tbuckley/cabot-search huggingface dataset:
ABCA1 and ABCG1 cholesterol transporters expression on metastatic renal cell carcinoma: Impact on immunotherapy outcomes (CHOMET study).
Authors: Giulia Claire Giudice, Giulia Mazzaschi, Michele Maffezzoli, Alessandro Acunzo, Letizia Gnetti, Enrico Maria Silini, Nicoletta Campanini, Elena Rapacchi, Giuseppe Caruso, Pietro Tuttobene, Sebastiano Buti
Journal: Journal of Clinical Oncology (2025)

568 Background: Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, most patients do not achieve benefits, emphasizing the need to understand the mechanisms of resistance. Previous analysis highlighted the association between blood cholesterol levels, passive cholesterol diffusion efflux and oncological outcomes. Here we reported the preliminary data of the CHOMET study, aimed at assessing the cholesterol transporters ABCA1 and ABCG1 expression in ICIs-treated patients with metastatic renal cell carcinoma (mRCC). Methods: The present is a monocentric retrospective study on patients with mRCC receiving first-line ICI-based combination. The primary objective was to assess the ABCA1/G1 expression by immunohistochemistry and its impact on overall survival (OS). The secondary objectives included the impact on progression-free survival (PFS) and disease control rate (DCR: complete and partial responses plus stable disease). Survival times were calculated by Kaplan-Meier method and comparisons between groups were performed by log-rank test. Results: 61 patients were enrolled, clear cell RCC was the most frequent histotype (78.8%). With a median follow-up of 30.4 months (22.1-37.0), median OS was 38.9 months (CI 33.9-NR) and median PFS was 24.4 months (CI 10.1-34.2). For the present analysis, the ABCA1/G1 histological evaluation of tumour samples was available for 43 and 41 patients, respectively. The median expression level was 50% for ABCA1 and 45% for ABCG1. We found a significant correlation between higher ABCA1/G1 staining intensity expression and both shorter median OS and PFS (Table). Similarly they were inversely related to DCR (Table). Conclusions: For the first time, we reported a high expression of ABCA1/G1 cholesterol transporter on kidney cancer. An inverse association between staining intensity expression and oncological outcomes in patients receiving ICIs combinations was found. Oncological outcomes according to ABCA1/G1 staining intensity expression. IHC mPFS months (95%CI) mOSmonths (95%CI) DCR% ABCA1 intensity expression 1+ 30.1 (25.8-NR) NR (NR-NR) 88.9 2+ 24.4 (9.9-NR) NR (33.9-NR) 72.7 3+ 4.5 (3.20-NR) 12.2 (8.2-NR) 25.0 p value 0.016 &lt; 0.001 0.013 ABCG1 intensity expression 1+ 62.7 (25.6-NR) NR (NR-NR) 87.5 2+ 17.4 (9.9-NR) NR (NR-NR) 68.2 3+ 6.65 (2.9-NR) 12.2 (3.8-NR) 37.5 p value 0.006 0.013 0.101 DCR: disease control rate, IHC: immunohistochemistry, mOS: median overall survival, mPFS: median progression-free survival, NR: not reached.
Defining subgroups of patients with intermediate risk prostate cancer for whom active surveillance is safe.
Authors: Ruben Del Castillo, Danny Vesprini, Stanley K Liu, Hon Leong, Mona Beera, Zeeba Sadiq, Liying Zhang, Alexandre Mamedov, Meghan Kulasingham-Poon, Laurence Klotz, Andrew Loblaw
Journal: Journal of Clinical Oncology (2025)

393 Background: A number of guideline groups recommend active surveillance (AS) for patients with low risk prostate cancer as well as selected patients with intermediate-risk prostate cancer (IRPC) – these groups are not well defined. Our group has previously shown that some patients with IRPC have high rates of progression to advanced disease. The goal of this study was to determine a subset of patients with IRPC where AS is safe. Methods: This single-institution, phase II study enrolled men with low-risk and selected IRPC patients since 1995. Patients were followed with PSA every 3-6 months, DRE every 6 months with repeat systematic biopsies at 1 year and every 3 years. Since 2013, MRI staging was done every 2 years with targeted and systematic biopsies done for new or growing lesions. Patients were followed until death or withdrawn consent. Time to treatment, metastasis-free survival (MFS), cause-specific survival (CSS) and overall survival were calculated from date of registration biopsy. Results: 1409 men were analyzed with a median follow-up of 11.0 years (range 1.2 – 26.4 years). Median age and PSA at registration biopsy were 67 years and 5.03 ng/ml. 86.4%, 11.8% and 1.7% had GG1, GG2 and GG3 disease. 72.9%, 5.8%, 7.3% and 13.6% had low, GG1 favourable IRPC (FIR), GG2 FIR and unfavourable risk ds (UIR). 996 men had at least one repeat biopsy, 768 reclassified, 604 underwent treatment, 166 had biochemical failure, 64 developed metastases and 41 died of prostate cancer. 10 year MFS was 97.4%. Absolute percentage pattern 4/5 (APP4) at baseline had a sensitivity of 36%, specificity of 86% and AUC of 64% with an optimal cutpoint of &gt;0.30 for predicting MFS. Multivariable analysis (MVA) revealed APP4 (HR 2.86) at baseline and at repeat biopsy (vs baseline) of high risk vs UIR (HR 5.61) and high risk vs GG2 FIR (HR 10.4) were independent predictors of MFS. 10 year CSS was 98.5%. MVA revealed APP4 (&gt;0.7, AUC 67%; HR 3.13) and high risk vs UIR (HR 34.4) were independent predictors of CSS. Conclusions: Patients with GG1 prostate cancer and those with GG2 FIR and APP4 &lt; 0.30 appear to have very low risk of metastases and prostate cancer death and are suitable for active surveillance.
TP53 Y220C mutations in advanced urothelial bladder cancer (UBC): A genomic landscape study.
Authors: Rosa Nadal, Joseph M Jacob, Gennady Bratslavsky, Alina Basnet, Jeffrey S. Ross, Douglas I Lin, Ole Gjoerup, Liang Cheng, Shilpa Gupta, Neeraj Agarwal, Philippe E. Spiess, Roger Li, Ashish M. Kamat, Andrea Necchi, Petros Grivas
Journal: Journal of Clinical Oncology (2025)

821 Background: TP53 is the most frequently altered gene in human cancers. Novel agents targeting the pathogenic TP53- Y220C mutation and p53-based cancer therapy have attracted significant interest. Evaluation of TP53- Y220C mutation and co-occurrent alterations in UBC is needed. Methods: FFPE tissue from 11,224 UBC patients (pts) underwent hybridization capture and comprehensive genomic profiling. A total of 324 cancer related genes including selected introns of 31 genes frequently rearranged in cancer were evaluated for genomic alterations (GA). We obtained an average sequencing depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were estimated using next-generation sequencing. TMB-high was defined as ≥10 mutations/Mb. PD-L1 expression was measured by IHC (DAKO 22C3). Comparisons were performed using the χ 2 method with Yates correction. Results: TP53 Y220C mutation (Y220C+) was identified in 73 UBC (0.65%). Age/gender were comparable between TP53 Y220C negative (Y220C-) and TP53 Y220C+ pts; 8.4% of TP53 Y220C+ and 8.2% of TP53 Y220C- UBC cases exhibited ≥1 GA. In TP53 Y220C+ UBC, the frequency of co-occurring GA was significantly lower for FGFR3 (8.2% vs 18.3%; P = .038), MTAP loss (13.3% vs 25.1%; P = .035), CDKN2A (26% vs 37.8%; P = .05), and CDKN2B (19.2% vs 30.2%; P = .05) vs TP53 Y220C- UBC. BRCA1 GA was significantly higher in TP53 Y220C+ UBC (8.2% vs 2.0%; P &lt; .0001). In TP53 Y220C+ UBC, trends were observed with numerically higher GA frequency in ERBB2 (20.5% vs 17.6%; not significant [NS]), RB1 (24.7% vs. 21.4%; NS) and numerically lower GA frequencies in TERT (61.1% vs 76.1%; NS), PIK3CA (15.1% vs 21.6%; NS). No significant differences in other GA frequencies: TSC1 (8.2% vs 9.0%, NS), ERBB3 (6.8% to 6.2%, NS), BRCA2 (4.1% to 3.2%, NS), FGFR2 (2.7% to 1.1%, NS), or in MSI / TMB status were detected between groups. PD-L1 low expression (1-49%) was observed in 7.3% of TP53 Y220C+ UBC. Conclusions: The TP53 Y220C mutation is rare in advanced UBC (&lt; 1% of cases). In our study, this mutation was associated with specific co-occurring GA, notably with a significantly lower frequency of FGFR3 and higher BRCA1 GA. TP53 Y220C mutation warrants further clinical investigation in basket trials, including UBC, e.g. NCT04585750. TP53 Y220C+ UBCn=73 TP53 Y220C- UBCn=11,151 p value BRCA1 8.2% 2% &lt;.0001 FGFR3 8.2% 18.3% .038 MTAP 13.3% 25.1% .035 CDKN2A 26% 37.8% .05 CDKN2B 19.2% 30.2% .05 MSI-high 0% 0.7% NS TMB-high 34.2% 34.1% NS
Clinical efficacy of enfortumab vedotin-pembrolizumab (EV-P) in locally advanced (LA) or metastatic urothelial carcinoma (mUC): A real-world retrospective study.
Authors: Prateek Jain, Syed Arsalan Ahmed Naqvi, Muhammad Umair Anjum, Muhammad Ali Khan, Muhammad Umar Afzal, Ji-Eun Yum, Kainat Warraich, Salman Ayub Jajja, Fnu Swati, Nikita Tripathi, Daniel S Childs, Jacob Orme, Yousef Zakharia, Mark Tyson, Nathan Y Yu, Irbaz Bin Riaz, Parminder Singh
Journal: Journal of Clinical Oncology (2025)

745 Background: The combination of EV-P therapy has recently been approved as first-line (1L) therapy for patients with LA/mUC based on the results of the EV-302 trial. Herein, we report the updated results from a cohort of patients with LA/mUC who received EV-P in real world clinical setting. Methods: This retrospective study included patients with LA/mUC (07/2022-08/2024) at the Mayo Clinic who completed at least one cycle of EV-P. The best overall response (BOR) was evaluated using radiographic imaging and was adjudicated as complete response (CR), partial response (PR), stable disease (SD), mixed response (MR), or progressive disease (PD). The median progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death, was estimated using the Kaplan-Meier method. Patients who had not experienced disease progression by their last follow-up were censored for the PFS analysis. Results: A total of 120 patients were included; 79 (65.8%) were males, 41 (34.1%) females, 109 (91%) White, and 119 (99%) were non-Hispanic/Latino. The median age was 72 years (IQR: 65-77). Of these, only 22 (18.3%) had locally advanced disease while the remaining had mUC; 62 (51.6%) had lower tract urothelial carcinoma (LUTC), 36 (30%) had upper tract urothelial carcinoma (UTUC). The median follow-up time was 7.1 months (IQR: 4.93-9.26). In terms of BOR, 56 patients (46.6%) experienced PR, 34 (28.3%) CR, 12 (10%) PD, 7 (5.8%) MR, and 8 (6.6%) experienced SD. 3 (2.5%) patients were not evaluable. The BOR across subgroups, LA and mUC, including LUTC and UTUC, is summarized in the table. Among the responders, the median number of treatment cycles to first response was 3 (IQR: 2.25–4). Within the follow-up, 28 patients (23.3%) experienced eventual radiographic disease progression; death was observed in 25 patients (20.8%). The median PFS was 12.7 months (95% CI: 9.8-NE), and OS was 25.1 months (16.3-NE). Conclusions: In real world setting, the combination of EV-P in LA/mUC demonstrated clinical efficacy compatible with the findings from the EV-302 trial. Our results showed comparable efficacy with EV-P in both UTUC and LUTC, highlighting it's broad therapeutic potential. However, clinical data at longer follow-up is required to fully evaluate overall survival and the durability of response. mUC LA Overall LUTC UTUC Total patients 98 62 36 22 BOR CR 23 (23.4%) 13 (20.9%) 10 (28.5%) 11 (50%) PR 49 (52.6%) 31 (50%) 18 (50%) 7 (31.8%) SD 6 (6.4%) 2 (3.2%) 4 (11.4%) 2 (9.0%) PD 10 (10.7%) 9 (15.5%) 1 (2.8%) 2 (9.0%) MR 7 (7.5%) 5 (8.6%) 2 (5.7%) 0 (0%)
Secondary outcomes by prior definitive treatment (tx) in patients (pts) with high-risk biochemically recurrent prostate cancer (hrBCR) treated with enzalutamide (enza) monotherapy (mono): EMBARK post hoc analysis.
Authors: Stephen J. Freedland, Ugo De Giorgi, Ronald F. Tutrone, Lawrence Ivan Karsh, Miguel Ramirez-Backhaus, Edward M. Uchio, Yiyun Tang, Ruslan Croitoru, Matt Rosales, Matko Kalac, Fong Wang, Neal D. Shore
Journal: Journal of Clinical Oncology (2025)

179 Background: The phase 3 EMBARK trial demonstrated clinically meaningful improvement in metastasis-free survival and secondary efficacy endpoints with enza mono vs leuprolide alone. Herein, we descriptively report secondary endpoints for enza mono vs leuprolide alone across prior definitive tx subgroups. Methods: Eligible pts had hrBCR, with a prostate-specific antigen (PSA) doubling time ≤9 months. Pts were randomized 1:1:1 to enza + leuprolide, leuprolide alone, or enza mono. Secondary endpoints included time to PSA progression, first use of new antineoplastic tx, distant metastasis, resumption of any hormonal therapy after tx suspension, and symptomatic progression. Post hoc subgroup analyses descriptively compared secondary endpoints for enza mono vs leuprolide alone in pts with radical prostatectomy (RP) only, radiotherapy (RT) only, or RP+RT. Results: In both tx groups (enza mono and leuprolide alone), nearly half of pts had prior RP+RT (Table). Enza mono vs leuprolide alone numerically reduced the risk of PSA progression, first use of new antineoplastic tx, distant metastasis, and symptomatic progression in all prior definitive tx subgroups (Table). Time to resumption of any hormonal therapy favored leuprolide alone vs enza mono across all prior definitive tx subgroups. Conclusions: Tx with enza mono showed improvements in all secondary endpoints except time to resumption of any hormonal therapy vs leuprolide alone, regardless of prior definitive tx. The small sample sizes of the non-randomized prior tx subgroups and low event numbers should be considered when interpreting the results. Interaction analyses of secondary endpoints across prior definitive tx subgroups will be reported in the presentation. Pfizer's generative AI tool, MAIA, was used to draft this abstract (accessed: 2024-10-01); the authors reviewed, edited, and take full responsibility for the content. Clinical trial information: NCT02319837 . Secondary endpoints Mono (n=355) Leuprolide alone(n=358) † RP only (n=99) RT only (n=90) RP+RT (n=166) RP only (n=75) RT only (n=104) RP+RT (n=179) Time to: Event, n HR (95% CI) Event, n HR (95% CI) Event, n HR (95% CI) Event, n Event, n Event, n PSA progression 12 0.62 (0.28, 1.34) 18 0.53 (0.30, 0.95) 7 0.14 (0.06, 0.33) 17 37 39 First use of new antineoplastic tx 23 0.68 (0.38, 1.22) 33 0.76 (0.48, 1.20) 28 0.37 (0.23, 0.58) 25 48 67 Distant metastasis 10 0.81 (0.32, 2.08) 14 0.65 (0.31, 1.34) 16 0.45 (0.24, 0.85) 9 20 30 Resumption of any hormonal therapy 77 1.68 (1.14, 2.46) 60 2.23 (1.46, 3.39) 142 1.58 (1.22, 2.03) 54 47 116 Symptomatic progression 28 0.61 (0.36, 1.03) 38 0.79 (0.52, 1.22) 51 0.56 (0.39, 0.80) 32 52 85 † Leuprolide alone was the comparator.
Application of canary histology classifier in prostate biopsies for risk stratification.
Authors: Chien-Kuang Cornelia Ding, Janet E Cowan, Nancy Greenland, Bradley A. Stohr, Deepika Sirohi, Matthew R. Cooperberg, Jeff Simko, Peter Carroll
Journal: Journal of Clinical Oncology (2025)

412 Background: Nguyen et al recently proposed an outcome-based radical prostatectomy (RP) histologic classifier (PMID 38828674, “Canary histology risk group”), combining all high-risk carcinoma histology patterns into “unfavorable histology,” versus absence as “favorable histology.” We examine whether this classifier, with additional stratification of favorable, is applicable to prostate biopsies for risk stratification. Methods: Archival databases of one single institution were searched for patients with long term clinical follow-up after RP and available prostate biopsy slides. Most recent biopsies underwent blinded re-review. Canary risk group was assigned based on highest risk patterns in any core. Unfavorable histology encompasses all Gleason pattern 5, large cribriform/intraductal carcinoma (&gt;0.25 mm), anastomosing cords of carcinoma, grade 3 stromogenic carcinoma, and complex intraluminal papillary architecture. To capture patterns potentially predictive of unsampled unfavorable histology, “biopsy borderline” combines small cribriform/glomeruloid (≤0.25 mm), simple glomerulations, predominance of extensive poorly formed glands, equivocal small anastomosing cords, grade 2 stromal response, and epithelial complexity associated with mucin (beyond mucinous fibroplasia). “Biopsy favorable” is defined as void of any unfavorable or biopsy borderline histology. Biopsy and RP Gleason Grade Group (GG), pT stage, and pN stage were recorded from original reports. Biochemical recurrence (BCR) was defined as consecutive PSA of ≥0.2 ng/mL 8 weeks after RP or receipt of salvage treatment. RP stage and GG were analyzed using chi-square. BCR-free survival was analyzed using Kaplan-Meier curve. Results: 360 patients were identified (median, IQR): Age at diagnosis 61 years (56, 66), PSA at diagnosis 5.38 ng/mL (4.2, 7.6), post-RP follow-up 9 years, (7, 12). The patients were classified as histologically unfavorable (n=63; 17.8%), biopsy borderline (n=92; 25.6%), and biopsy favorable (n=205; 56.9%). The three-tiered classification is significantly associated with earlier BCR (log-rank p-value &lt;.01), RP GG (&lt;.01), pT stage (&lt;.01), and pN stage (&lt;.01) (Table). Conclusions: Unfavorable histology on biopsy was associated with highest risk of BCR after RP, compared to “biopsy borderline” and “biopsy favorable” groups. This proof-of-principle study demonstrates the three-tiered histology-based classifier could be applicable in biopsies for risk stratification. Canary Histology Risk Group N (%) GG3+ at RP pT3a at RP pT3b at RP pN1 BCR event within 7 years of RP Unfavorable 63 (18%) 46 (73%) 30 (48%) 11 (17%) 11 (17%) 53 (84%) Biopsy Borderline 92 (26%) 21 (23%) 32 (35%) 5 (5%) 1 (1%) 60 (63%) Biopsy Favorable 205 (57%) 22 (11%) 69 (34%) 3 (1%) 0 (0%) 110 (54%) All patients 360 (100%) 89 (25%) 131 (36%) 19 (5%) 12 (3%) 223 (62%)
THERATEST: A multi-centre observational cohort feasibility study of de-escalation therapies for stage II seminoma.
Authors: Nasreen Abdul Aziz, Kenrick Ng, Constantine Alifrangis, Ben Tran, Ciara Conduit, Elizabeth Chien Hern Liow, Charlotte Ackerman, Ramona Georgescu, Tanim Jamal, Clare Relton, Erik Mayer, David Nicol, Walter Cazzaniga, Robert A Huddart, Alison Helen Reid, Jonathan Shamash, Prabhakar Rajan
Journal: Journal of Clinical Oncology (2025)

TPS651 Background: Standard of care (SOC) for stage II seminoma involves primary orchidectomy with combination chemotherapy or external beam radiotherapy, and yield high survival rates but with significant toxicities. Three cycles of Carboplatin AUC10 or robotic retroperitoneal lymph node dissection (rRPLND) with or without adjuvant chemotherapy are promising de-escalation strategies to minimise treatment associated toxicities whilst maintaining oncological outcomes. However, they are not widely adopted due to a lack of comparative data in prospective clinical trials. Therapy De-escalation for Testicular Cancer (THERATEST) aims to assess the feasibility of recruitment for de-escalation strategies for stage II seminoma. Methods: Thirty participants will be recruited over 12 months and treated with either Carboplatin AUC10 or rRPLND with or without adjuvant treatments based on whether the institution offers this treatment as a de-escalation strategy. If participants decline or are not eligible, they will be offered SOC but remain within the study. Both cohorts will be followed up for 2-years. Data collection includes recruitment and retention rates, disease status, surgical outcomes, adverse events and patient-reported outcomes using validated questionnaires which are EORTC QLQ-TC26, EORTC QLQ-C30, the Brief Male Sexual Function Inventory (BMSFI) and additional enquiries on anejaculation. Results: THERATEST has recently commenced recruitment at Barts Health and the Royal Marsden Hospital NHS Trusts. Conclusions: THERATEST is the first endeavour to prospectively evaluate Carboplatin AUC10 and rRPLND as de-escalation strategies for stage II seminoma in a single study. Feasibility of recruitment and retention as well as qualitative and quantitative outcomes data will inform a large-scale multicentre trial. Clinical trial information: ISRCTN61007118 .
Primary sarcomas of urinary bladder: A SEER analysis.
Authors: Joseph Han, Hyun Lee, Ayush Kaushish, Bohdan Baralo, Asit KR Paul
Journal: Journal of Clinical Oncology (2025)

878 Background: Primary bladder sarcoma (PBS) is a rare entity. In this study, we analyzed demographics, clinical characteristics, and survival outcomes of PBS using the Surveillance, Epidemiology and End Results (SEER) database. Methods: We identified patients with urinary bladder sarcoma in the SEER database from the years 2000 to 2020 using the primary cancer site codes for urinary bladder as well as histological codes (ICD-O-3) that match the list of sarcoma histology found in the NCCN soft tissue sarcoma and bone cancer guidelines. Data for demographics, disease extent, median overall survival (OS), and treatment modalities were obtained. Sarcomas mixed with carcinomas, so-called carcinosarcomas, were included in the analysis. From the same database, OS data on urothelial carcinomas were obtained for comparison. Results: During the period of analysis, a total of 349,326 patients with primary bladder neoplasms were identified. Among them, 707 (0.002%) patients had PBS. The majority were Caucasian (71.9%) followed by Hispanics (12.9%) and African Americans (11.0%). There were 445 males (62.9%) with PBS. The most common histology was carcinosarcoma (40.9%), followed by leiomyosarcoma (20.4%), rhabdomyosarcoma (13%), and unspecified sarcoma (9.3%). Among the 654 patients with known extent of disease, 56.7%, 24.9%, and 18.3% had localized, locoregional, and distant metastatic disease, respectively. OS for patients with localized, regional, and distant diseases were 32, 12, and 4 months, respectively (P&lt;0.0001). Bladder sarcomas were associated with worse survival than urothelial carcinomas (14 months vs. 92 months, P&lt;0.01). OS was longer in patients with pure sarcomas compared to patients with mixed sarcomas (26 months vs. 9 months, P&lt; 0.001). Among the 697 patients with treatment data available, 34 (4.9%) received chemotherapy only, 468 (67.1%) received surgical resection only, 152 (21.8%) received both, and 43 (6.2%) received neither. Both chemotherapy and surgery were associated with longer median OS. Those who received chemotherapy showed a median OS of 42 months compared to 9 months seen in the no chemotherapy group (P&lt;0.001). As for surgical resection, median OS of those who underwent surgery was 16 months compared to 8 months in those who did not (P=0.014). Conclusions: Bladder sarcomas are rare and associated with worse outcomes when compared to urothelial carcinoma. Carcinosarcomas are associated with worse survival when compared with pure sarcomas. More than half of the bladder sarcomas were diagnosed as localized disease and survival was better when compared with locoregional or distant disease. Chemotherapy and surgical resection were associated with longer median OS, but prospective studies are needed to ascertain these findings after controlling for confounders.