally selected rank statistics. The effect of CCI on OS and time-to-treatment failure (TTF) was assessed using multivariable Cox regression models. Results: Overall, 311 patients were included. The median age was 63 years (Q1-Q3: 58-69), and most patients had clear-cell mRCC (89.7%). A total of 167 (53.7%) and 144 (46.3%) patients were treated with IO+IO and IO+anti-VEGF, respectively. The most prevalent comorbidities were cardiovascular disease (20.2%) and diabetes (18.6%). In terms of CCI, 241 (77.5%) and 70 (22.5%) patients were categorized as CCI-low and CCI-high, respectively. Median follow-up was 40.8 months (Q1-Q3: 34.4-47.2) for OS. OS (aHR: 1.89, 95% CI: 1.16-3.06, p=0.010) and TTF (aHR: 1.56, 95% CI: 1.04-2.33, p=0.029) were worse in the CCI-high group (vs. CCI-low group) after adjusting for covariates (IMDC groups, age, Karnofsky score, histology, sarcomatoid features, sites of metastases, treatment type, and nephrectomy status). Rates of all adverse events (AEs) (66% vs. 65.5%) and immune-related AEs (42.1% vs. 35.9%) were comparable between the CCI-low and CCI-high groups, respectively. Conclusions: We report for the first time that comorbidity burden is an adverse prognostic factor in patients with mRCC undergoing IO-based combinations, highlighting the need for multidisciplinary care and tailored treatment strategies in this vulnerable patient population. Interestingly, despite the observed difference in survival outcomes, the incidence and profile of AEs were similar between the high- and low-comorbidity groups, suggesting that comorbidity burden does not substantially alter the safety profile of IO-based treatments.
Pulmonary Embolism–Related Mortality in Patients With Cancer
Authors: Marco Zuin, Anju Nohria, Stanislav Henkin, Darsiya Krishnathasan, Alyssa Sato, Gregory Piazza
Journal: JAMA Network Open (2025)

Importance Acute pulmonary embolism (PE) is a major cause of morbidity and mortality in patients with cancer in the US and worldwide. Objectives To assess the trends in PE-related mortality from 2011 to 2020 among US patients with cancer across age, sex, ethnic and racial groups, urbanicity, and regionality. Design, Setting, and Participants This cohort study used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system to determine national trends in age-adjusted mortality rates (AAMRs) due to acute PE among US patients with cancer aged 15 years or older from January 2011 to December 2020. Concomitant trends in cancer mortality and incidence that may have contributed to PE-related mortality were obtained from US Cancer Statistics. Data were analyzed from September to November 2024. Exposure PE-related mortality. Main Outcomes and Measures The primary outcome was PE-related deaths among individuals with cancer. AAMRs and cancer incidence were assessed using joinpoint regression modeling, expressed as an average annual percentage change (AAPC) with relative 95% CIs. Results From 2011 to 2020, a total of 27 280 194 individuals aged 15 years or older (13 897 519 male [50.9%]; 13 382 675 female [49.1%]) died in the US. The AAMR for PE-related mortality in patients with cancer increased during this time period (AAPC, 2.5%; 95% CI, 1.4% to 3.6%; P = .001), without differences between sexes ( P for parallelism = .38). The AAMR increased among those aged 15 to 64 years (AAPC, 3.2%; 95% CI, 1.9% to 4.6%; P = .001), non-Hispanic and non-Latinx White individuals (AAPC, 2.7%; 95% CI, 1.52% to 3.94%; P = .001), non-Hispanic and non-Latinx Black or African American individuals (AAPC, 2.2%; 95% CI, 0.7% to 3.7%; P = .001), Hispanic and Latinx individuals (AAPC, 2.6%; 95% CI, 0.7% to 4.5%; P = .006), and among individuals residing in the Southern US (AAPC, 3.7%; 95% CI, 1.3% to 6.2%; P = .003). During the same period, age-adjusted cancer incidence and cancer-related mortality decreased while the absolute number of new cancer diagnoses and cancer-related deaths increased. Conclusions and Relevance This cohort study found that despite decreases in cancer-related mortality rates, age-adjusted PE-related mortality in US patients with cancer increased over the last decade; concerning trends included rising PE-related mortality in younger individuals aged 15 to 64 years, particular ethnic and racial groups, and the Southern region of the US. Recognition of such patterns may inform further research into thromboprophylaxis and treatment of PE as a complication of cancer and cancer-directed therapy.
Management strategies and patient outcomes among LPC patients with persistently positive PSA after RP.
Authors: Shawn Malone, Christopher J.D. Wallis, Ilias Cagiannos, Robert James Hamilton, Naveen S. Basappa, Cristiano Ferrario, Geoffrey Gotto, Ricardo Fernandes, Tamim Niazi, Chris Morash, Ricardo A. Rendon, Fred Saad, Sebastien J Hotte, Brendan J.W. Osborne, Katherine Chan, Anousheh Zardan, Bobby Shayegan
Journal: Journal of Clinical Oncology (2025)

353 Background: Patients (pts) with localized high-risk/very high-risk prostate cancer (PCa) have an elevated risk of metastases and Prostate Cancer (PC)-specific death following local therapy. This risk is significantly higher for patients with a persistently elevated PSA (pPSA) after Radical Prostatectomy (RP) We aim to better understand the current management strategies for this population using real world data. Methods: We performed a retrospective population-based cohort study using province-wide linked administrative data from 2010-2022, in Ontario, Canada. Patterns of patient management in the intermediate (IR)/High-/very high risk (h/vHR) LPC patients who underwent RP with persistently elevated PSA≥0.1 ng/ml were analyzed. Results: In this retrospective cohort between 2010-2021, 31,571 patients diagnosed with LPC were identified. Cohorts were stratified by IR (58.2%, n=18,365) and H/vHR (41.8%, n=13,206). Overall, 13493 pts with IH/HvHR received RP as their treatment for LPC, from which 314 pts (Intermediate Risk=127; High-Very high risk=187) had a persistently positive PSA after RP. 46.8% (n=147) of pts with pPSA received RT, 40.4% (n=127) ADT and 21.7% (n=68) RT+ADT as their next line of treatment (p=&lt;.0001; SD=0.880). PSA value after RP and immediately preceding start of next line of therapy was 0.6 ng/ml (Median IQR: 0.2-1.5 ng/ml) in the RT subgroup and 5.8 ng/ml (Median IQR 2.9-10.5 ng/ml) and 0.9 ng/ml in ADT and ADT+RT groups respectively (Median IQR 0.2-4.3 ng/ml; p=&lt;.0001). Median (IQR) time to CRPC was 9 years (7-11.3) in pts without a pPSA and 7.4 years (5.2-10) in patients with a persistent PSA (P=&lt;.0001). Conclusions: Patients who do not achieve a PSA&lt;0.1 ng/ml after radical prostatectomy have a worse prognosis. LPC patients should be monitored closely after RP to identify the sub-population with persistent PSA that could benefit from additional therapies intensified systemic therapies including Androgen Receptor Pathway Inhibitors (ARPIs). Time to progression to CRPC, PC event, and mortality by persistent PSA status among patients with RP. Persistent PSA Label Total No Yes P Value Variable (Sample size) N=14,084 N=13,770 N=314 Time to CRPC n (%) 186 (1.3%) 148 (1.1%) 38 (12.1%) &lt;.0001 Median (IQR), Years 9.1 (7-11.3) 9 (7-11.3) 7.4 (5.2-10) &lt;.0001 Time to PC event n (%) 6,001 (42.6%) 5,744 (41.7%) 257 (81.8%) &lt;.0001 Median (IQR), Years 6.7 (1.9-3.6) 6.8 (1.5-10) 0.8 (0.4-4) &lt;.0001 PSA value before RP (PSA test closest to RP) Median (IQR), (1) ng/ml 6.7 (5.1-9.6) 6.7 (5.0-9.6) 9.0 (5.9-12.8) &lt;.0001
A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in metastatic hormone sensitive prostate cancer patients with HRR gene mutation: Updated analysis of PROact.
Authors: Junlong Zhuang, Shun Zhang, Xuyu Zhang, Xuefeng Qiu, Xi Zheng, Jie Gao, Hongqian Guo
Journal: Journal of Clinical Oncology (2025)

TPS292 Background: Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged radiographic progression-free survival (rPFS) in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy of this combination therapy in patients with mHSPC. Here, we report the updated analysis of PROact study, the first phase II trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation. Methods: This was a single center, single arm, phase II trial (NCT05167175) conducted in male patients with mHSPC who had at least one HRR gene mutation ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51D and RAD54L ) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Safety and efficacy data with a median follow-up of 9.5 months have been reported. Here, we present the updated efficacy data categorized by gene. Results: Thirty patients were enrolled, all of whom had de novo mHSPC, consisting of 30% (9/30) with low-volume and 70% (21/30) with high-volume disease. As of the data cut-off (September 6, 2024), the median follow-up duration was 14.0 months. 13 patients had measurable disease; the confirmed ORR was 84.6% (11/13). One patient with ATM mutation achieved complete response. Ten patients obtained partial response, including four with BRCA2 , two with ATM , two with CDK12 , one with RAD51B mutations and one with co-mutation of three pathogenic genes. Furthermore, two patients harboring BRCA2 mutation experienced progressive disease (Table). Clinical trial information: NCT05167175 . Gene by gene efficacy evaluation. HRR mutation Totally number RECIST assessment CR PR PD BRCA2 11 6 0 4 2 CDK12 7 2 0 2 0 ATM 6 3 1 2 0 PALB2 2 0 - - - CHEK2 1 0 - - - RAD51B 1 1 0 1 0 RAD51D 1 0 - - - CDK12, CHEK2, RAD51B 1 1 0 1 0