tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA as a prognostic biomarker to predict retroperitoneal histology in patients undergoing retroperitoneal lymph node dissection.
Authors: Parth Thakker, Connor Drake, Jiping Zeng, Timothy A. Masterson, Clint Cary
Journal: Journal of Clinical Oncology (2025)

646 Background: Serum tumor markers (STM) are used in the management of patients with testicular cancer. However, a proportion have normal STM even with cancer present. Circulating tumor DNA (ctDNA) has shown promise in for detection of persistent disease. We sought to determine the utility of ctDNA for predicting retroperitoneal histology by comparing patients’ retroperitoneal lymph node dissection (RPLND) histology with their pre-operative ctDNA status. Methods: Patients undergoing primary (P-RPLND) or post-chemotherapy (PC-RPLND) from March 2023 to January 2024 had prospectively collected plasma ctDNA assay (Signatera, Natera Inc.) The association between ctDNA and RPLND histology was assessed. Sensitivity (SN), specificity (SP), and positive (PPV) and negative predictive values (NPV) were calculated for ctDNA to detect active cancer or teratoma alone in the RPLND histology. Results: Forty-six patients undergoing RPLND had pre-operative ctDNA collection with a median age of 33.5 (IQR:27-38.8). Plasma was collected on average, 8.6 days pre-operatively. Twenty (43.5%) patients underwent P-RPLND and 26 (56.5%) patients underwent PC-RPLND. ctDNA was positive in 23 (50%) patients. Two patients underwent P-RPLND for stage I disease and both had (-) ctDNA and histology. Eighteen patients underwent P-RPLND for stage II disease. Of these, 16 had active cancer, 1 had pure teratoma, and 1 had negative histology. ctDNA was positive in 15 of these patients all of which were found to have either teratoma or active cancer on pathology. Of the 3 patients with (-) ctDNA, 1 had negative histology, 1 had mixed, teratoma and seminoma, and 1 had pure seminoma. There were 26 patients who had ctDNA drawn prior to PC-RPLND. Of these, 4 had active cancer, 16 had pure teratoma, and 6 had necrosis on final RPLND histology. ctDNA was positive in 8 patients all of whom had either teratoma or active cancer on histology. Of the 18 PC-RPLND patients with a (-) ctDNA test, 1 had active cancer, 11 had teratoma, and 6 had necrosis. There were no false positive tests in the entire cohort. The SN, SP, PPV, and NPV were 85%, 77%, 74%, 87%, respectively for predicting active cancer. These numbers vary by primary or PC-RPLND patients (Table). Conclusions: To our knowledge, this is the first study evaluating test characteristics of ctDNA results in relation to RPLND histology. These findings suggest that ctDNA may be a useful adjunctive screening tool to predict active cancer or teratoma in the RP. Test characteristics of ctDNA stratified by primary or post-chemotherapy RPLND. Sensitivity Specificity PPV NPV P-RPLND GCT and/or Teratoma 88% 100% 100% 60% GCT only 88% 75% 93% 60% Teratoma only 100% 26% 7% 100% PC-RPLND GCT and/or teratoma 40% 100% 100% 33% GCT only 75% 77% 38% 94% Teratoma only 31% 70% 63% 39%
Cardiovascular mortality risk in primary penile cancer patients: A retrospective cohort study from 2000 to 2021.
Authors: Asfand Yar Cheema, Mishaal Munir, Aashray Mandala, Oboseh John Ogedegbe, Serhan Unlu, Praveena Shree Thiagarajan
Journal: Journal of Clinical Oncology (2025)

7 Background: Primary penile cancer is a rare malignancy, representing less than 1% of all cancers in men in developed countries. The disease predominantly affects older males and is frequently associated with risk factors such as human papillomavirus (HPV) infection, chronic inflammation, smoking, and poor hygiene. Given the age and comorbidities of patients diagnosed with penile cancer, cardiovascular disease (CVD) is a significant concern. Penile cancer patients often present with multiple risk factors for CVD, including advanced age, smoking, obesity, and pre-existing hypertension. Despite improvements in cancer-specific survival, non-cancer causes of death, particularly cardiovascular mortality (CVM), may disproportionately affect these patients. Understanding the cardiovascular mortality in penile cancer patients is crucial for holistic care and survivorship. Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with primary penile cancer who experienced cardiovascular mortality (CVM) between 2000 and 2021. CVM was defined as mortality resulting from heart disease, hypertension (without concomitant heart disease), cerebrovascular disease, atherosclerosis, aortic aneurysm and dissection, and other diseases of the arteries, arterioles, and capillaries. Standardized mortality rates (SMR) were calculated to assess the relative risk of CVM among penile cancer patients compared to the general population. Absolute excess risk (AER) was also estimated to quantify the additional number of CVM-related deaths attributed to this patient population. Results: Out of a total cohort of 6,889 patients diagnosed with primary penile cancer, 689 experienced cardiovascular mortality. Patients with Non-cardiovascular death and patients with unknown ag, race and cancer stage were excluded. We compared the CVM of each group to the general US population. In our cohort based on race we didn't note statistically significant increase in CVD SMRs. Regarding race American Indians/Alaska Natives has (SMR 0.99, CI 0.24-3.98), Asians or Pacific Islanders (SMR 0.99 CI 0.68-1.46), Blacks (SMR 0.99 CI 0.75-1.33), Whites (SMR 1.00 CI 0.91-1.08). In terms of age, patients aged 30-50 years (n=27) had SMR of 0.99 (CI 0.68-1.44), 50-79 year (n=359) had SMR of 0.99 (CI 0.90-1.10), while 80 years and above (n=222) had SMR of 1.00 (CI 0.87-1.14). Conclusions: Our analysis evaluates the burden of CVD-related mortality in patients with primary penile carcinoma. In this cohort, no statistically significant increase in cardiovascular mortality was observed when compared to the general U.S. population, stratified by race and age. Further research is required to better understand potential associations or disparities and to identify any underlying factors that may influence cardiovascular outcomes in this population.
Initial biopsy results of the PATROL study: Prostate screening for people with inherited risk of developing aggressive prostate cancer.
Authors: Daniel Lee, Caitlin Orr, Kara N. Maxwell, Andrew Amini, Christopher L. Amling, Aileen J Feng, Stephanie Goettl, Kristin Follmer, Grace Jun, Chenee Holcomb, Shelley McCormick, Margaret O'Dea, Maxwell Poole, Linda Rodgers, Alexandra Sokolova, Maliha N Tayeb, Erika Wolff, Keyan Salari, Heather H. Cheng, Daniel W. Lin
Journal: Journal of Clinical Oncology (2025)

426 Background: Germline pathogenic variants (gPV) in prostate cancer (PrCa) risk genes are associated with aggressive disease and worse outcomes. However, the degree of risk by gene, the optimal PSA thresholds for biopsy, and the utility of MRI for screening are not well characterized. Therefore, we developed the PATROL study (clinicaltrials.gov: NCT04472338), a prospective multi-center early detection study for people at risk for PrCa due to variants in PrCa risk genes. Here, we report initial biopsy results of participants enrolled to date. Methods: The primary endpoint of PATROL is to determine the positive predictive value of predefined age-adjusted PSA thresholds and prostate-specific imaging for biopsy. Key eligibility criteria include: people ≥40y with prostates that carry a gPV in one or more of 13 PrCa risk genes. Participants undergo prostate biopsy per age-adjusted PSA threshold recommendations: PSA &gt;1.0 ng/mL if &lt;50y; PSA &gt;1.5 ng/mL if 50-59y; PSA &gt;2.0 ng/mL if ≥60y). Patients are encouraged to receive a prostate MRI at baseline and/or within one year of biopsy. Clinically significant prostate cancer (csPrCa) was defined as ≥Grade Group 2 (GG2). Results: Of 291 patients enrolled in PATROL at the time of this analysis, gPVs were most frequent in BRCA2 (n=141, 48%) and BRCA1 (n=71, 24%). 55 patients have undergone biopsy, with a median age of 57 (IQR 52-66) and median PSA of 2.2 (IQR 1.2-4.4) at time of biopsy. Of these biopsies, 10 (18.2%) had GG1 disease, and 11 (20%) had csPrCa. Of the men with csPrCa, six (55%) had PSA above the PATROL age-adjusted threshold but less than standard-of-care 4 ng/ml. An additional three (27%) patients had abnormal MRI with normal age-adjusted PSA. All 11 men with csPrCa underwent definitive treatment, while 7 of the men (70%) with GG1 initiated active surveillance. In a logistic regression model adjusting for age, gPV and PSA level, having a PIRADS 4 or 5 lesion was associated with csPrCa (OR 34.3, p=0.001). Conclusions: Screening gPV carriers using age-adjusted PSA and MRI resulted in 20% of biopsies detecting clinically significant prostate cancer. Conventional PSA thresholds for biopsy would have missed more than 80% of the clinically significant prostate cancer in men with gPV. Ongoing enrollment, site expansion and longer-term follow-up in this study, along with other studies will help improve the early detection of significant prostate cancer among men with gPV. Clinical trial information: NCT04472338 .
PPARG protein expression in advanced urothelial carcinoma and selection for response to FX-909, a first-in-class PPARG-targeting agent.
Authors: Evisa Gjini, William Motley, Adarsh Joshi, Bijal Kakrecha, Jennifer Mertz, Kaylyn Williamson, Stefan Kirov, Michaela Bowden
Journal: Journal of Clinical Oncology (2025)

856 Background: FX-909, a PPARG inverse agonist, is being evaluated in a first-in-human, dose escalation and expansion study in patients with advanced urothelial carcinoma (UC; NCT05929235). PPARG drives development of UC and its expression is associated with the luminal lineage, which accounts for ~65% of all advanced UC patients 2 . An IHC prototype assay was developed to detect PPARG expression in formalin-fixed paraffin-embedded UC tissues. Our data show that PPARG protein expression correlated with PPARG RNA expression in a retrospective cohort of archival tissue from high-grade localized UC. Methods: Commercial antibodies, clones C26H12, K.242.9 and E-8, were tested and validated using UC and control normal tissues. The E-8 clone was selected for further development based on demonstration of good specificity, sensitivity, range, and linearity. Specificity of the PPARG staining was demonstrated in cell lysates, where PPARG expression level was confirmed by Western blot (HEK293, BC3C, UMUC9, and RT112). Assay performance was evaluated in a cohort of 25 high-grade localized, stage III-IV UC patient samples. Semi-quantitative analysis [percent (%) tumor score and H-score] was conducted by a pathologist. Gene expression values from RNAseq were normalized by transcripts-per-million (TPM). Molecular classification was performed using non-negative matrix factorization rank 5 following the Robertson method 3 derived from RNAseq. Results: The E-8 clone detected a broad range of PPARG expression, with a predominantly nuclear staining pattern at staining intensities from 0 to +3. Each sample exhibited different staining intensities, highlighting the heterogeneity of PPARG expression. Eighty-eight percent of cases showed PPARG expression in more than 50% of their tumor cells (22 out of 25). H-scores varied from 0 to 270 (Median H-Score = 146), where 64% of the cases showed a moderate PPARG expression with H-scores ranging between 100 and 200. PPARG protein expression quantitated based upon the % tumor area with 2+ or greater staining correlated with RNA expression levels (Spearman correlation coefficient r = 0.66; p-value &lt;0.01). Similarly to previous data 2,5 , 52% of the cases in this cohort were of luminal lineage. The median RNA expression level of PPARG was significantly higher in the luminal subgroup compared to the non-luminal subgroup (6.0 Log2[TPM+1] vs 3.53 Log2[TPM+1], p &lt;0.01). Conclusions: These data show the IHC assay is sensitive and specific for the detection of PPARG expression in advanced UC with utility to identify patients with potential to respond to FX-909, a first-in-class PPARG-targeting agent 4 . 1. Sims R, AACR 2023, Fl; 2. Motley W, et al. EORTC 2022; 3. Robertson AG, et al. Cell 2017; 4. Iyer G, et al. ASCO GU 2024, CA; 5. Kirov S, AACR-NCI-EORTC 2023, MA.
Assessment of cardiovascular (CV) toxicity by providers in advanced prostate cancer (PCa) patients (pts) on novel hormonal therapy (NHT).
Authors: Dalia Kaakour, Eunah Cho, Aya Ozaki, Ali Raad, Amanda Macaraeg, Jeanah Go, Steven Neema Seyedin, Ali Naqvi, Nataliya Mar
Journal: Journal of Clinical Oncology (2025)

125 Background: Addition of NHT, including Abiraterone, Enzalutamide, Apalutamide, and Darolutamide, to androgen deprivation therapy in patients with advanced PCa demonstrated improved survival in large randomized controlled trials. However, NHTs are associated with development of metabolic syndrome and CV toxicity. Treatment related adverse events (TRAEs) may include hypertension (HTN), hyperglycemia, atrial fibrillation, myocardial infarction (MI), congestive heart failure (CHF), and stroke. As such, monitoring for these toxicities by treating providers is essential. Cardio-oncology is an emerging field that addresses CV needs of cancer pts and fosters collaboration between oncologists and cardiologists. Methods: This is a retrospective analysis of 92 pts with advanced PCa, who initiated an NHT in 2022 at the University of California Irvine. Medical records were analyzed for various metrics relating to CV risk assessment performed by treating providers. Results: Pts of 11 different providers, including medical and urologic oncology, were examined. Characteristics of the study population at NHT start are described (Table). Within specific study population subgroups outlined, corresponding provider interventions within 3 months of NHT start are also listed. Conclusions: In this dataset of pts with pre-existing features of metabolic syndrome and CV risk factors at NHT start, only a minority had screening for hyperglycemia, hyperlipidemia, and cardiac dysfunction as well as had counseling about appropriate nutrition or referred to cardiology. Provider education about NHT-related TRAEs and emphasis on early screening for CV toxicity is key. Characteristics of the study population and corresponding provider interventions. Pt characteristic at NHT start % of pts Had lipid panel checked (%) Had hemoglobin A1C checked (%) Seen by cardiology before NHT start (%) Referred to cardiology post NHT start (%) Had documented counseling about nutrition (%) Had echocardiogram (%) Body mass index (BMI) 25.0 - 29.9 50.0 26.1 32.6 23.9 6.5 10.9 23.9 BMI ≥30 21.7 40.0 40.0 35.0 0.0 10.0 30.0 Former or active smoker 41.3 42.1 42.1 23.7 5.3 5.3 34.2 Hx of HTN 69.6 29.7 42.2 29.7 3.1 7.8 23.4 On ≥2 blood pressure (BP) agents 29.3 48.1 55.6 40.7 3.7 3.7 40.7 Hx of hyperlipidemia 64.1 30.5 35.6 28.8 1.7 8.5 25.4 On a statin 51.1 31.9 34.0 29.8 2.1 8.5 27.7 Hx of MI 20.7 36.8 36.8 52.6 0.0 5.3 31.6 Hx of CHF 9.8 44.4 77.8 55.6 11.1 0.0 55.6 Hx of arrhythmia 20.7 42.1 57.9 57.9 0.0 0.0 31.6 Hx of stroke 8.7 25.0 62.5 37.5 0.0 0.0 25.0 Hx of diabetes mellitus (DM) 34.8 34.4 50.0 37.5 3.1 9.4 31.3 On a non-insulin DM agent 38.0 28.6 37.1 28.6 2.9 14.3 25.7 On insulin for DM 14.1 23.1 61.5 23.1 0.0 7.7 15.4
Comprehensive proteomic profiling of plasma samples associated with response or resistance to immune checkpoint inhibitors (ICI) in patients with renal cell carcinoma (RCC).
Authors: Soki Kashima, Wenxin Xu, John Canniff, Renee Maria Saliby, Maxine Sun, Gwo-Shu Mary Lee, Marc Machaalani, Sabina Signoretti, Bradley Alexander McGregor, Rana R. McKay, Toni K. Choueiri, David A. Braun
Journal: Journal of Clinical Oncology (2025)

562 Background: ICI-based therapies are the cornerstone of treatment for advanced RCC. While many studies have focused on tumor-based biomarkers, circulating factors play an important role in therapeutic response. This study utilized a high dimensional proteomic platform to investigate plasma proteins from RCC patients undergoing ICI-based therapies to identify potential biomarkers associated with treatment outcomes. Methods: A total of 43 plasma samples (n = 40 clear cell; n = 3 non-clear cell) were collected from 33 advanced RCC patients, with 16 paired samples (pre- and post-treatment) from 6 patients and 27 unpaired samples. The cohort included patients treated with ICI monotherapy (n = 22), ICI + ICI (n = 13), ICI + VEGF inhibitors (n = 7), and ICI + CCR2/CCR5 antagonist (n = 1). For this study, we analyzed pre-treatment samples from responders (R) (n = 8; complete or partial responses), and non-responders (NR) (n = 4; progressive disease). We performed plasma proteomic analysis using the SomaScan 11k proteomic platform, and Mann-Whitney U-test comparisons between ICI-naïve samples of R and NR groups. We also performed a paired test between ICI-naïve and ICI-exposed samples in R (n = 3 patients with paired samples). Nominal p-values are reported. Results: All 43 samples passed quality control. In ICI-naïve samples, we observed that ICAM1 and ITIH3 levels were significantly higher in R compared to NR (p = 0.016 for both). Conversely, CILP2 and leptin were significantly elevated in NR (p = 0.016, p = 0.004, respectively). Further analysis for treatment evolution through paired samples showed that PD-1, CXCL9, and HLA-B were significantly elevated in ICI-exposed samples compared to ICI-naïve samples in R (p = 0.021, p = 0.022, p = 0.041, respectively). Conclusions: Our exploratory proteomic analysis identified higher ICAM1 and ITIH3 levels in ICI responders, which may reflect anti-tumor inflammation and the recruitment of immune cells to tumors. Elevated CILP2 and leptin levels were observed in ICI non-responders, highlighting their potential contributions to an immunosuppressive environment through Tregs and the TGF-β pathway. Beyond the potential biomarkers, the post-ICI elevation of CXCL9 and HLA-B in responders suggests that these may be linked to sustained immune activation during treatment, offering a foundation to understand treatment evolution in RCC.
Evaluating survival in aggressive variant prostate cancer patients undergoing PSMA radioligand therapy.
Authors: Moein Moradpour, Abuzar Moradi Tuchayi, Irene Burger, Sabin George. Pop, Ana Aparicio, Ivan de Kouchkovsky, Thomas A. Hope
Journal: Journal of Clinical Oncology (2025)

259 Background: Aggressive variant prostate cancer (AVPC) is a subtype of metastatic castrate-resistant prostate cancer (mCRPC) characterized by several high-risk features. AVPC is associated with poorer overall survival and has limited response to androgen receptor targeted therapy, although it often shows some responsiveness to chemotherapy. In this study, we evaluated the outcomes of AVPC patients who received Prostate-Specific Membrane Antigen (PSMA) radioligand therapy (RLT). Methods: This retrospective study included 201 mCRPC patients who received Lutetium-177, [ 177 Lu]-PSMA RLT at two academic centers. Patients were classified as having AVPC based on the presence of at least one of the following eight criteria: exclusive visceral metastases (n=1), predominantly lytic bone metastasis (n=1), bulky lymphadenopathy or pelvic mass (≥5 cm) (n=4), low PSA (≤10 ng/mL) at initial presentation plus high-volume (≥20) bone metastases (n=0), serum CEA and/or LDH levels twice the upper limit of normal at the time of treatment (n=5), a short interval (≤6 months) to CRPC (n=7), small cell/neuroendocrine carcinoma morphology (n=5), and the presence of two or more genomic defects among TP53, RB1, and PTEN (n=13). Results: Of the 201 patients, 34 (16.9%) were classified as having AVPC (Table). The PSA50 response rate was 55% in the AVPC group and 60% in the non-AVPC group. The median overall survival (OS) (median time from the start of therapy to the last follow-up or death) was 171 days for the AVPC group and 282 days for the non-AVPC group. Although, the Kaplan-Meier plot only suggested a trend toward worse survival in AVPC patients compared to non-AVPC patients, the difference did not reach statistical significance (log-rank test p-value = 0.179). Conclusions: Our study suggests patients with AVPC may benefit from PSMA RLT and should be considered for this treatment if they are eligibly. Further studies are needed for a better understanding of this patient population. Details of patients. AVPC Non AVPC N=201 34 167 Age 1 (mean, year) 64.38 64.09 PSA 2 (mean, ng/mL) 331 251 PSA 3 (mean, ng/mL) 717 504 PSA50 (%) 55 60 OS/FU (median, day) 171 282 1 Age at the time of therapy. 2 Baseline PSA at diagnosis. 3 Most recent PSA prior to therapy.
Evaluating cost-effectiveness in the evolving treatment landscape for metastatic urothelial carcinoma.
Authors: Constantin Rieger, David A. Pfister, Joerg Schluechtermann, Axel Heidenreich, Richard Weiten, Enno Storz
Journal: Journal of Clinical Oncology (2025)

695 Background: Metastatic urothelial carcinoma (mUCa) is the most expensive cancer to treat on a per-patient basis, largely due to the need for frequent interventions and costly follow-up care. In examining first-line therapies, combinations such as enfortumab-vedotin plus pembrolizumab (EV + P) and gemcitabine/cisplatin plus nivolumab show substantial overall survival advantages over the standard treatment (SoC) of gemcitabine/cisplatin. This study presents a cost-effectiveness analysis for mUCa. Methods: We developed a Markov model from a payer's perspective, utilizing clinical data derived from the Phase III Checkmate-901 and EV302/Keynote-A39 trials. To identify the optimal treatment from a socioeconomic standpoint, we employed Monte Carlo simulation, focusing on Germany and the United States (US). Subsequently, we compared the incremental cost-effectiveness ratio (ICER) for each treatment modality across various willingness-to-pay (WTP) thresholds. Results: At a lifetime horizon, SoC, gemcitabine/cisplatin plus nivolumab and EV + P were associated with average costs of €163,424 (US: $458,006), €206,853 (US: $597,802), and €401,170 (US: $1,228,455), respectively, while achieving QALYs of 1.21, 1.71, and 2.31, respectively. The ICERs for the newer treatment strategies were €87,340 (US: $281,142) for gemcitabine/cisplatin plus nivolumab and €216,140 (US: $700,448) for EV + P. At a commonly accepted WTP threshold of €/$100,000, gemcitabine/cisplatin plus nivolumab emerged as the optimal strategy in Germany, while EV + P would necessitate a price reduction of 46% (US: 82%) to achieve cost-effectiveness. Conclusions: QALYs nearly double with the combination of EV + P compared to the current SoC; however, the associated costs may not be justifiable from a strict socioeconomic perspective. Despite offering lower oncological benefits, gemcitabine/cisplatin plus nivolumab should be considered for first-line therapy due to its favorable cost-effectiveness, particularly in Europe. Furthermore, identifying individual risk factors is crucial for optimizing therapeutic responses and managing treatment costs in the future.