tbuckley/cabot-search huggingface dataset:
The comparison of clinical utility between pan-cancer panel and PCa-specific panel for mCRPC.
Authors: Baijun Dong
Journal: Journal of Clinical Oncology (2025)

47 Background: To compare the diagnostic efficiency of pathogenic variants and the value for clinical decision making between a pan-cancer panel and a prostate cancer (PCa)-specific panel among patients with metastatic castration-resistant PCa (mCRPC). Methods: 637 mCRPC patients underwent panel-based targeted gene sequencing (Cohort A), among which, 327 patients underwent genomic profiling with a PCa-specific panel of 50 genes and 310 patients with a pan-cancer panel of 672 genes. Furthermore, 56 patients in Cohort A received both panel-based targeted gene sequencing approaches at the same time (Cohort B). The comparisons of the diagnostic efficiencies of pathogenic variants and clinical actionable variants (CAVs) were analyzed by proportion test. Results: The diagnostic efficiency of pathogenic variants was significantly higher in pan-cancer panel group than in PCa-specific panel group either in cohort A or cohort B (p&lt;0.0001). In cohort A, 504 of 970 genomic variants were defined as pathogenic variants among which 304 were classified as CAVs in PCa-specific panel group. In pan-cancer panel group, 1457 of 4205 genomic variants were defined as pathogenic variants among which only 304 were classified as CAVs. In cohort B, 96 of 182 genomic variants were defined as pathogenic variants among which 56 were classified as CAVs in PCa-specific panel group. In pan-cancer panel group, 260 of 788 genomic variants were defined as pathogenic variants among which only 59 were classified as CAVs. The detection rate of CAVs between the two groups was no difference either in cohort A or cohort B (p&gt;0.05). Conclusions: The pan-cancer panel had increased detection yield of pathogenic variants and provided a rich source of data, which was helpful for genetic researches. However, the PCa-specific panel proved to be as powerful as the pan-cancer panel in the detection of CAVs for tailored treatments, which might be better in guiding clinical decision making in a cost-effectiveness and time-saving way. Thus, the NGS panels available in different sizes might be chosen depending on basic research or clinical objectives.
Use of integrated multi-omics profiling in renal cell carcinoma to identify molecular subtypes and associated clinical outcomes and therapeutic vulnerabilities.
Authors: Chang Gon Kim, Harim Koo, Woo Sun Kwon, Woo Kyun Bae, Eu Chang Hwang, Won Sik Ham, Nam Hoon Cho, Jason Sa, Jong Bae Park, Sun Young Rha
Journal: Journal of Clinical Oncology (2025)

588 Background: Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conducted comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. Methods: Tumor and matched normal tissues were subjected to proteomic and phosphoproteomic analysis (N=113), whole exome sequencing (N=74), and whole transcriptomic sequencing (N=70). Results: RCC tumors are molecularly distinct from corresponding normal tissues, revealing the loss of tissue identity and de-differentiation. Various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest angiogenesis signaling pathway activation with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways along with genetic alteration in BAP1 (24.0%). C3 (N=19) was characterized by chromosome 7q amplification and associated with enrichment in inflammatory response with dismal prognosis along with therapeutic resistance to tyrosine kinase inhibitors and/or immunotherapy. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. VHL had significant trans -acting effects on various protein and phosphoprotein substrates, whereas PBRM1 and SETD2 had differential cis - and trans -acting profiles. Based on the in silico and in vitro exploration, we also identified CDK5, located on chromosome 7q and highly upregulated in C3 subtype, as a valuable target which can be modulated by small molecule inhibitors. Conclusions: This study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multiomics-derived phenotypes to clinical outcomes of RCC.
Time to metastasis after prostatectomy (TTM) and survival outcomes in patients (pts) with metachronous metastatic hormone-sensitive prostate cancer (mHSPC): A secondary analysis of the SWOG 1216 phase 3 trial.
Authors: Nicolas Sayegh, Yeonjung Jo, Umang Swami, Chadi Hage Chehade, Zeynep Irem Ozay, Georges Gebrael, Benjamin L. Maughan, Melissa Plets, Maha H. A. Hussain, Tanya B. Dorff, Primo N Lara, Amir Goldkorn, Seth P. Lerner, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2025)

173 Background: It is well-established that pts with de-novo mHSPC have poorer survival compared to those with metachronous disease. However, the impact of timing of metastatic recurrence after definitive therapy on survival has not been extensively evaluated in pts with mHSPC. Therefore, we assessed the prognostic value of TTM using the SWOG 1216 trial data which randomized pts with mHSPC to androgen deprivation therapy (ADT) with orteronel (ORT) or bicalutamide (bic) (NCT01809691). Methods: Eligibility: Only pts with metachronous mHSPC who underwent prostatectomy were included in the analysis. Metachronous disease was defined as no evidence of metastasis within 90 days of initial prostate cancer diagnosis. TTM was defined from the time of prostatectomy to the time of initial metastatic diagnosis and was analyzed as a continuous variable, then categorized. Multivariable analyses for progression-free survival (PFS) and overall survival (OS) were performed using a Cox proportional hazards model, adjusting for treatment arm, disease burden, Gleason score, performance status, log-transformed PSA, and age. Results: Of the 1279 study participants, 301 underwent prostatectomy and had metachronous mHSPC, of whom 161 were in the experimental arm and 140 in the control arm. In the overall cohort, a longer TTM was not associated with improved PFS (HR 1.0, P=0.3) and OS (HR 1.0, P=0.14). Similarly, after stratification of TTM using 1, 2, 3, and 4 year-thresholds, there was no association with PFS and OS. Results remained comparable in the subgroups of pts receiving ADT + bic and ADT + ORT separately (Table). Conclusions: The timing of metastatic disease after prostatectomy in pts with metachronous mHSPC did not appear to be related to survival and should not be used as a prognostic factor nor to predict treatment outcomes. ADT + ORT ADT Overall HR (P-value) PFS OS PFS OS PFS OS TTM Continuous 1.0 (0.8) 1.0 (0.8) 1.0 (0.3) 1.0 (0.1) 1.0 (0.3) 1.0 ( 0.1) TTM &lt;1 vs ≥1 1.1 (0.8) 1.4 (0.5) 0.9 (0.9) 1.7 (0.2) 1.1 (0.8) 1.6 (0.1) TTM &lt;2 vs ≥2 1.1 (0.7) 1.6 (0.3) 1.1 (0.6) 1.9 (0.1) 1.2 (0.3) 1.8 (0.04) TTM &lt;3 vs ≥3 1.1 (0.7) 1.4 (0.4) 1.5 (0.1) 1.7 (0.1) 1.4 (0.08) 1.6 (0.09) TTM &lt;4 vs ≥4 0.9 (0.8) 0.9 (0.9) 1.7 (0.03) 1.4 (0.4) 1.5 (0.05) 1.3 (0.4)
Discordance in HER2 expression in primary and recurrent/metastatic lesions of upper tract urothelial carcinoma: A study focusing on temporal heterogeneity.
Authors: Jianjun Ye, Xinyang Liao, Qihao Wang, Lei Zheng, Kai Chen, Qiang Wei, Yige Bao
Journal: Journal of Clinical Oncology (2025)

839 Background: The promising performance of HER2 antibody–drug conjugates (ADC) in clinical trials suggested that HER2-targerted therapy, particularly ADCs, may be a suitable treatment option for metastatic UTUC. However, we have observed cases where ADCs were ineffectiveness for recurrent/metastatic lesions in patients with HER2-positive primary UTUC. Thus, we conducted a retrospective study of UTUC patients to investigate the specific HER2 expression in paired primary and recurrent/metastatic lesions. Methods: Data of 290 UTUC patients who underwent radical nephroureterectomy at West China Hospital of Sichuan University from Jan 2020 and Oct 2023 without neoadjuvant treatment were retrospectively included. The HER2 expression was independently evaluated through immunohistochemistry by our professional genitourinary pathologists. HER2 2+ and HER2 3+ were considered HER2-positive whereas others were considered HER2-negative. Results: A total of 249 patients had HER2 expression evaluation of their specimens, with 92 patients (39.36%) showing HER2-positivity (IHC HER2 2+ or 3+). During rigorous follow-up, 31 patients (12.45%) developed local recurrence or distant metastasis. The majority of those patients had locally advanced UTUC (pT ≥ 3) and high grade disease. We observed discordance in HER2 expression between primary and recurrent/metastatic lesions in 22 cases (70.97%), with 9 cases (29.03%) showing an increase in HER2 expression and 13 cases (41.94%) showing a loss of HER2 expression. The conversion from HER2 negative to positive or vice versa occured in 5 cases (16.13%) and 10 cases (32.26%), respectively. Notably, all primary lesions with HER2 0 expression obtained HER2 expression in recurrent/metastatic lesions (5/5, 100%). Conclusions: Our findings highlight the discordance in HER2 expression between primary and recurrent/metastatic lesions in UTUC, underscoring the need for further investigation and potential modifications in disease management.
Mass cytometry-based deep immune cell profiling of metastatic clear cell renal cell carcinoma patients refractory to combined immune checkpoint and tyrosine kinase inhibitor therapy.
Authors: Luigi Formisano, Stefania Belli, Angela Vallefuoco, Giovanna Pecoraro, Fortuna Migliaccio, Chiara Barraco, Arianna Scipilliti, Daniela Esposito, Giovanna Attanasio, Marjolijn Hameetman, Tamar Tak, Ernesto Lopez, Sarah Scagliarini, Alberto Servetto, Roberto Bianco
Journal: Journal of Clinical Oncology (2025)

576 Background: Combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) improved outcomes for patients with metastatic clear cell renal cell carcinoma (mccRCC). However, some patients experience rapid disease progression. Identifying specific immune phenotypes and predictive circulating biomarkers is essential for the early detection of patients who may be refractory to ICI-TKI therapy. Methods: Serum samples and peripheral blood mononuclear cells (PBMCs) were collected from patients classified as complete responders (CR, n=4), partial responders (PR, n=10), and non-responders (NR, n=8) after 15 days (T1) and 1 month (T2) of nivolumab (ICI) and cabozantinib (TKI) therapy. Serum cytokines were analyzed using LEGENDplex, while PBMC immunophenotyping was performed using CyTOF to assess 37 immune cell populations and T cell markers related to activation, migration, and exhaustion. Results: In both responding and non-responding patients a common significant 90% reduction of PD1+TM3-CD8+ cells (p=0.0096 and p=0.0001, in CR and NR, respectively) and dendritic cells (decrease of 47% p=0.0004 in CR, 70% p=0.0059 in PR and 62% decrease p=0.0396 in NR) following therapy was observed. PD1+ Treg cells decreased significantly (93% decrease, p=0.0068) only in the CR after therapy. Additionally, CRs exhibited higher levels of exhausted PD1+ Treg cells (2.88 fold, p=0.0084) at baseline and an increased number of pro-inflammatory CD4+ Th2 cells (2 fold, p=0.0170) after one month compared to the other groups. PRs and NRs showed lower levels of natural killer cells (2.2 fold, p=0.0069), and a significant decrease of monocytes populations after therapy (45% decrease p=0.0008 in PRs, 40% decrease p=0.0012 in NRs). The CRs exhibited elevated levels of IL-23 (18 fold higher vs. NRs and 3 fold higher vs. PRs, p= 0.0094; p=0.0011) and IL-27 at baseline , and higher IL-15 and IL-18 levels post-therapy compared to the PR and NR. Kaplan-Meier plot analysis indicated that higher IL-23 levels correlated with an improved probability of PFS in all cancer patients treated with nivolumab (2.97 vs. 29.7 months in low vs. high expression cohorts; HR= 0.53 [95% CI 0.33 - 0.85], log-rank P = 0.0074). Conclusions: Our results suggest that patient’s initial immune profile might be significant predictor of treatment success and the likelihood of developing resistance.
Use of urinary cell-free DNA methylation assay to identify tumor fraction for early detection and recurrence monitoring in urothelial carcinoma.
Authors: Huan Zhao, Hang Dong, Haoran Tang, Zhihui Zhang, Na Wei, Jingjing Xu, Pan Du, Shidong Jia, Ting Xiao, Huiqin Guo
Journal: Journal of Clinical Oncology (2025)

844 Background: Urothelial carcinoma (UC) remains one of the most common urologic cancers, presenting challenges in both initial diagnosis and follow-up due to the invasive nature of traditional diagnostic procedures. Urinary cell-free DNA (ucfDNA) analysis offers a non-invasive alternative, with DNA methylation patterns providing a promising avenue for identifying tumor-derived cfDNA. This study explores the utility of ucfDNA methylation-based tumor fraction (mTF) for early detection and monitoring recurrence in UC patients. Methods: A case-control study was conducted with 121 participants, analyzing ucfDNA from patients with pathologically confirmed malignant tumors and benign lesions. A panel of UC-specific methylation markers was developed to quantify tumor-derived ucfDNA in a tissue-agnostic manner. The methylation-based tumor fraction (mTF) was then correlated with reference circulating tumor DNA (ctDNA) levels and clinical urine cytology indicators. Results: Our analysis revealed a significantly higher mTF in UC patients compared to controls (Wilcoxon test, p-value = 3.3 x 10 -9 ). Utilizing mTF as an independent biomarker for distinguishing malignant from benign cases achieved a positive predictive value (PPV) of 92% and a negative predictive value (NPV) of 90%. Moreover, relapse signals (mTF &gt; 0.005) were detected in follow-up urine samples from all patients (7/7) who had undergone transurethral resection of bladder tumor (TURBT). Conclusions: The urinary cfDNA methylation-based tumor fraction presents a promising non-invasive biomarker for both early detection and recurrence monitoring of urothelial carcinoma. This approach could significantly improve patient management by providing a valuable tool for diagnosis and ongoing surveillance, underscoring the need for innovative diagnostic strategies in UC.
Association between vascular patterns of clear cell renal cell carcinoma and immune cell infiltration and therapeutic response.
Authors: Marieta Toma, Tim Kempchen, Yangping Li, Katharina Baschun, Fabian Hörst, Melina Kehl, Niklas Klümper, Joerg Ellinger, Manuel Ritter, Kati Erdmann, Arndt Hartmann, Glen Kristiansen, Thomas Pinetz, Viktor Grünwald, Alexander Effland, Michael Hölzel
Journal: Journal of Clinical Oncology (2025)

575 Background: Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor with histological heterogenous appearance. We explored whether vascular pattern (VP) are predictive to response of therapy. Methods: We defined three categories of VP in the publicly available TCGA cohort: high-branching (HB), low-branching (LB) and sinusoid. VP-based gene signatures were generated by integrating the transcriptomes of matched ccRCC samples. We developed a learning-based (AI) algorithm for the classification of VP based on CD31 immunohistochemistry and analyzed histology specimens from patients treated with tyrosine kinase inhibitors +/- immunotherapy (TKI) (University Clinic Dresden, retrospective cohort n=38, and NivoSwitch trial NCT: NCT03013946 , n=38 respectively) as well as the publicly available transcriptome datasets from two phase III clinical trials (JAVELIN Renal 101; IMmotion 151). Multiplex immunofluorescence (CODEX) was used for spatial mapping. Outcome measures employed KM-plots and log-rank analyses. Results: We identified a trajectory from a HB to LB vascular phenotype, paralleled by a decline in the expression of proximal tubule cell lineage traits. Applying the VP gene signatures to the transcriptome datasets from JR101 and IM151 we found that the progression-free survival (PFS) benefit from adding immunotherapy to anti-angiogenic therapy (IMmotion151: Bevacizumab; JAVELIN Renal 101: Axitinib) was limited to low-branching ccRCC (IM151: HR (95% CI): 0.64 (0.51-0.80), JR101: HR (95% CI): 0.45 (0.33-0.61, both p &lt; 0.001), respectively) and linked to an immune cell infiltrated microenvironment. Patients with a HB ccRCC demonstrated prolonged PFS in the Dresden TKI cohort (p = 0.026) and in the NivoSwitch trial (p = 0.01). CODEX analysis using the SPACEc pipeline revealed profound differences in cellular neighborhoods, characterized by dense immune cell infiltration of ccRCC with LB compared to HB vascular patterns. Using 30 ccRCC patient-derived organoid in air-liquid interface (ALI) cultures, we confirmed the association between LB pattern and higher T cell infiltration, resulting in reduced viability of LB ccRCC organoids under immune-stimulating conditions. Conclusions: Vascular pattern can reliably predict therapy response in advanced ccRCC. Tumors with high branching phenotype respond better to anti-angiogenic TKI therapy. Low branching pattern was associated with improved response to immunotherapy.
Prognostic significance of PSA in the outcomes of patients with high risk localized prostate cancer.
Authors: Mohammad Arfat Ganiyani, Atulya Aman Khosla, Pushan Prabhakar, Arjun Pon Avudaiappan, Karan Jatwani, Manmeet Singh Ahluwalia, Murugesan Manoharan, Rohan Garje
Journal: Journal of Clinical Oncology (2025)

347 Background: Patients diagnosed with localized high-risk prostate adenocarcinoma (LHRPC) with high Gleason scores (8-10) and prostate-specific antigen (PSA) levels ≤ 4 may experience an altered clinical course. In these patients, low PSA levels may reflect cellular dedifferentiation, indicating more aggressive tumor behavior despite appearing to have a low disease burden. We aim to investigate the impact of PSA levels in patients with LHRPC to better understand prognosis and optimize treatment strategies. Methods: We included patients diagnosed with LHRPC based on TNM stage (T1-T4, N0, M0) and Gleason 8–10 from 2004 to 2020, using data from the National Cancer Database. We stratified patients based on PSA levels (≤4 and &gt;4 ng/dl) and treatment approaches. We utilized Kaplan-Meier analysis and Cox proportional hazard model to study survival outcomes in patients with LHRPC. Results: We included 160,971 patients diagnosed with LHRPC, of which 86.69% (139,546) had PSA &gt;4 ng/dl, while only 13.31% (21,425) had PSA ≤4 ng/dl. Our cohort had 69.55% (111,953) patients aged ≥ 65 years and 30.45% (49,018) aged &lt; 65 years. Regarding race, the cohort was predominantly white, comprising 81.69% (131,497), followed by black at 14.47% (23,292), and other racial categories at 3.84% (6,182). In our cohort 34.43% (55,425) underwent surgery only (S), 9.62% (15,484) received radiation therapy only (RT), 46.81% (75,350) had radiation therapy combined with androgen deprivation therapy (RT + ADT), and 9.14% (14,712) received androgen deprivation therapy only (ADT). In our multivariate cox proportional hazard analysis, LHRPC patients with PSA &gt;4 ng/dL had a 7% (HR 0.93, 95% CI: 0.90–0.95; p&lt;0.001) decreased risk of death compared to those with PSA ≤4 ng/dL. Conclusions: In our study, LHRPC patients with PSA ≤4 ng/dL had poorer survival outcomes after adjusting for the treatment approach, race, age category, income, insurance status, facility type, and location. Further research is required to explore potential biological differences in patients with low PSA-secreting LHRPC. Cox proportional hazard analysis in patients with LHRPC, GS 8-10. Categories Hazard Ratio (95% CI) P-value Treatment type: Surgery only reference RT only 2.27 (2.19, 2.36) &lt;0.001 RT + ADT 2.37 (2.30, 2.44) &lt;0.001 ADT only 5.68 (5.49, 5.87) &lt;0.001 Charlson Deyson score : 0 reference &gt;=1 1.43 (1.40, 1.46) &lt;0.001 Facility type : Academic reference Non-Academic 1.20 (1.17, 1.23) &lt;0.001 PSA ≤ 4 ng/dl reference PSA &gt; 4 ng/dl 0.93 (0.90, 0.95) &lt;0.001
Characterizing the activity of inflammasome genes and their association with oncological outcomes in prostate cancer.
Authors: Alireza Ghoreifi, Mohammed Alshalalfa, Elai Davicioni, Yangyang Hao, Daniel Eidelberg Spratt, R. Jeffrey Karnes, J. Todd Purves, Francis M. Hughes Jr., Judd W. Moul, Michael R Abern
Journal: Journal of Clinical Oncology (2025)

410 Background: Inflammasomes are multiprotein complexes that regulate inflammation-associated signaling pathways. Although inflammation plays a crucial role in cancer cell proliferation, the specific role of inflammasomes in prostate cancer (PCa) remains underexplored. This study aims to elucidate the expression of inflammasome-related genes in PCa and assess their association with clinical outcomes. Methods: De-identified transcriptome data from a cohort of 52,266 radical prostatectomy (RP) samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) were retrieved from the GRID registry (NCT02609269). Expression analysis focused on 33 genes involved in inflammatory pathways. Outcomes analysis was conducted on a retrospective cohort of 855 patients treated with RP (META855), using Cox regression analysis, adjusting for baseline pathological characteristics. Results: Analysis of baseline gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Higher expression of most genes was associated with higher rate of Gleason grade group 4 or 5 in the GRID RP cohort. On survival analysis of the META855 cohort, higher expression (top 25%) of AIM2 and HSP90AB1 were associated with worse metastasis-free survival (p&lt;0.05 for both). Conversely, both high and low expression levels of NLRP3 were associated with better metastasis-free survival outcomes following RP compared to average expression (p&lt;0.05). On multivariable Cox regression analysis, adjusting for grade group, seminal vesicle involvement, lymph node involvement, and margin status, higher expression of AIM1 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP (p&lt;0.05 for both). Conclusions: There is a molecular heterogeneity within pro-inflammatory genes among patients with PCa.Our findings showed thathigher expression of HSP90AB1 is linked to poorer oncological outcomes, whereas both high and low expression levels of NLRP3 are associated with better outcomes following RP.Further refinement is required to build a robust signature, along with external validation of these findings in other cohorts.