tbuckley/cabot-search huggingface dataset:
Characterization of circulating tumor DNA (ctDNA) burden and its association with real-world overall survival among prostate cancer (PC) patients.
Authors: Ping Du, Jiemin Liao, Angela Watkins, Razvan Cristescu, Nicole Barkley, Julia Markensohn
Journal: Journal of Clinical Oncology (2025)

69 Background: Circulating tumor DNA (ctDNA) from blood-based liquid biopsies is emerging as a promising biomarker with potential prognostic and predictive value for managing patients across tumor types and therapeutic areas. Yet data and understanding of how ctDNA might be used as a prognostic biomarker in prostate cancer (PC) are limited. This study used real-world data (RWD) to evaluate the association between ctDNA burden and clinical characteristics and outcomes in PC. Methods: Prostate cancer patients were identified from the Guardant INFORM real-world clinical-genomic database, which connects ctDNA results obtained through the plasma-based next-generation sequencing Guardant360 assay (G360) to de-identified claims data. U.S. PC patients who underwent a G360 test between June 2014 and June 2023 were included. A 6-month baseline period prior to the first G360 test (index) was used to gather clinical information on these patients. ctDNA burden for each patient was defined as the maximum variant allele frequency (MVAF) of all somatic variants. The median MVAF across all samples was used to classify patients into high or low ctDNA burden groups. The association between ctDNA and real-world overall survival (rwOS) was assessed using log rank tests and multivariable Cox proportional hazards models adjusted for age, race/ethnicity, year of test, comorbidity indices, metastasis status, PC clinical state, and presence of androgen receptor ligand binding domain (AR LBD) mutations. Results: 16,757 PC patients were identified, of which, 13% had undetectable ctDNA burden. Using a median MVAF cut-off of 1.9% (range: 0.01% to 96.4%), 7,216 had low ctDNA burden and 7,330 had high ctDNA burden. Among patients with detectable ctDNA, higher ctDNA burden was observed in patients with metastatic castration resistant prostate cancer (N=5,996, median=2.4%), smokers (N=2,580, median=2.5%), with higher comorbidity burden (N=3,336, median=3.0%), and those AR LBD mutations (N=2,624, median=8.6%). Patients with high ctDNA burden showed significantly shorter rwOS after the index date (16.4 months [95%CI: 15.8-17.0]) than low and undetectable ctDNA burden groups (34.8 [95%CI: 32.8-37.0] and 53.1 months [95%CI: 48.6-65.9], respectively). Multivariable Cox models showed similar results (high ctDNA vs undetectable ctDNA hazard ratio [HR] = 3.16; low ctDNA vs undetectable ctDNA HR = 1.45; high ctDNA vs low ctDNA HR = 2.18). Conclusions: In this real-world study with large PC population, ctDNA burden varied by severity of disease and was negatively associated with overall survival after adjustment for other prognostic features. Our study adds to the body of evidence suggesting the utility of ctDNA as a potential prognostic biomarker in PC patients to monitor disease progression and patient outcomes in routine clinical practice.
Nectin-4 targeted ADC, SHR-A2102, in patients with advanced or metastatic urothelial carcinoma: A phase 1 study.
Authors: Bixia Tang, Xinan Sheng, Jun Guo, Haitao Niu, Yali Shen, Shusuan Jiang, Bin Fu, Jianming Guo, Wasilijiang Wahafu, Kai Yao, Nan Liu, Jiang Gu, Yu Chen, Zhenhua Li, Tianxin Lin, Liping Ma, Jiaqin Lin, Chi Zhang, Wenliang Wang
Journal: Journal of Clinical Oncology (2025)

657 Background: SHR-A2102 is a novel ADC that consists of a fully humanized IgG1 monoclonal antibody targeting nectin-4, a cleavable linker, and a topoisomerase I inhibitor payload with high membrane permeability and potent cell-killing efficacy. We have initiated a first-in-human phase 1 study to assess the safety, tolerability, and efficacy of SHR-A2102 in advanced solid tumors. Here, we present preliminary findings, focusing on urothelial carcinoma. Methods: Patients (pts) with locally advanced unresectable or metastatic urothelial carcinoma, who had failed or were intolerant to standard therapies, were eligible. SHR-A2102 was given intravenously at 1, 2, 4, 6, 8 mg/kg on D1 Q3W and 4 mg/kg on D1 and D8 Q3W during dose escalation. 6 and 8 mg/kg were selected for dose and efficacy expansions. Results: As of Aug 2, 2024, 73 UC pts were enrolled (median age: 65 yrs; ≥2 lines of prior systemic therapies: 57.5%; prior ADC: 42.5%). Efficacy outcomes were summarized in Table. Confirmed ORR was 38.4% (28/73; 95% CI, 27.2–50.5) in all pts, and was 32.3% (10/31; 95% CI, 16.7–51.4) in the 6 mg/kg dose group and 50.0% (16/32; 95% CI, 31.9–68.1) in the 8 mg/kg dose group. 6-mo DoR rate was 59.3% (95% CI, 23.1–83.0) in all pts, and was 66.7% (95% CI, 5.4–94.5) and 54.0% (95% CI, 12.7–83.2) in the 6 and 8 mg/kg groups, respectively. Of note, 31 pts had received ADC prior to study treatment; among them, 12 (38.7%; 95% CI, 21.9–57.8) pts achieved confirmed PR. Overall, TRAEs of grade 3 or worse occurred in 32 (43.8%) pts, with the most common (≥10%) being anemia (23.3%), decreased WBC count (19.2%), and decreased neutrophil count (17.8%). Conclusions: SHR-A2102 showed promising anti-tumor activity in pts with advanced or metastatic urothelial carcinoma, even after ADC therapy, along with manageable safety profile. Clinical trial information: NCT05735275 . Efficacy summary. All UC pts(N=73) 6 mg/kg(N=31) 8 mg/kg (N=32) ADC pretreated pts (N=31) Best overall response, n (%) Confirmed PR 28 (38.4) 10 (32.3) 16 (50.0) 12 (38.7) SD 30 (41.1) 18 (58.1) 10 (31.3) 11 (35.5) PD 12 (16.4) 3 (9.7) 3 (9.4) 7 (22.6) NE 3 (4.1) 0 3 (9.4) 1 (3.2) Confirmed ORR, % (95% CI) 38.4 (27.2–50.5) 32.3 (16.7–51.4) 50.0 (31.9–68.1) 38.7 (21.9–57.8) DCR, % (95% CI) 79.5 (68.4–88.0) 90.3 (74.3–98.0) 81.3 (63.6–92.8) 74.2 (55.4–88.1) 6-mo DoR rate, % (95% CI) 59.3 (23.1–83.0) 66.7 (5.4–94.5) 54.0 (12.7–83.2) 60.0 (12. 6–88.2) 6-mo PFS rate, % (95% CI) 41.4 (23.6–58.4) 54.7 (24.0–77.4) 38.0 (13.4–62.7) 39.1 (16.6–61.3)
Prostate Cancer Supportive Care (PCSC) program: An alternative to consolidated framework for implementation research (CFIR) model.
Authors: Celestia S. Higano, Rosalie Ho, Daniella Sare, Judy Shih, Angela Hwang, Monita Sundar
Journal: Journal of Clinical Oncology (2025)

346 Background: The CFIR model is one approach to implementing supportive care services. It requires extensive resources, staff training, and reliance on infrastructure. In contrast, the PCSC Program grew organically based on knowledge of patient-expressed needs. Rather than tailoring services to individuals, the PCSC Program offers a menu of services that the patient can choose from with the help of a program coordinator. Methods: We compared the implementation considerations for CFIR (1) to those of the PCSC Program. Results: Patient Needs Assessment &amp; Staffing: CFIR assesses needs at diagnosis using specific tools in the EHR and recommends a care plan formulated by a multidisciplinary team. In contrast, PCSC empowers patients to self-select services from eight modules (see table below) based on their needs after registration, whether at diagnosis or beyond. This flexibility allows the program to operate efficiently, freeing up clinician time for delivering group education sessions and clinic appointments. Resource Management and follow-up: CFIR identifies community resources with a multidisciplinary team. This may require referrals and clinic-specific communication. This approach may lead to inconsistencies and variation in patient experience. In contrast, PCSC provides all services at a single site that is familiar to many patients as it is across from the urology clinic. Clinic visits are in person or virtual, allowing access to all patients across the province. This model eliminates the need for extensive documentation, and the quality of the services is controlled centrally. Since there is transparency on available services from the outset, patients may return as needed, negating the need for individualized formal follow-up assessments. Sustainability and Impact: While CFIR is process-driven, PCSC’s model has supported over 5,288 patients and their families, free of charge, with $3.25 million in philanthropic support over 11 years in addition to grants and government funding, underscoring the community's trust in the program's efficacy and value. Conclusions: CFIR is a structured and resource-intensive approach that focuses on the individual patient. The PCSC Program presents patients with a menu of services known to be of importance to this population and offers a flexible, patient-driven approach. The longevity of the PCSC Program and the patient satisfaction responses suggest that this is an alternative model for delivering supportive care. 1. Stout et al JCO Oncol Pract 20:1173-1181. Attendance for 5288 registrants from 2013 to 09/2024. Modules Attendees 2013-9/2024, n Introduction to PC and Primary Treatment Options 1994 Managing Sexual Function and Intimacy 2461 Management of side effects of ADT 809 Pelvic Floor Physiotherapy for Incontinence 1890 Counselling 852 Metastatic Disease Management 162 Nutrition 1527 Exercise 1336
CD39 expression as a predictive biomarker for neoadjuvant treatment in muscle-invasive bladder cancer.
Authors: Oscar Buisan, Jordi Senserrich, Pol Servian, Maria Sanchez, Elisabet Garcia, Joan Pagès, Roger Freixa, Anna Colomer, Jordi Cervera, Joan Areal, Bonaventura Clotet, Joaquim Bellmunt, Cecilia Cabrera
Journal: Journal of Clinical Oncology (2025)

850 Background: Neoadjuvant therapy before radical cystectomy (RC) is the the standard treatment for muscle-invasive bladder cancer (MIBC). However, a significant number of patients do not respond to these therapies. Identifying biomarkers predictive of treatment response and developing novel therapeutic strategies are crucial to improving patient management and survival. This study aims to investigate non-invasive biomarkers that can predict response to neoadjuvant therapy in MIBC patients and explore their potential use in the design of new therapies. Methods: Immunophenotyping was performed on blood and bladder tissue samples from MIBC patients at pre-treatment (transurethral tumor resection (TUR); n=17; chemotherapy n=13 and immunotherapy n=4) and post-neoadjuvant treatment (RC, n=21; chemotherapy n=18 and immunotherapy n=3). Plasma soluble CD39 (sCD39) and adenosine levels were measured by ELISA and an enzymatic assay, respectively. Treatment response was evaluated at RC, and patients were classified as non responders (³ypT2³N1) or responders (&lt;ypT2ypN0). Results: Non responder patients exhibited a significant higher percentage of CD39 + cells in circulating total and different maturation CD4 + T cells subsets, particularly at TUR, suggesting a potential role in treatment resistance. CD39 + CD4 + T cells showed elevated PD-1 expression, decreased levels of Granzyme-B and Perforin, and strong correlations with the regulatory T cell marker FoxP3 and the checkpoint inhibitor TIGIT. Intratumoral CD39 + CD4 + T cells were also more frequent in non responder patients, correlating positively with the expression of tumor checkpoint inhibitors TIGIT and ICOS and the regulatory marker FoxP3. In blood, CD39 + CD4 + T cell frequencies correlated with sCD39 levels, which in turn were associated with adenosine concentration in plasma. Conclusions: CD39 expression in CD4 + T cells and its plasma levels emerge as promising biomarkers for predicting response to neoadjuvant treatment in MIBC. Targeting CD39 may offer a novel therapeutic strategy to overcome treatment resistance, potentially improving outcomes in MIBC patients.
Metabolic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma.
Authors: Renee Maria Saliby, Chris Labaki, Tejas Jammihal, Hanna Soulati, Juan Gallegos, Arnau Peris, Dustin Barrett McCurry, Valisha Shah, Deepak Poduval, Talal El Zarif, Nourhan El Ahmar, Yasmin Nabil Laimon, Aseman Bagheri Sheshdeh, Marc Eid, Katherine Krajewski, Sabina Signoretti, Eliezer Van Allen, Sachet A Shukla, Toni K. Choueiri, David A. Braun
Journal: Journal of Clinical Oncology (2025)

571 Background: Immune checkpoint inhibitors (ICI) have led to remarkable, long-lasting responses in a subset of patients with metastatic renal cell carcinoma (RCC). However, the molecular mechanisms driving these exceptional responses (ER) are not fully characterized. We previously observed that a high tertiary lymphoid structure (TLS) signature is associated with ER. Here, we explore metabolic molecular determinants that may influence ER in patients treated with ICI and VEGF inhibitors. Methods: We analyzed genomic and transcriptomic data from 357 treatment-naïve patients with advanced clear cell RCC who were given PD1/L1 and VEGF inhibitors (ICI/VEGFi) in a phase III clinical trial. Patients were categorized into three groups: (a) extreme responders (ER), including those with complete response (CR) and progression-free survival (PFS) of at least 12 months, or partial response (PR) with significant tumor shrinkage and prolonged PFS; (b) intermediate responders (IR), patients with CR or PR not meeting ER criteria; and (c) patients with progressive disease (PD). Whole exome sequencing (WES) was used to analyze somatic mutations, copy number changes, and compute clonal neoantigen load (CNL). Gene set enrichment analysis (GSEA) was performed to explore molecular pathways, and multivariate Cox proportional hazards analysis identified PFS predictors. Results: Metabolic pathway enrichment was notable in ER patients with low TLS signatures, with pathways such as peroxisome function, xenobiotic and bile acid metabolism, adipogenesis, fatty acid metabolism, and oxidative phosphorylation showing upregulation. These findings held after adjusting for tumor purity. Next, we defined a metabolic gene signature based on the enriched metabolic genes in TLS-low ER samples compared to TLS-high ER samples. ER patients with low TLS scores had significantly higher metabolic signature scores than IR (p=0.00062) and PD (p=0.00012) patients. Higher metabolic signature scores correlated with improved PFS (p=0.054) and overall survival (OS) (p=0.0037). Multivariable analysis confirmed that favorable IMDC risk (p&lt;0.001) and a high metabolic signature (p=0.01) were independent predictors of ER. Conclusions: Metabolic pathways are critical drivers of exceptional responses to ICI in RCC, especially in patients with low TLS scores. A high metabolic gene signature may serve as a predictive biomarker for ER, offering insights into new therapeutic strategies targeting metabolic reprogramming in this unique subset of patients.
Use of urinary cell-free DNA fragmentomics in urothelial carcinoma diagnosis.
Authors: Huan Zhao, Shuang Gan, Hang Dong, Haoran Tang, Zhihui Zhang, Na Wei, Jingjing Xu, Pan Du, Shidong Jia, Ting Xiao, Huiqin Guo
Journal: Journal of Clinical Oncology (2025)

846 Background: Traditional diagnostic procedures for urothelial carcinoma (UC) are often limited by patient burden and reduced sensitivity, impacting diagnostic accuracy. Liquid biopsy-based molecular detection, particularly through fragmentomics analysis, offers a promising supplement to clinical applications. Fragmentomics, which examines the unique fragmentation patterns of tumor DNA, can provide crucial insights into tumor origin and behavior. This study aims to leverage urinary cell-free DNA (ucfDNA) fragmentomics patterns to enhance the diagnostic capabilities for urothelial carcinoma. Methods: We conducted a case-control study to investigate cfDNA fragment size distributions in urine samples. The study included patients diagnosed with malignant UC (cases) and individuals with benign conditions (controls). High-throughput sequencing was used to identify distinct fragmentomics patterns, including variations in fragment size, end motifs, and genomic coverage at transcription factor binding sites. Diagnostic performance was evaluated using sensitivity, precision, and the area under the curve (AUC). Results: UC patients exhibited distinct fragmentation patterns, characterized by a shift towards shorter cfDNA fragments compared to controls. Analysis of fragment size and genomic coverage provided additional diagnostic insights when combined with methylation data, significantly improving early-stage UC detection. Fragmentomics combined with methylation markers achieved an AUC of 86.25%, with a sensitivity of 89.3% and a precision of 75.76%, demonstrating substantial improvements in diagnostic accuracy. Conclusions: Urinary cfDNA fragmentomics provides valuable complementary information to traditional molecular markers for detecting urothelial carcinoma. This innovative approach enhances diagnostic precision and shows potential for improving early detection strategies, with promising applications in non-invasive cancer screening and monitoring.
Surgical variables and risk factors associated with urinary leak following partial nephrectomy: Insights from a high-risk population.
Authors: Milan Patel, Lauren Loebach, Ruben Blachman-Braun, Braden Millan, Jaskirat Saini, Sandeep Gurram, W Marston Linehan, Mark Wayne Ball
Journal: Journal of Clinical Oncology (2025)

604 Background: Urinary leak (UL) is a common complication following partial nephrectomy (PN). This study aims to identify the risk factors and surgical variables associated with the development of UL following PN in a cohort that includes a significant number of patients with hereditary renal cancer syndromes, multiple tumors, and a history of prior PNs. Methods: A retrospective chart review was conducted to identify patients who underwent PN at our institution from January 2006 to December 2023. Clinical, demographic, and surgical characteristics were recorded and analyzed. Statistical analysis was performed with SPSS v.29.0. Results: A total of 1173 PNs were analyzed, of which 89 (7.6%) had a UL. Patients had a median age at time of surgery of 50 [Interquartile range (IQR): 38 - 59] years, and 3 [IQR: 1 - 6] tumors removed per procedure. The robotic approach was utilized in 61.6% of cases, and the most common diagnosis was von Hippel-Lindau disease (47.4%). The frequency of UL was 5.1% for first-time PN, 10.4% for second, and 19.6% for third. Multivariable-adjusted analysis demonstrated an increased risk of UL with 3 rd PN (OR 2.379; p = 0.013), higher intraoperative estimated blood loss (per 100mL: OR 1.016; p = 0.006) and a decreased risk with robotic approach (OR 0.376; p &lt; 0.001). (Table) Overall, 98.9% of UL cases (88 patients) were successfully managed with conservative management (post-op drain and foley), ureteral stent placement, percutaneous drain, or nephrostomy tube. Conclusions: In this cohort, UL is associated with the complexity of the surgery (repeat PN and higher EBL). A robotic approach had a lower risk of UL, while all but one UL were effectively managed non-operatively. Future research should investigate intraoperative and postoperative strategies to minimize this complication. Multivariable-adjusted logistic regression analysis evaluating the association between clinical variables and urinary leak after partial nephrectomy.* OR 95% CI p-value Partial nephrectomy count 1 1 2 1.693 0.973 - 2.944 0.062 3 2.379 1.200 - 4.714 0.013 ≥ 4 1.121 0.326 - 3.848 0.856 Surgical approach Open 1 Laparoscopic 0.324 0.042 - 2.517 0.281 Robotic 0.376 0.225 - 0.631 &lt; 0.001 EBL (per 100 mL) 1.016 1.004 - 1.028 0.006 CI: Confidence interval, EBL: Estimated blood loss, OR: Odds ratio. *Analysis conducted using variables listed as well as age, gender, kidney laterality, race, ethnicity, presence of solitary kidney, surgical technique, total number of tumors removed, and size of largest tumor removed.
Radium 223 without androgen deprivation therapy (ADT) in patients (Pts) with biochemically recurrent prostate cancer (BCR) and PET findings in the bones.
Authors: Melissa Lauren Abel, Fatima Karzai, Philip M. Arlen, Clara Chen, Esther Mena, Liza Lindenberg, Jeanny B. Aragon-Ching, Lisa M. Cordes, Katherine Lee-Wisdom, Amy Hankin, Monique Williams, Yolanda L McKinney, James L Gulley, William Douglas Figg, Peter Choyke, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2025)

180 Background: BCR pts have a rising PSA after definitive surgery or radiation, but negative CT/Tc99 scans. While ADT-based strategies are commonly used, they can be associated with life-altering toxicities and have not been shown to improve survival. Radium 223 is an alpha-emitting radiopharmaceutical that accumulates in areas of high bone turnover and has demonstrated a survival benefit in metastatic prostate cancer, but its benefits as a monotherapy in BCR without ADT have not been explored prior to this study. This strategy may be important as bone metastasis drives morbidity/mortality in prostate cancer. Methods: Eligible pts in this study (NCT04206319) have BCR following definitive therapy, testosterone (T) &gt;100ng/dL, normal organ and marrow function, and negative CT/Tc99 imaging. Pts must have findings on a NaF or PSMA PET suspicious for metastatic bone disease not seen on Tc99. Pts are treated with Radium 223 at the approved dosing of 55 kBq/kg for 6 cycles. PSA declines were defined as 2 or more confirmed declines from an intra-study apex PSA (ISAP; Madan ASCO GU 2018). All pts have pre- and post-treatment PSMA and NaF imaging. Immune responses (primary endpoint) are to be evaluated at study completion. Results: 18 pts have enrolled with 16 currently evaluable for response, with a median age of 67 yrs (58-80) and PSA of 1.75 ng/ml (0.2-49.5). 14/16 pts had PSMA+ scans. 13/16 pts had NaF+ scans. There have been no missed cycles for toxicity and no grade &gt;3 toxicities. Grade 2 toxicities have been rare and no Grade 1 or 2 changes in hemoglobin or platelets have occurred. 2 pts with rapid PSA doubling times came off for progression and were not evaluable for follow up imaging. Five pts (31%) had confirmed ISAP PSA declines of 14%, 21%, 24%, 33%, and 57% lasting 84, 173, 292, 246+, and 661+ days, respectively. 8/11 evaluable pts had evidence of decreased standard uptake value (SUV) on NaF PET imaging after treatment. Two pts had resolution of multiple PSMA+ bone findings, and one of them remains with negative bone findings on PET after 2+ years and with a stable PSA. Conclusions: Radium 223 in BCR is safe and associated with rare grade 1/2 toxicities. Decreases in SUV seen on most NaF scans suggest Radium 223 targeting of suspicious lesions. Substantial improvements in PSMA imaging have been observed. Delayed but confirmed PSA declines have been seen in 31% of pts. Radium 223 monotherapy may have a therapeutic activity in BCR and further studies are needed to define its potential role in PET+ BCR. Clinical trial information: NCT04206319 .