tbuckley/cabot-search huggingface dataset:
Clinical and molecular characterization of urothelial (UC) vs. small cell carcinoma (SCC) of the urinary tract.
Authors: Neal Shiv Chawla, Benjamin D. Mercier, Ameish Govindarajan, Xiaochen Li, Daniela V. Castro, Hedyeh Ebrahimi, Regina Barragan-Carrillo, Peter D. Zang, Alexis Ann LeVee, Nazli Dizman, Joann Hsu, Luis A Meza, Zeynep Busra Zengin, Nicholas Salgia, Alex Chehrazi-Raffle, Tanya B. Dorff, Sumanta Kumar Pal, Abhishek Tripathi
Journal: Journal of Clinical Oncology (2024)

682 Background: SCC is an uncommon variant of bladder cancer with sparse data pertaining to its genomic landscape. Utilizing Tempus Lens, a real world clinical and genomic dataset, we investigated the clinical and genomic characteristics of SCC compared to UC. Methods: The de-identified Tempus Lens dataset was queried for patients diagnosed with UC or SCC of the bladder or ureter, of any stage. Baseline demographic, pathologic features, and results from blood or tissue-based genomic sequencing were catalogued. Clinical and pathological variables were summarized using descriptive statistics to compare the UC and SCC groups, using a Chi-square or Fisher’s exact test for a significance threshold of P&lt;0.05. The prevalence of genomic alterations in the two groups were compared using a two proportions Z-test with a significance level of 0.00167, calculated using the Bonferroni correction for multiple comparisons. Results: A total of 4,569 pts (UC: 4429; SCC: 140) were included in the analysis. Gender, race, the proportion of patients ≥65 years, stage, and tumor grade were similar between the two groups. Use of blood based genomic sequencing was relatively similar (29.8% and 27.1%) between UC and SCC patients, respectively. Compared to UC, the SCC cohort had a significantly higher prevalence of TP53 (93.6% vs 60.8%; P&lt;0.001), RB1 (73.6% vs 21.5%; P&lt;0.001), and PTEN (13.6% vs 5.1%; P&lt;0.001) alterations, and a lower frequency of CDKN2A (7.1% vs 29.5%; P&lt;0.001), MTAP (2.9% vs 18%; P &lt;0.001) and FGFR3 (6.4% vs 15.6%; P=0.003) mutations. Actionable alterations in SCC cohort included PIK3CA (21.4%), ERBB2 (13.6%), ATR (13.6%), ATM (9.3%), BRCA2 (8.6%), MSH6 (5.7%), TSC1/2 (4.9%), and PMS2 (4.3%). Conclusions: This is the largest study characterizing the genomic features of SCC. Our findings are consistent with prior studies suggesting a distinct genomic profile of SCC, with actionable alterations in a significant subset of patients. The impact of these alterations on outcomes and therapeutic strategies targeting these mutations warrant further investigation.
Prognostic value of circulating tumor DNA fraction (TF) for patients with metastatic renal cell carcinoma (mRCC).
Authors: Amado J. Zurita, Natalie Danziger, Takara Scott, Ole Gjoerup, Lei Zhong, Hanna Tukachinsky, Jeffrey S. Ross, Ryon Graf
Journal: Journal of Clinical Oncology (2024)

455 Background: Risk stratification, based on the IMDC classification, is central to treatment decisions for patients with mRCC. The strongest prognostic feature in the original validation was the clinical assessment of patient frailty through performance status (PS). Although inexpensive and ubiquitous, clinical features such as PS are prone to degrees of subjectivity and considerable variation in assessment from practitioner to practitioner. Recent work (Reichert et al. 2022, Annals of Oncology) observed that TF levels around the initiation of new treatment were prognostic independently of standard clinical features including ECOG PS, in advanced/metastatic lung, breast, prostate, and colorectal cancers, but has not yet been investigated in mRCC. Methods: This study used a cohort of patients in the de-identified nationwide, U.S. based Flatiron Health-Foundation Medicine renal cell clinico-genomic database, which originated from approximately 280 US cancer clinics (~800 sites of care), who underwent genomic testing as part of routine care. TF estimation on FoundationOne Liquid CDx was based on a composite algorithm incorporating multiple factors including aneuploidy and variant allele frequency of canonical alterations. Clinical characteristics, laboratory and treatment data were captured from the electronic health record. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by TF level. Results: 45 patients with mRCC and liquid biopsy testing had TF assessments within 90 days of start of new treatment. Patients with TF≥1% (15 of 45) had younger median age (58y vs. 66y, p = 0.041) and higher prevalence of calcium levels above upper limit of normal (46% vs. 4%, p &lt; 0.001). Higher TF (≥1%) was associated with less favorable rwPFS (hazard ratio (HR) 1.41, 0.70-2.82, p=0.34) and rwOS (HR 2.54, 1.08-5.96, p=0.033). In the 15 patients with TF ≥1%, we observed detection of known pathogenic genomic alterations in VHL (7/15, 47%), SETD2 (4/15, 27%), PBRM1 (4/15, 27%), BAP1 (3/15, 20%). Conclusions: In this initial cohort study, ctDNA TF shows prognostic significance in mRCC with potential to inform expected longevity of patients. Liquid biopsy detects alterations characteristic of mRCC genomics, supporting its utility to identify drivers and potential targetable alterations. Risk stratification based entirely upon algorithmic determination independent of human interpretation has the potential to improve risk stratification in mRCC and improve treatment decisions. Expansion of our cohort and survival data maturation will allow for evaluation of whether TF may be a useful addition to the established IMDC clinical classification and improve risk stratification and treatment assignment.
A phase I/II, open label, single arm study on safety, tolerability and anti-tumour effiacy of orellanine treatment in patients with metastatic clear-cell or papillary renal cell carcinoma.
Authors: Sven Lundstam, Boerje Haraldsson, Jenny Nystrom, Jeffrey Yachnin
Journal: Journal of Clinical Oncology (2024)

TPS486 Background: Poisoning by the mushroom ”deadly webcap”( Cortinarius sp.) causes irreversible kidney damage but there are no known effects on other organs. The fungal toxin, orellanine, selectively targets proximal tubular cells in rats and in humans by disturbing the cell metabolism causing decreased protein synthesis and apoptosis. Clear cell and papillary renal cell carcinoma (RCC) originate from proximal tubule cells. Orellanine induced concentration-dependent decline in viability in RCC cell lines and in primary cultures from human clear cell and papillary RCC. Orellanine induced apoptosis and tumour shrinkage in RCC(SKRC-17) transplanted to rats on peritoneal dialysis and the tumours become necrotic with almost no viable tissue. Based on these data a drug has been developed based on chemically synthesized orellanine ( www.oncorena.com ). Methods: The primary objectives of this study are to evaluate the safety and tolerability and to determine the maximum tolerable dose (MTD) of orellanine in patients with metastatic clear cell or papillary RCC and end stage renal disease who are on chronic haemodialysis and who have failed standard of care treatment. The secondary objectives are to study the pharmacokinetic (PK)profile of orellanine and to assess the efficacy of orellanine in treating these patients with respect to objective response (OR). Exploratory objectives are to access progression free and overall survival (PFS and OS) and to conduct analysis of circulating tumour specific DNA in the blood. Serum will be collected for unspecific future research which may include sequencing or genomic analyses. Orellanine will be given intravenously once monthly. A total of 6 to 20 patients will be enrolled in a dose escalation phase to determine MTD or a dose causing complete response (CR). An independent Data Review Committee (DRC) will access cumulative data and provide recommendations and decisions for every change in dose level. Once MTD has been determined up to 20 patients will be treated in a dose expansion phase to better characterize safety, tolerability and primary efficacy. CT/MRI will occur every 4 weeks (Q4W) during dose escalation phase and Q8W during the dose expansion phase. Enrollment has started and since the occurrence of end stage renal disease in patients with metastatic RCC is uncommon, patients in this first in man study are recruited both from western Europe and north America. The study is performed in the Centre for Clinical Cancer Studies (CKC) at Karolinska University Hospital, Stockholm, Sweden Reference: Lisa Buvall et. al. Orellanine specifically targets renal cell carcinoma.Oncotarget. 2017; 8:91085-91098. https://doi.org/10.18632/oncotarget.19555 . Clinical trial information: NCT05287945 .
Long-term results of radiation with or without anti-androgens (AAT) in patients receiving salvage prostate bed radiation therapy (sRT) post prostatectomy.
Authors: Himu Lukka, Stephanie L. Pugh, William U. Shipley, Pierre Major, A. Oliver Sartor, Ian S. Dayes, Jean-Paul Bahary, Jason A. Efstathiou, Thomas Michael Pisansky, Kenneth Lee Zeitzer, Colleen Anne Lawton, Robert Timothy Dess, Andrew S Camarata, Alexander G. Balogh, Luis Souhami, Seth A. Rosenthal, Wendy Seiferheld, Felix Y Feng, Howard M. Sandler
Journal: Journal of Clinical Oncology (2024)

320 Background: sRT is used in men with prostate cancer (PC) recurrence following radical prostatectomy (RP) signaled by a persistent or delayed elevation in PSA. It was previously reported that the use of AAT with RT improved cancer control and overall survival (OS). Long-term follow-up (FU) results are presented here. Methods: From 1998to 2003, 760 eligible post-RP patients with Stage pT3N0 or with pT2N0 and positive margins and PSA from 0.2 to 4.0 ng/mL were randomly assigned on a double-blinded, placebo-controlled trial of RT + placebo vs. RT + anti-androgen therapy (AAT) (24 months of bicalutamide, 150mg daily) during and after RT (64.8 Gy in 36 fractions prostate bed). The primary endpoint was OS estimated using Kaplan-Meier method. Time to PC death and metastatic PC (competing risk of death without an event) was estimated using cumulative incidence. The hazard ratio (HR) was obtained using Cox models (OS) and subdistribution HRs (sHRs) used the Fine-Gray model (time to PC death and metastatic PC). All tests are one-sided based on study design. Results: Median FU for surviving patients was 19 years. OS at 18 years was 53% [95% confidence interval (CI): 47-58%] for RT + AAT and 43% [95% CI: 38-48%] for RT + placebo (adjusted HR 0.82 [95% CI: 0.67-1.00], p = 0.025). The 18-year incidence of centrally reviewed PC deaths were 18% [95% CI: 14-22%] RT + AAT and 28% [95% CI: 23-32%] RT + placebo (adjusted sHR = 0.57 [95% CI: 0.42-0.78], p&lt;0.001). The 18-year incidence of metastatic PC was 22% [95% CI: 18-26%] and 31% [95% CI: 26-35%] for AAT and placebo arms respectively with adjusted sHR = 0.59 [95% CI: 0.44-0.80, p&lt;0.001]. Subgroup analyses is shown in the Table. Conclusions: Long term results of 24-month duration AAT during and after sRT are consistent with the primary report with significantly improved long-term OS, reduced incidence of metastatic PC and PC death for RT+AAT. Statistically significant metastatic PC was noted for Gleason score 8-10, study entry PSA&gt;1.5 and margin positive patients and borderline significance was observed in patients with study entry PSA 0.7-1.5. Clinical trial information: NCT00002874 . [Table: see text]
Platinum eligibility (PE) criteria for patients with metastatic urothelial carcinoma (mUC): Results of a physician survey in 5 European countries.
Authors: Shilpa Gupta, Thomas Powles, Mairead Kearney, Laura Panattoni, Natalie Land, Thomas Flottemesch, Patrick Sullivan, Melissa Kirker, Murtuza Bharmal, Silke Guenther, Nuno Costa, Enrique Grande
Journal: Journal of Clinical Oncology (2024)

696 Background: The standard of care for mUC is platinum-based chemotherapy (PBC) followed by avelumab first-line (1L) maintenance in patients without disease progression. Guidelines for mUC recommend 1L treatment based on eligibility for PBC (cisplatin or carboplatin), but the definition of PE remains unclear, and little is known about criteria used by European physicians to define PE in clinical practice. In this cross-sectional study, we assessed treatment decision-making factors and clinical thresholds used by European physicians determine PE and examined their alignment with published US physician thresholds. Methods: Physicians from France, Germany, Italy, Spain, and the UK completed a quantitative online survey in Aug/Sep 2022. We adapted Gupta et al’s ASCO-GU 2019 and ASCO 2022 US-based surveys, which identified thresholds for clinical criteria used by US physicians to define PE. This EU survey included clinical parameters with different age and creatinine clearance (CrCl) thresholds, plus Eastern Cooperative Oncology Group performance status (ECOG PS) and other relevant criteria. Participants reported the percentage of patients they perceived were platinum eligible and ranked criteria to determine PE. All analyses used descriptive statistics. Results: 503 physicians (69% oncologists, 31% urologists) completed the quota-based survey. Most had been in practice for &gt;10 years (69%), treated 5-19 patients with mUC per month (58%), and practiced in a public teaching hospital (40%). Most patients who received 1L systemic treatment were PE (77%), ranging from 75% in Italy to 79% in Spain. Most respondents chose &gt;80 years (33.2%) or &gt;75 years (24.1%) as the age threshold for platinum ineligibility. Age thresholds selected were significantly different across countries, years of practice, and practice settings (p&lt;0.001). Responses for ECOG PS and peripheral neuropathy thresholds for platinum ineligibility were evenly split between ECOG PS ≥2 (40.6%) and ≥3 (45.3%) and between grade ≥2 (44.3%) and ≥3 (41.7%) peripheral neuropathy. The most frequent responses are summarized (Table). Conclusions: Physicians in Europe considered most patients with mUC to be platinum eligible. Criteria to determine PE were broadly consistent with previous US-based studies, except for age. The low age threshold observed is at odds with the older age of the mUC patient population. Wider use of these criteria could support clinical decision-making, reduce variations in care, and improve patient outcomes. [Table: see text]
Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk/very high-risk localized prostate cancer: A multicenter, open-labeled, single-arm phase II trial.
Authors: Junlong Zhuang, Yuwen Wang, Shun Zhang, Xuefeng Qiu, Feng Zhou, Yao Fu, Xuedong Wei, Linfeng Xu, Hongqian Guo
Journal: Journal of Clinical Oncology (2024)

321 Background: Radical prostatectomy (RP) is associated with adverse surgical outcomes and an increased risk of disease progression in patients with high-risk/very high-risk localized prostate cancer (HRLPC/VHRLPC). This study aimed to evaluate the efficacy and safety of neoadjuvant darolutamide, a next-generation androgen receptor inhibitor, plus androgen deprivation therapy (ADT) for patients with HRLPC/VHRLPC undergoing RP. Methods: In this multicenter, single-arm phase II clinical trial, patients aged 18-75 year with HRLPC/VHRLPC (defined as Gleason ≥ 8 and/or cT3-4N0-1 and/or PSA ≥ 20 ng/mL). Patients with at least one of the following features were diagnosed with VHRLPC: cT3b-cT4, primary Gleason pattern 5, 2 or 3 high risk features, &gt; 4 cores with Grade Group 4 or 5. Eligible patients received 6-month neoadjuvant darolutamide plus ADT followed by RP. The primary endpoint was pathological response rate (the proportion of patients with pathologic complete response [pCR] or minimal residual disease [MRD]). The secondary endpoints included safety, PSA progression-free survival, positive surgical margins rate, downstaging rate and PSA response rate. Results: Thirty patients were enrolled, and all patients had received robotic-assisted RP. The median age was 71.0 (interquartile range [IQR], 65.2-73.0) years, and the median PSA level was 37.8 (IQR, 21.0-94.7) ng/mL at baseline. A majority of the patients had VHRLPC (93.3%), while 6.7% had HRLPC, among whom N1 disease, cT3-4, Gleason 8-10, and PSA ≥ 20 ng/mL accounted for 26.7%, 86.7%, 90% and 77% of cases, respectively. The median prostate volume before RP was 19.4 mL (IQR, 15.6-28.4). Twenty-seven patients (90%) had undetectable PSA levels (＜0.01 ng/mL). The pCR rate was 6.7% and the MRD rate was 33.3%, resulting in a pathological response rate of 40.0%. Twenty patients (66.7%) achieved downstaging, and only four case (13.3%) had positive surgical margins. Eleven patients (36.6%) had extracapsular extension. The details of clinical and pathological outcome after neoadjuvant therapy are described in the Table. Conclusions: Darolutamide plus ADT for six months before RP improved clinical and pathological responses in men with HRLPC/VHRLPC, with favorable safety profile. Clinical trial information: NCT05249712 .[Table: see text]
AI-based morphologic model for prediction of individual patient response to immune checkpoint inhibitors for bladder cancer.
Authors: Monica Nair, Ross Liao, Parag Jain, Chensu Xie, Hassan Muhammad, Wei Huang, Hirak S Basu, George Wilding, Rajat Roy, C. Marcela Diaz-Montero, Tae Hyun Hwang, Scott Dawsey, Jane Nguyen, Eric A. Klein, Shilpa Gupta, Omar Y. Mian
Journal: Journal of Clinical Oncology (2024)

686 Background: Immune checkpoint inhibitors (ICI) have been used to treat advanced muscle invasive and/or metastatic bladder cancer. However, ICIs are only effective in 30-40% of cases. In light of potentially significant IRAE’s, tools to predict individual patient level benefits are desirable. AI technology offers the opportunity to apply computational methods to predict outcomes from readily available digitized pathology slides. We investigated the utility of an AI platform integrating computational biomarkers based on morphological characterization of digitized H&amp;E slide whole images (WSI) to predict response to ICI. Methods: We analyzed H&amp;E-stained whole slide images (WSI) of bladder tumor tissue collected from transurethral resection of bladder tumor (TURBT) from 116 patients with advanced or metastatic bladder cancer at a single institution between 2015-2020. Adjacent multiplex IHC stained specimens were analyzed myeloid and lymphoid marker panels. 20 patients from the overall cohort treated with ICI were designated ‘responders’ (complete response, partial response, stable disease) and 20 patients were identified as non-responders (progressive disease) based on ICI best clinical/radiographic response. WSIs were divided into small non-overlapping image patches. These image tiles were processed into multiple AI encoder models to extract morphological features. The tile morphological features, represented by high dimensional vectors, were combined by an aggregation model to represent the whole slide morphology and then used to classify the patients into responders vs non-responders to immunotherapy. Area-under-the-receiver operating characteristic (AUC) was used to measure the performance of response prediction. Results: Our method shows AUC of 0.708 at classification of the patients (n=40) into responder and non-responder groups. With a cutoff that identifies the top 50% patients (n=20) of high probability of responding to immunotherapy predicted by our models, 75% of them are responders. In the bottom 50% patients (n=20) of the low scores, 75% of them are non-responders. . Multiplex IHC (myeloid and lymphoid panel) was performed using adjacent sections and were characterized yielding deeper mechanistic insight into the inflammatory populations driving predictive morphologic patterns. Conclusions: By applying innovative AI morphological analysis on patient WSIs, we generated a computational biomarker that shows promising ability to predict patient response to immunotherapy in bladder cancer. This approach merits future prospective validation and additional patient level analysis in broader cohorts. [Table: see text]
Longitudinal whole exome sequencing of cell-free DNA in advanced bladder cancer.
Authors: Arvind Ravi, Ilana Epstein, Dory Freeman, Praful Ravi, Tim Coorens, Brian Danysh, Mendy Miller, Ignaty Leshchiner, Julian Hess, Chip Stewart, Irbaz Bin Riaz, Bradley Alexander McGregor, Joaquim Bellmunt, Eliezer Mendel Van Allen, Charlene Mantia, Kerry L. Kilbridge, Timothy Clinton, Matthew Mossanen, Kent William Mouw, Michelle S. Hirsch
Journal: Journal of Clinical Oncology (2024)

681 Background: The recent approval of agents from novel therapeutic classes including immunotherapy and antibody-drug conjugates has transformed the treatment landscape of advanced bladder cancer. However, even among patients with initially favorable responses to therapy, a subset of patients develop acquired resistance for reasons that are yet to be fully elucidated. Methods: To gain insight into the dynamics of tumor evolution during the course of treatment, we performed longitudinal profiling of plasma cell-free DNA in a cohort of 71 patients with muscle-invasive or advanced disease before, during, and/or after specific lines of therapy. To further resolve evolutionary dynamics during the course of treatment, we additionally performed Whole Exome Sequencing (WES) on 47 plasma samples across 25 patients. Results: We observed a median tumor purity of 3.8% in the plasma with a range from undetectable (N = 24 samples out of 217 total) to 61%, with tumor purity generally increasing in patients with progressing disease as compared to stable (p = 0.037) or to responding disease (p = 0.002), consistent with the notion that tumor DNA content in the circulation may act as a proxy for overall tumor burden. Phylogenetic reconstruction in 14 patients using WES data identified growing subclones with potential resistance drivers including TP53, PTEN, and FAM46C. In addition, we identified two cases in which growing subclones showed few shared mutations with regressing clones, demonstrating instead largely distinct somatic mutation profiles. Conclusions: Longitudinal WES of cfDNA is feasible in a subset of advanced bladder cancer patients with sufficiently high tumor purity in the blood. In addition, based on our findings of substantial variation in somatic mutations within two reconstructed patient phylogenies, we hypothesize that acquired resistance could in some cases be enabled by marked transitions in the neoantigen repertoire.