tbuckley/cabot-search huggingface dataset:
Formula-01: A phase Ⅱ study of disitamab vedotin (RC48) intravenous injection combined with BCG intravesical instillation in high-risk non-muscle invasive bladder cancer with HER2 high expression.
Authors: Xingliang Tan, Yanjun Wang, Zhiming Wu, Wensu Wei, Qianghua Zhou, Chichen Zhang, Xinpei Deng, Runhao Zheng, Jiamin Zeng, Qiuhong Chen, Kai Yao
Journal: Journal of Clinical Oncology (2025)

TPS894 Background: Intravesical instillation of bacillus Calmette-Guérin (BCG) is the first-choice treatment for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). However, our previous study has demonstrated that HER2 was an independent predictor of poor BCG efficacy in NMIBC (Tan et al., European Urology Oncology, 2023). We found that high-risk NMIBC patients with HER2 high expression had the highest risk of disease recurrence and progression with 46.9% 2yr-RFS rate and 23.0% 2yr-PFS rate. Disitamab Vedotin (RC48) is an antibody-drugconjugate(ADC) targeting HER2 with a payload of MMAE. Formula-01 will evaluate the efficacy and safety of RC48 combining with BCG instillation in HER2 overexpression high-risk NMIBC patients. Methods: Formula-01 is an open-label, non-randomized, phase 2 trial. Patients must receive complete transurethral resection (TURBT) of bladder tumor (R0 resection) and did not accept BCG intravesical instillation and neoadjuvant chemotherapy or radiotherapy before. NMIBC was pathologically confirmed for all patients according to the 8th edition of the TNM staging system and the risk stratification was recorded basing on the American Urological Association (AUA)/Society of Urologic Oncology (SUO) guidelines.The pathology of NMIBC must be pure urothelial carcinoma and any divergent differentiation subtypes are excluded. This study is open at the Sun Yat-sen University Cancer Center (SYSUCC) and 70 patients are enrolled. The single-arm cohort will receive RC48 intravenous injection (2.0 mg/kg, iv drip, d1, Q2W, 8 cycles) combining with BCG intravesical instillation at least one year (D2PB302 strain, 1.2×10 8 CFU, 120 mg, dissolved in 40–50 ml of saline, 19 times in 1 yr). The primary endpoint is 2yr-RFS rate. Secondary endpoints include 1yr-RFS, 1yr-PFS, 2yr-PFS rate, bladder retention rate and safety. Exploratory analyses include determination of Her2 expression, molecular subtypes. The sample size calculation is based on the historical results of specific subgroup patients with 2yr-RFS rate of 46.9%, and we expected improvements to 70.0%. One-sample long-rank test was used to calculate the enrollment of 70 patients (α=0.05, β=0.8, lost-to-follow-up rate of 5.0%). The study began enrollment in February, 2024 and completed enrollment in October, 2024. Research approval was obtained from the SYSUCC Ethics Committee. Clinical trial information: ChiCTR2400080767 .
Organ perforation and fistula formation as adverse events in patients receiving tyrosine kinase inhibitors: A post-market analysis.
Authors: Zin Myint, Ning Li, Carleton Scott Ellis, Ashlyn War Whitesell, Donglin Yan
Journal: Journal of Clinical Oncology (2025)

528 Background: Vascular Endothelial Growth Factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs), such as lenvatinib and cabozantinib, offer significant survival benefits in solid tumors, including renal cell carcinoma (RCC), thyroid cancer, hepatocellular carcinoma, and endometrial cancer. However, rare but serious adverse events (AEs), such as organ perforation and fistula formation, have been reported. This study evaluates the incidence and risk of these events in patients treated with VEGF-TKIs using post-marketing data from the FDA Adverse Event Reporting System (FAERS). Methods: We queried the FAERS database for reports of organ perforation and fistula formation associated with cabozantinib, lenvatinib, axitinib, and tivozanib from January 1, 2012, to June 30, 2024. A disproportionality analysis was performed using reporting odds ratios (ROR) to assess the association between VEGF-TKIs and these adverse events. Cases were categorized by organ site, with a focus on gastrointestinal (GI) tract-related events. Results: We identified 65,194 reports, including 917 cases of organ perforation and 482 cases of fistula formation. Among the perforation cases, 245 (27%) were intestinal, followed by gastric (5%). Fistula cases included 11% anal, 9% female genital tract and 6% were GI-related. Regarding TKI distribution, 19% of perforation cases were linked to cabozantinib, 35% to lenvatinib, and 46% to other TKIs (axitinib, tivozanib, or multiple TKIs). For fistula cases, 18% were associated with cabozantinib, 41% with lenvatinib, and 41% with other TKIs. Among these reports, 27% of perforations and 20% of fistulas occurred in patients with RCC. Disproportionality analysis revealed a significantly higher risk of both organ perforation (ROR: 3.41, 95% CI: 2.36–4.93) and fistula formation (ROR: 17.06, 95% CI: 14.46–20.12) in VEGF-TKI treated patients. Conclusions: Patients treated with VEGF-targeted TKIs, particularly lenvatinib, have a significantly increased risk of organ perforation and fistula formation. Lenvatinib was associated with a higher incidence of these adverse events compared to cabozantinib. These findings highlight the need for increased clinical awareness and monitoring, particularly in patients with RCC. Further research is necessary to better understand the mechanisms underlying these complications and to develop preventive strategies.
The CABOLD study: A real life prospective cohort evaluating the combination of cabozantinib and nivolumab among older patients with renal-cell carcinoma.
Authors: Maxime Frelaut, Natacha Naoun, Arnaud Pages, Ronan Flippot, Zoé AP Thomas, Capucine Baldini, Laurence Albiges
Journal: Journal of Clinical Oncology (2025)

TPS607 Background: In the era of combination therapy, and due to age-related physiological changes, management of older patients with Clear-cell renal cell carcinoma (ccRCC) is a challenge. The combination of cabozantinib and nivolumab is one of the recommended treatments in untreated metastatic or locally advanced ccRCC. However, data regarding the use of this treatment among 70 years old or more (70+) patients are scarce. The CABOLD study seeks to address these gaps by assessing the real-life use of this combination in older patients. Methods: The CABOLD study is a prospective, multicentric, single-arm cohort trial conducted across 10 centers in France. It aims to enroll 50 patients aged 70 years and above with advanced or metastatic ccRCC, who are treatment-naïve in this setting. Eligible participants must have a Performance Status (PS) of 0 to 2. Patients will receive standard-of-care treatment consisting of cabozantinib at 40 mg daily and nivolumab on a 28-day cycle (240 mg on Days 1 and 15 for the first two cycles, followed by 480 mg on Day 1 for subsequent cycles). The starting dose of cabozantinib may be reduced to 20 mg daily at the investigator’s discretion. Patients will benefit of a multi-modal follow-up including medical oncologists, geriatricians and trained nurses to monitor safety closely. Abbreviated geriatric assessment, using G-CODE, will be performed at inclusion, under treatment, and during follow-up, along with quality of life (QoL) evaluation. Optional pharmacological monitoring for cabozantinib will be conducted to assess potential associations with clinical outcomes. Patients will be followed for 12 months in the study, followed by a long-term follow-up after one year. Primary objective is to describe real-life treatment patterns of nivolumab-cabozantinib, including dose modifications and interruptions due to toxicity. Main secondary objectives include efficacy, survival, tolerance, QoL. Enrollment for the study has not yet begun at the time of submission. The CABOLD study is designed to provide insights into the real-world use of cabozantinib and nivolumab in 70+ patients with metastatic ccRCC. By incorporating geriatric assessments and pharmacological monitoring, the trial aims to improve our understanding of treatment tolerability, efficacy, and quality of life in this vulnerable population, potentially guiding tailored therapeutic strategies for older adults with RCC.
Differences in health-related quality of life between rural and urban bladder cancer patients following radical cystectomy.
Authors: Thilo Westhofen, Alexander Buchner, Gerald Bastian Schulz, Lennert Eismann, Severin Rodler, Elena Berg, Can Aydogdu, Darjusch Askari, Armin Becker, Christian G. Stief, Alexander Kretschmer
Journal: Journal of Clinical Oncology (2025)

766 Background: Bladder cancer (BC) patients from rural areas (RA) may have more difficult access to health care with potentially detrimental impact on oncological outcome following radical cystectomy (RC). However, little is known on differences in health-related quality of life (HRQOL) between rural- and urban residents treated with RC for BC. We therefore aimed to assess these differences between rural and urban BC-patients by providing HRQOL data from a large prospective cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: n=1514 consecutive patients [n=576 from urban areas (UA), n=938 from rural areas (RA)] who underwent RC at a large tertiary care center were included. Exclusion criteria encompassed age &lt;30 yr and RC due to benign diseases. HRQOL was assessed preoperatively, at 3 months, then annually until a maximum follow-up of 120 months, applying the validated EORTC QLQ-C30- as well as the bladder cancer-specific QLQ-BLM30- and FACT-BL-questionnaires. Separate modeling of longitudinal HRQOL for rural- and urban patients was performed. Spearman’s rank correlation was applied to identify residential-specific factors influencing HRQOL. Results: At baseline rural- and urban residents showed no significant difference in general HRQOL assessed by the global health status domain (GHS) (p=.983). In line no differences regarding symptom-related subscales were observed between both cohorts (p-range: .189 - .907). Postoperatively and in longitudinal analysis, rural residents reported significantly better general HRQOL up to 96 months after RC (p-range: .001 - .037). At 12 months, a significant correlation between physical-, emotional functioning or urinary continence and better general HRQOL was observed for both, rural- and urban residents (each p&lt; .001). No significant correlation was found between sexual functioning and increased general HRQOL. While a significant correlation between Social/Family wellbeing and increased general HRQOL was found for rural residents (p=.042), no correlation was found for urban residents (p=.594). Conclusions: The current study provides prospective data from a contemporary cohort of BC-patients, which display residential-specific differences in the natural course of HRQOL following RC. Those results are important to guide individualized treatment decision-making for patients with BC.
PSMA-positive tumor vessels around renal cell carcinoma with high angiogenic potential as therapeutic targets and predictors of tumor recurrence.
Authors: Ryuta Watanabe, Keito Kagimoto, Mami Chosei, Haruna Arai, Tomohisa Sakaue, Mie Kurata, Noriyoshi Miura, Riko Kitazawa, Tadahiko Kikugawa, Shigeki Higashiyama, Takashi Saika
Journal: Journal of Clinical Oncology (2025)

561 Background: The expression of prostate-specific membrane antigen (PSMA) protein increases as prostate cancer advances and metastasizes. Recently, 68Ga-labeled PSMA PET has been used in diagnosing prostate cancer. Our previous studies demonstrated that PSMA-positive vesicles secreted by prostate cancer cells enhance the angiogenic activity of vascular endothelial cells, suggesting a role for PSMA in tumor angiogenesis. In this study, we focus on renal cell carcinoma, examining the relationship between PSMA expression in peritumoral blood vessels and clinical outcomes, particularly tumor recurrence, in surgically excised renal cancer specimens. Methods: Immunohistochemical analysis was performed on renal cell carcinoma samples from 45 patients who underwent nephrectomy or partial nephrectomy at our institution between January 2018 and December 2022. The correlation between PSMA expression levels in tumor-associated vessels and the rate of recurrence was evaluated. In addition, PSMA levels in human umbilical vein endothelial cells (HUVECs) treated with conditioned medium (CM) from renal cancer cell lines Caki1 and ACHN were analyzed by Western blotting (WB) and immunofluorescence (IF). Angiogenic activity was measured using a tube formation assay, and RNA sequencing (RNA-seq) was conducted to examine gene expression changes in endothelial cells influenced by vesicles secreted from renal cancer cells. Spatial gene expression analysis was performed to compare differences in gene expression between tumor vessels near and vessels away from the tumor. Results: Immunohistochemical staining for PSMA and CD31 revealed that only peritumoral vessels exhibited PSMA positivity. PSMA expression was categorized into three levels: weak (18 cases), moderate (11 cases), and strong (16 cases), with these levels corresponding to different recurrence rates. When the 10,000 g pellet fraction of CM from renal cancer cell lines was applied to HUVECs, they became PSMA-positive, leading to enhanced tube formation. RNA-seq analysis further demonstrated that HUVECs exposed to CM from renal cancer cells showed upregulation of pathways associated with angiogenesis. Conclusions: Vesicles secreted by renal cancer cells promote PSMA expression in vascular endothelial cells and boost angiogenic activity. Future research will aim to elucidate the mechanism by which PSMA becomes expressed in normal vascular endothelial cells, with the potential to pave the way for new anti-angiogenic therapies.
Effects of emerin dysregulation on the very-small-nuclear phenotype and neuronal differentiation and its association with a clinically aggressive subtype of prostate cancer.
Authors: Le Zhang, Pai-Chi Teng, Karen Angelica Cavassani, Catherine Grasso, Joshua Watson, Jasmine Jiemei Wang, Zijing Chen, Kai Han Tu, Brenda Salumbides, Lilit Gevorkian, Minhyung Kim, Sungyong You, Dolores Di Vizio, Howard M. Sandler, Timothy Daskivich, Neil Bhowmick, Michael Freeman, Hsian-Rong Tseng, Jie-Fu Chen, Edwin Melencio Posadas
Journal: Journal of Clinical Oncology (2025)

207 Background: Circulating tumor cells (CTCs) with a very-small-nuclear (vsn) phenotype (i.e., vsnCTCs) in prostate cancer (PCa) represent a distinct subset of CTCs characterized by nuclei smaller than 8.5 μm. Our previous studies established a link between vsnCTCs and the presence of visceral metastasis. Emerging evidence suggests that the reduction of emerin (EMD), a nuclear envelope protein, contributes to PCa metastasis and is associated with nuclear shape instability. This study aims to validate vsnCTCs as a biomarker in metastatic castration-resistant prostate cancer (mCRPC) and investigate the correlation between EMD expression and the vsnCTC phenotype. Methods: CTCs were isolated from 93 mCRPC patients using the NanoVelcro CTC assay and categorized as either vsnCTC-positive (vsnCTC+) or vsnCTC-negative (vsnCTC-). We compared overall survival (OS) and progression-free survival (PFS) between these two groups. In vitro experiments were conducted using PCa cell lines (C4-2B, 22Rv1, and DU145) with EMD knockdown via siRNA or shRNA to study its impact on cellular phenotypes. Additionally, we measured EMD expression and nuclear size in abiraterone- and enzalutamide-resistant (Abi-R/Enza-R) C4-2B cells. Results: vsnCTC+ patients had significantly worse OS and PFS compared to vsnCTC- patients. Multivariate analysis revealed that vsnCTC+ status was independently associated with poorer OS and PFS. EMD expression was markedly reduced in CTCs from vsnCTC+ patients compared to vsnCTC- patients, with a significant positive correlation between EMD expression and CTC nuclear size. EMD knockdown in PCa cells resulted in smaller nuclei, enhanced invasion, and the upregulation of genes associated with neuronal de-differentiation (e.g., SOX2, CHGA, MYCN, and AURKA). Additionally, C4-2B Abi-R/Enza-R cells had significantly smaller nuclei and lower EMD expression, consistent with our clinical observation of the vsnCTCs association with ARSI resistance. These resistant cells also demonstrated elevated expression of neuronal de-differentiation genes. Conclusions: The presence of vsnCTCs represents a novel hallmark of an aggressive subtype of mCRPC, closely linked to EMD dysregulation and neuroendocrine differentiation. These findings highlight the potential of vsnCTCs and associated biological changes as a predictive biomarker. Our findings underscore the importance of EMD in the progression and therapeutic resistance of advanced PCa.
Characterizing immunogenicity of <i>MYC-</i> amplified, metastatic prostate cancer as reflected by the recovery rates of adaptive immune receptor recombinations from RNAseq files.
Authors: Sunny Kahlon, Vayda Barker, Mallika Varkhedi, Alex Wang, Taha Huda, George Blanck
Journal: Journal of Clinical Oncology (2025)

241 Background: In prostate cancer, identifying biomarkers to predict patients who are at higher risk for metastatic disease remains a key question. The interaction of oncogenes such as MYC with the adaptive immune system may be a potential marker for worse progression; for example, MYC -amplified neuroblastoma has been shown to be immunologically cold both in vitro and with respect to the amount of adaptive immune receptor (IR) recombinations recovered from genomics files. Thus, we performed a correlative study identifying the relationship between MYC amplification and detection of adaptive IR recombinations in genomics files in prostate cancer. Methods: We utilized datasets for this study: The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD, n = 475), Count Me In-Metastatic Prostate Cancer (CMI-MPC, n= 63) and West Coast Dream Team – Metastatic Castration Resistant Prostate Cancer (WCDT-MCRPC, n = 76). Copy number variation (CNV) assessments were done for the cases in these studies, identifying oncogene amplification as those with high ratios of exome, tumor to blood sequencing read counts for a given gene. We also mined productive IR recombination sequencing reads from RNAseq files, with associated V and J-IDs, as described in Chobrutskiy et al. 2020, which yielded reads for TRA , TRB , TRD , TRG , IGH , IGK , and IGL . Then, MYC-amplified cases and MYC-deficient cases were compared with a two-proportion test for progression-free survival and with a t-test for the counts of IR receptors. Results: We first determined that, for TCGA-PRAD dataset, cases representing the top 20 MYC read tumor to blood count ratios, in comparison to all other cases, represented a poorer progression free survival (p = 0.01) at the 70-month timepoint. We also noted that average MYC CN in both metastatic prostate cancer datasets (CMI-MPC and WCDT-MCRPC) was higher than in the TCGA-PRAD dataset, which represented primary tumor samples (p &lt; 0.001 for both analyses). Further, for the WCDT-MCRPC dataset, we found that MYC -amplified cases were associated with significantly reduced IGH , IGK , and IGL recombination reads in RNA-seq files (p = 0.005, 0.01, 0.004 respectively). For the WCDT-MCPRC dataset, we found that MYC -amplified cases were associated with reduced TRA and TRB recombination reads in WGS files (p = 0.008 and 0.017 respectively). Conclusions: This report further evidences the negative effects of MYC amplification with regard to immune evasion and being a key driver of prostate cancer metastasis. This report thus supports risk stratification by MYC-amplification, as well as noting that patients with MYC-amplification may benefit more from immune-boosting therapies. In particular, this report identifies immunoglobulins and by proxy, B-cells, as a major deficiency in those with MYC-amplified prostate cancer.
Impact of PSMA PET staging on initial treatment in newly diagnosed prostate cancer: An emulated randomized controlled trial.
Authors: Sean Ryan Miller, Rachel Tucker Gonzalez, William C. Jackson, Megan Veresh Caram, Phoebe A. Tsao, Kristian Stensland, Yashesh Shah, Daniel Wale, David Elliott, Ka Kit Wong, Benjamin Viglianti, Tanner C. Caverly, Timothy Hofer, Sameer D Saini, Michael D Green, Matthew J. Schipper, Robert Timothy Dess, Alex K. Bryant
Journal: Journal of Clinical Oncology (2025)

350 Background: Prostate-specific membrane antigen (PSMA) PET/CT has become a common initial staging modality for localized prostate cancer due to its increased sensitivity and specificity over conventional staging. However, the causal impact of widespread PSMA staging on initial prostate cancer treatments has not been described. Methods: We used electronic medical record data from a national, diverse health system (Veterans Health Administration) to emulate a randomized controlled trial in which patients with newly diagnosed conventionally localized unfavorable intermediate, high, and very high-risk prostate cancer were allocated to either upfront PSMA staging or conventional imaging with technetium-99 bone scan and pelvic CT or MRI. Primary outcomes included the use of any androgen deprivation therapy (ADT), advanced androgen receptor pathway inhibitors (ARPIs), radiotherapy, and radical prostatectomy assessed in the year after diagnosis. We used the cloning, censoring, and weighting technique to estimate the causal effect of PSMA staging, controlling for potential confounders. In exploratory analyses, we extracted radiographic stage from PSMA reports using a natural language processing algorithm and assessed the influence of PSMA findings (N0M0, N1M0, or M1) on treatment patterns. Results: 9,049 patients met criteria for inclusion in the emulated trial, of whom 35% underwent PSMA staging and 46% underwent bone scan. In the emulated trial, PSMA staging was associated with higher rates of any ADT usage relative to conventional staging (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.19-1.44), higher ARPI usage (aHR 1.52, 95% CI 1.33-1.78), lower prostatectomy usage (aHR 0.69, 95% CI 0.56-0.83), and no effect on radiotherapy usage (aHR 1.10, 95% CI 0.99-1.25). Compared to patients with PSMA N0M0, ARPI usage was higher in patients with N1M0 (aHR 6.87, 95% CI 5.41-8.73) and M1 (aHR 10.13, 95% CI 8.16-1.2.58). Patients with N1M0 or M1 disease were less likely to undergo prostatectomy compared to N0M0. Similar patterns were seen in subgroup analyses within risk groups. Conclusions: In this emulated randomized trial, PSMA staging of localized prostate cancer was associated with increased rates of any ADT and ARPI use and lower rates of prostatectomy relative to conventional staging. The implications of these treatment changes on oncologic outcomes require further study.