tbuckley/cabot-search huggingface dataset:
Identification of potential immune evasion mechanisms in aggressive small renal cell carcinomas through single-cell and bulk RNA sequencing.
Authors: Jee Soo Park, Eun Chae Kim, Seol Song, Jongchan Kim, Won Sik Jang, Byungjin Hwang, Won Sik Ham
Journal: Journal of Clinical Oncology (2025)

574 Background: Small renal cell carcinoma (RCC) is generally nonaggressive but in some cases, small RCCs exhibit distant metastasis. The biology and biomarker of small aggressive RCCs remain unclear, necessitating appropriate evaluation to avoid undertreatment. Previous biomarker studies via genetic profiling of tumor tissues were hindered by RCC heterogeneity. We utilized bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) of blood samples to identify genetic biomarkers and characterize the tumor immune microenvironment in patients with aggressive small RCC. Methods: We identified four T1a (≤4 cm) clear cell RCCs (ccRCC) with synchronous distant metastasis as aggressive, and four age-, sex-, and tumor size-matched ccRCC patients without metastasis as non-aggressive, from a prospective cohort (ClinicalTrials.gov Identifier: NCT03694912). Two healthy kidney donors served as controls. Using the 10X Genomics platform, we performed scRNA-seq and bulk analysis on ten peripheral blood mononuclear cell (PBMC) samples. Samples were demultiplexed with Souporcell, and sequencing reads were normalized and analyzed using R/Seurat. Cellular components were identified with marker genes, and bulk analysis included differential gene expression and pathway enrichment. Results: The mean tumor size and age of the eight ccRCC patients were 2.5 cm and 63 years, respectively. Among the four aggressive ccRCCs, two had lung metastasis and two had bone metastasis. We analyzed 32,417 cells, identifying 41 subpopulations. Single-cell analysis revealed variations in T and natural killer (NK) cell proportions among aggressive, non-aggressive, and normal groups, with significant differences. The aggressive group showed increased MYOM2, OVCH1-AS1, and HLA-DQA2 expression. Despite an increased proportion of CD4+ cytotoxic T lymphocytes (CTLs) with disease severity, key cytotoxic and immune regulatory genes like GNLY, CD247, CCL4, NKG7, and TGFB1 were decreased, suggesting compromised antitumor function in aggressive states. Conclusions: This study offers insights into the molecular and cellular characteristics of aggressive small RCCs via PBMC analysis using single-cell and bulk RNA sequencing. The increased proportion of CD4+ CTLs with decreased expression of critical cytotoxic and immune regulatory genes in aggressive RCCs suggests a mechanism for immune evasion. These findings enhance our understanding of aggressive small RCC biology and highlight potential biomarkers and therapeutic targets for adjuvant treatment. Clinical trial information: NCT03694912 .
Long-term results of a phase 2 study of neoadjuvant chemotherapy combined with tislelizumab followed by radiotherapy for bladder-preserving treatment in selected high-risk/locally advanced muscle invasive urothelial bladder cancer (HOPE-02).
Authors: Feng Wen, Tianhai Lin, Ping Tan, Jiani Deng, Min Ren, Mengni Zhang, Xiaonan Zheng, Peng Zhang, Yali Shen
Journal: Journal of Clinical Oncology (2025)

786 Background: The “bladder-sparing” trimodal therapy (TMT) has gained popularity among selected patients with muscle-invasive bladder cancer (MIBC) who are either unfit for or decline radical cystectomy (RC). This Phase 2 study aimed to evaluate the bladder-sparing efficacy of neoadjuvant chemotherapy combined with tislelizumab, followed by radiotherapy for high-risk, locally advanced MIBC, who were considered as non-ideal candidates for bladder-sparing treatment (Trial registration number: ChiCTR2100045213). Methods: Patients diagnosed with cT2-4bN0-3M0-1a MIBC will be included in the study if they demonstrate non-progression of disease (PD) after two cycles of neoadjuvant chemotherapy (gemcitabine and cisplatin or carboplatin) combined with tislelizumab. Radiotherapy will be administered to patients after one or two additional cycles of neoadjuvant therapy, and tislelizumab will continue for up to one year. The primary endpoint is the complete response rate (CR, including T0/Ta/Tis) after radiotherapy, while the secondary endpoints include progression-free survival (PFS), bladder-intact disease-free survival (BI-DFS), overall survival (OS), and toxicity. Results: Preliminary results of safety were presented at the ASCO-GU meeting in 2023, and we are now reporting the long-term outcomes. A total of 45 patients were enrolled. The median follow-up time was 36.10 ± 2.92 months. All participants completed 3 to 4 cycles of neoadjuvant therapy, resulting in a CR rate of 51.11%. Among the patients, 36 completed radiotherapy and underwent efficacy evaluations through imaging and cystoscopic biopsy. However, nine patients withdrew from the study due to personal requests for surgery, traditional Chinese medicine, or changes in systemic therapy. Of the 36 patients, 2 were Tis, and 31 were T0 after radiotherapy, indicating a primary CR rate of 100%. The 2 Tis patients received intravesical BCG vaccine therapy and achieved T0 by the time of the second therapeutic evaluation. No patient underwent radical cystectomy. 3-year PFS rate and 3-year BI-DFS were 76.0%, and 3-year OS was 81.0%. One patient experienced bladder recurrence with T1, while 3 patients developed distant metastases. Four patients died, with 2 deaths attributed to other reasons. Conclusions: Neoadjuvant chemotherapy combined with tislelizumab provides an opportunity for suboptimal candidates to become suitable for bladder-sparing approaches, and radiotherapy-based bladder-preserving treatment demonstrated excellent long-term efficacy and acceptable toxicity, making it a potentially optimal strategy for high-risk, locally advanced MIBC patients who wish to preserve their bladder. Clinical trial information: ChiCTR2100045213.
Survival impact of concomitant squamous differentiation in upper tract urothelial carcinoma patients receiving adjuvant chemotherapy.
Authors: Jianjun Ye, Xinyang Liao, Shiyu Zhang, Qiang Wei, Yige Bao
Journal: Journal of Clinical Oncology (2025)

729 Background: Adjuvant platinum-based chemotherapy after radical nephroureterectomy (RNU) was a strong recommendation for patients with pT2–4 and/or pN+ upper tract urothelial carcinoma (UTUC). However, the efficacy of adjuvant chemotherapy (AC) on UTUC with squamous differentiation (UTUCSD) remains unclear. This study was conducted to investigate survival impact of SD on UTUC patients receiving AC, and further assessed the efficacy of AC on UTUCSD. Methods: Data of 868 UTUC patients who underwent RNU at West China Hospital of Sichuan University from May 2003 to June 2021 were retrospectively included, and only patients with the history of postoperative adjuvant chemotherapy were further analyzed. The end points included overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Propensity score matching (PSM), Kaplan‒Meier curves and Cox proportional hazard model were utilized. Results: Overall, the prevalence rate of UTUCSD is 10.7% (93/868), and UTUCSD significantly tended to be locally advanced (pT&gt;2), high grade and lymph node metastasis (LNM) disease. After PSM for tumor stage, grade, and LNM, 32 paired cohorts at a ratio of 1 to 3 among patients received chemotherapy (according to the presence/absence of SD) were derived. Compared with pure UTUC patients receiving AC, UTUCSD patients showed significantly inferior OS (HR 1.99, 95% CI 1.06-3.71) and CSS (HR 1.95, 95% CI 1.09-3.47) but comparable MFS (HR 1.33, 95% CI 1.0.71-2.50). Furthermore, AC could not bring significant survival benefit to patients with UTUCSD in terms of OS (HR 0.73, 95% CI 0.40-1.31) and CSS (HR 0.88, 95% CI 0.46-1.69). Conclusions: Concomitant SD acted as an inferior survival predictor among UTUC patients receiving AC. UTUCSD is less sensitive to chemotherapy and effective treatments need to be further studied.
RAD-SG: Adaptive radiation therapy with concurrent sacituzumab govitecan (SG) for bladder preservation in patients (pts) with muscle invasive bladder cancer (MIBC).
Authors: Shilpa Gupta, Nima Almassi, Laura Bukavina, Christopher Eing Wee, Kevin L. Stephans, C. Marcela Diaz-Montero, Rahul D. Tendulkar, Omar Y. Mian, Timothy An-thy Chan
Journal: Journal of Clinical Oncology (2025)

TPS896 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for pts with MIBC interested in bladder-preservation and/or not candidates for radical cystectomy (RC). Systemic radio-sensitizing chemotherapy may have off target side effects and exploring novel agents with radiation is an unmet need. SG is an antibody drug conjugate (ADC) and has shown efficacy in metastatic urothelial cancer (UC). RAD-SG is a single-arm phase 1 trial investigating the concurrent administration of SG with adaptive radiotherapy (RT) in pts with MIBC. Methods: Eligibility criteria include pts with localized MIBC (T2-T4aN0M0), ECOG PS Score of 0-2, normal organ and marrow function including creatinine clearance ≥ 30 mL/min, must undergo a TURBT within ≤ 60 days prior to treatment. Variant subtypes are allowed. Pts must not have had UC or any histological variant at any site outside of bladder within 24 months except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal, pelvis, and ureter if underwent complete nephroureterectomy. Other exclusion criteria include bilateral hydronephrosis and prior pelvic / local RT for MIBC or any other cancer type. SG targets TROP-2, a surface protein expressed in UC, it will be given IV at 7.5 mg/kg every 21days starting prior to RT and 2 subsequent cycles with concurrent adaptive RT over a period of 6 weeks (64 Gy). The primary endpoint is safety, tolerability, and feasibility of trimodality therapy with concurrent SG and adaptive image-guided radiation therapy for patients with localized MIBC. The secondary endpoints are bladder intact event-free survival (BI-EFS) with concurrent SG and RT for MIBC and compare historical controls with other concurrent CRT regimens. BI-EFS is defined as the time from treatment to the first documented occurrence of residual/recurrent MIBC, nodal or distant metastases on imaging, RC, or death from any cause. Correlative objectives include 1) elucidation of the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined ADC plus RT and 2) characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with SG plus RT. The study will accrue 20 pts at Cleveland Clinic Foundation and enrollment is ongoing. (NCT05833867). Clinical trial information: NCT05833867 .
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for individuals aged 11-50 years with intermediate and poor-risk metastatic germ cell tumours (GCTs).
Authors: Blossom Mak, Ben Tran, Hayley Thomas, Farzana D. Pashankar, Aaron Richard Hansen, Darren R. Feldman, Robert A Huddart, Matthew Wheater, Elaine Dunwoodie, Danish Mazhar, Nicola Jane Lawrence, Amanda Gwendolyn Stevanovic, Alison Jane Birtle, Olabode Oladipo, David Wyld, Jay Michael S. Balagtas, Martin R Stockler, Peter S. Grimison
Journal: Journal of Clinical Oncology (2025)

TPS653 Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 is standard first-line chemotherapy for intermediate and poor-risk metastatic GCT. Acceleration of standard chemotherapy regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP is the first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. It aims to determine the superiority of accelerated BEP versus standard BEP in this setting. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2 stages. The primary endpoint for stage 1 (n = 150) was favourable response; and for stage 2 (n = 500) is progression free survival (PFS). These sample sizes provide &gt; 80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 21% in the favourable response rate (stage 1) and of 7% in the PFS (stage 2). The target population is males and females aged 11 to 50 with intermediate-risk or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (3-weekly) or accelerated BEP (2-weekly) with cisplatin 20mg/m 2 D1-5, etoposide 100mg/m 2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF 6mg D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour tissue and baseline blood samples are collected for translational substudies. As of 26 September 2024, 321 participants have been recruited from 21 ANZ sites, 22 UK sites (led by Cambridge Clinical Trials Unit), and 148 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n = 76) identified no safety concerns. The stage 1 analysis of safety and activity (response rate) for the first 150 patients was reviewed by the Independent Data Safety Monitoring Committee, which recommended continuation of the trial as per protocol. Clinical trial information: NCT02582697 .
Baseline fracture risk for prostate cancer patients initiating long-term androgen deprivation therapy.
Authors: Jonathan Trinh, Sandra Frimpong, Yue Zhan, Kaeli Samson, Laura A. Graeff-Armas, Benjamin A. Teply
Journal: Journal of Clinical Oncology (2025)

122 Background: Androgen deprivation therapy (ADT) is essential for management of advanced prostate cancer, yet it carries risks including osteoporosis and fragility fractures. Antiresorptive therapy is recommended to reduce fractures for patients at high risk. However, precisely which patients should undergo formal screening with dual-energy X-ray absorptiometry (DEXA) at baseline has been relatively unexplored. This study aims to describe these baseline fracture risks, the utility of DEXA screening based upon Fracture Risk Assessment Tool (FRAX) scores, and the impact of specific risk factors in this population. Methods: We performed a retrospective cross-sectional study of patients at our institution with prostate cancer treated with ≥1 year of ADT between 2011 and 2024. Patients were excluded if their FRAX scores were incalculable or if they received antiresorptive therapy prior to starting ADT. Ten-year hip and combined major osteoporotic fracture risks were calculated using FRAX without femoral neck T-scores for all patients and with femoral neck T-scores for patients who received DEXA scans. A high fracture risk was defined as a 10-year hip fracture ≥3% or a combined major osteoporotic fracture risk ≥20%. Differences between dichotomous groups were assessed using independent samples t-tests, Chi-square tests, or Fisher’s exact tests. Results: We identified 515 patients with an average age of 70.1 years and average BMI of 29.5 kg/m 2 . Four hundred and forty-eight (87%) patients received leuprolide as ADT, 70 (13.6%) patients were on a prednisone-containing regimen, and 66 (12.8%) patients were active smokers. Based upon clinical data at ADT initiation (without including T-scores from DEXA), 201 (39.0%) patients had a high 10-year risk of hip or combined major osteoporotic fracture by FRAX. Among the 183 patients who did have DEXA scans, 85 (46.4%) met criteria for osteopenia while 14 (7.7%) had osteoporosis by T-score. Additionally, 48 (26.2%) patients had high 10-year fracture risks by FRAX and met criteria for initiation of antiresorptive therapy. The patients meeting criteria for antiresorptive therapy, in general, were older (73.3 years vs. 67.9 years) and weighed less (87.8 kilograms vs. 96.3 kilograms). Conclusions: In our institutional experience, nearly half of patients starting long term ADT have significant fracture risk warranting further risk stratification and risk mitigation strategies. This baseline data should inform systematic approaches to select those that do—and do not—require bisphosphonate or denosumab in the hormone sensitive setting.
Oncological benefit of avelumab maintenance therapy for advanced or metastatic urothelial carcinoma in comparison with patients with conventional chemotherapy alone era.
Authors: Shingo Hatakeyama, Yuya Sekine, Masanao Shinohara, Kazuyuki Numakura, Takahiro Yoneyama, Yohei Kawashima, Satoshi Sato, Tomonori Habuchi, Chikara Ohyama
Journal: Journal of Clinical Oncology (2025)

711 Background: The benefit of avelumab maintenance therapy for advanced or metastatic urothelial carcinoma in real world practice remains unknown. We evaluated the oncological outcomes of avelumab maintenance therapy in comparison with conventional platinum-based 1 st line chemotherapy in real-world practice. Methods: We retrospectively evaluated 302 and 85 patients treated with and conventional platinum-based first-line chemotherapy without avelumab (chemo group) and avelumab maintenance therapy (avelumab group) between March 2004 to Sep 2024. We compared overall survival (OS) between the patients with the chemo and avelumab groups stratified by the number of cycles of first-line chemotherapy. Primary outcome was the comparison of OS in patients without progression disease (non-PD) at cycle 4 between the chemo and avelumab groups. Secondary outcomes were the impact of the administration of pembrolizumab on OS in patients with non-PD at cycle 4 in the chemo group and the comparison of OS in patients with non-PD at cycle 2-3 between the chemo and avelumab groups. Exploratory outcomes were disease-free survival (DFS) and OS based on response rate of first-line chemotherapy, first-line treatment regimen, and number of first-line chemotherapy cycles in the avelumab group. Results: We identified 124 and 49 patients with non-PD at cycle 4 in the chemo and avelumab groups, respectively. The OS from the initiation of first-line chemotherapy in the avelumab group was significantly longer than that in the chemo group (70 vs. 23 months, P = 0.009). We identified 104 and 33 patients with non-PD at cycle 2-3 in the chemo and avelumab groups, respectively. The OS from the initiation of first-line chemotherapy in the avelumab group was significantly longer than that in the chemo group (33 vs. 13 months, P = 0.002). A multivariable Cox regression analysis showed administration of avelumab was significantly associated with reduced risk of OS (hazard ratio, 0.41; P &lt; 0.001). Of 85 patients with avelumab, the median DFS was 17 months from first-line therapy and 8.1 months from the avelumab maintenance therapy, respectively. No significant differences were observed in DFS and OS between first-line treatment regimens, and between the object response rate for first-line chemotherapy. However, the DFS and OS tended to improve in patients with first-line chemotherapy 4 cycles or more. Conclusions: We found a potential benefit of avelumab maintenance therapy on oncological outcome in real-world practice regardless of number of first-line chemotherapy. No progression within first 4 cycles of platinum-based chemotherapy might be one of the key factors for improved outcome. Further long-term follow-up is necessary.
Docetaxel rechallenge versus cabazitaxel in patients previously treated with docetaxel for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Pedro C. Barata, June Corrigan, John Culnan, Karlynn N Dulberger, Jennifer La, Elliot Akama-Garren, Clark DuMontier, Jason Edward Hansen, Rhonda L. Bitting, Heather H. Cheng, Matthew R. Cooperberg, Tanya B. Dorff, Susan Halabi, Stacy Loeb, David M. Nanus, Chong-xian Pan, Martin W. Schoen, Nathanael Fillmore, Channing Judith Paller, Matthew Rettig
Journal: Journal of Clinical Oncology (2025)

154 Background: In 2004, docetaxel (DOC), a semi-synthetic taxane, received regulatory approval for mCRPC based on improved overall survival (OS). Cabazitaxel (CAB), a closely related analog of DOC, was approved in 2010 for mCRPC patients previously exposed to DOC. For patients previously treated with DOC, the relative benefits of docetaxel rechallenge (rDOC) versus a taxane switch to CAB are unknown. We aimed to evaluate the relative impact of rDOC versus CAB for patients who had previously received DOC for mCRPC. Methods: This retrospective cohort study compared outcomes of mCRPC patients in the nationwide VA healthcare system who received initial DOC, discontinued DOC for a reason other than disease progression, and later received rDOC or CAB after mCRPC diagnosis. Patients were eligible for inclusion if they received at least 3 cycles of DOC and at least 90 days later received a second course of DOC or CAB. The index date was the date of the start of the second course of taxane treatment. Time-to-event outcomes were evaluated from index date. Inverse probability of treatment weighting (IPTW) was used to control for potential confounders. Results: Between 1/2010 and 12/2023, a total of 669 patients (407 CAB, 262 rDOC) with median age 72, 29% Black, 27% CD, 39% CKD, 38% DM2, were included in final analysis. For the first instance of docetaxel, patients received a median of 6 (IQR: 4-10) cycles with a PSA50 = 20%, PSA90 = 3% and a median of 1 (IQR: 0-1) additional systemic treatment prior to subsequent taxane. At the time of the initiation of the second taxane, 73% of patients had bone and 18% visceral metastases and median initial PSA of 75 ng/mL. Compared to CAB, rDOC had higher PSA90 (11% vs 3%, p&lt;0.001), longer OS (12.5 vs 9.6 months, p&lt;0.001) and numerically longer time to next systemic treatment (16.4 vs 12.4 months, p=0.2), shorter time on treatment (2.1 vs. 2.6 months, p=0.56), and similar PSA50 (8% vs 9%, p=0.31). The use of platinum (9% vs 6%, p=0.15), immunotherapy (2 vs 1%, p=0.79) and PARP inhibitors (6% vs 5%, p=0.67) after the second instance of a taxane was not statistically different between groups. Conclusions: In this study, rDOC was associated with better survival and deeper response than cabazitaxel. The findings of this large-scale study provide guidance for making well-informed decisions about sequential use of taxanes for mCRPC treatment.