tbuckley/cabot-search huggingface dataset:
Real world outcomes of first line (1L) nivolumab and ipilimumab (NIVO IPI) in metastatic renal cell carcinoma (mRCC): An update from the International mRCC Database Consortium (IMDC).
Authors: Connor Wells, Evan Ferrier, Audreylie Lemelin, Thomas Powles, Sumanta Kumar Pal, Hedyeh Ebrahimi, Neeraj Agarwal, Benoit Beuselinck, Georg A. Bjarnason, Lori Wood, Christina M. Canil, Renee Maria Saliby, Guillermo de Velasco, Rana R. McKay, Ben Tran, Cristina Suárez, Arnoud J. Templeton, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2024)

395 Background: NIVO IPI is one of several 1L treatment options for mRCC and is limited to intermediate and poor risk disease in many jurisdictions. We report the outcomes of 1L NIVO IPI from the IMDC. Methods: All IMDC patients who received 1L NIVO IPI were retrospectively analyzed. Key outcomes were compared between IMDC risk groups and included overall survival (OS), time to treatment discontinuation (TTD), time to next treatment (TTNT; defined as time from 1L initiation to next treatment) and response rates. Conditional OS by 6- and 12-month survival are described. Results: 1145 patients received 1L NIVO IPI, including 94 favourable, 559 intermediate, and 313 poor risk patients. 818/980 (86%) of patients had clear cell histology and 14% had sarcomatoid features. The median follow up was 20.0 months. 837/1145 (73%) patients had stopped 1L NIVO IPI and 363/1145 (32%) were deceased. Key outcomes of interest are summarized in Table 1. Subsequent 2L therapy was received by 438/727 (60%) patients and was most frequently sunitinib (37%) and cabozantinib (28%). 3L therapy was received by 160/477 (34%) patients, most often cabozantinib (29%). Immune related adverse events were documented in 48% (274/572) of patients. Conditional survival analysis showed that if a patient was alive at 6 months after starting 1L NIVO IPI, they had an 81% likelihood of being alive for an additional year and a 68% likelihood of surviving two years. If alive at 12 months, there was an 81% chance of surviving one additional year and 68% chance of surviving two additional years. If a patient remained on 1L NIVO IPI for 6 months, there was a 91% likelihood of being alive for one additional year and 76% likelihood of being alive for two years. If they remained on NIVO IPI for 12 months, there was a 94% chance of being alive for one additional year and an 84% chance of surviving two additional years. Conclusions: This large cohort of real-world patients provides benchmark data for clinical trial design and patient counselling, with a median OS surpassing 50 months for intermediate risk patients.[Table: see text]
Comparative cost-effectiveness of trimodal therapy and radical cystectomy for management of muscle-invasive bladder cancer.
Authors: Daniel D. Joyce, Kevin Wymer, Stephen A. Boorjian, John L. Gore, Ali Raza Khaki, Ann Caroline Raldow, Stephen B. Williams, Angela B. Smith, Vidit Sharma
Journal: Journal of Clinical Oncology (2024)

572 Background: Bladder preservation with trimodal therapy (TMT), which consists of maximal transurethral resection of bladder tumors followed by chemoradiation, is now included in guidelines with radical cystectomy (RC) as options for definitive management of muscle-invasive bladder cancer (MIBC). Prospective randomized controlled trial data to help guide treatment selection are lacking, and prior efforts to bridge this knowledge gap have failed primarily due to poor accrual. A recent retrospective analysis comparing TMT to RC reported similar oncologic outcomes between these treatments when performed in highly selected patients. However, treatment toxicities and costs vary significantly between these management options. To investigate the impact of these outcomes on relative treatment value, we evaluated the comparative cost-effectiveness of TMT and RC for treatment of MIBC. Methods: Cost-effectiveness was compared between TMT and RC for patients with a solitary, muscle-invasive tumor less than 7cm, no or unilateral hydronephrosis, limited carcinoma in situ, and adequate bladder function (criteria utilized in a recent retrospective comparative series) using a microsimulation model with a 5-year horizon from a Medicare payer perspective. Additionally, a 10-year lifetime horizon was evaluated to better understand the impact of long-term outcome uncertainty on cost-effectiveness. Based on recently published multicenter retrospective propensity score matched data, metastatic progression and survival probabilities were assumed to be equivalent between treatments. Utility values and additional probabilities, including both short and long-term treatment toxicities, were obtained from published literature. Primary outcomes of interest included effectiveness measured in quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) using a willingness-to-pay threshold of $100,000/QALY. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the model. Results: At 5 years, the average cost was $32,286.35 higher for TMT versus RC. The average QALYs were 3.88 and 3.96 for RC and TMT respectively. TMT was not cost-effective at 5-year (ICER: $379,917.21/QALY) or 10-year (ICER: $222,704.78/QALY) time horizons. On one-way sensitivity analyses, TMT would become cost effective if: 1) TMT costs were less than $16,152; or 2) TMT resulted in a 13.3% improvement in metastasis free survival relative to RC. Conclusions: Although it resulted in similar quality and duration of life, TMT was not cost-effective relative to RC at 5 and 10 years given higher treatment costs. These findings support the role of both TMT and RC in management of MIBC and highlight the need for continued efforts to reduce healthcare costs associated with TMT.
Endogenous retrovirus expression and its impact on tumor-infiltrating immune cells in papillary renal cell carcinoma.
Authors: Joseph Vento, Jared Brewer, Anupama Reddy, Aguirre De Cubas, Katy Beckermann, Brian I. Rini, W. Kimryn Rathmell, Scott Mattox Haake
Journal: Journal of Clinical Oncology (2024)

453 Background: Endogenous retroviruses (ERVs) represent 5-8% of the human genome, and their expression in cancer cells correlates with response to immunotherapy in clear cell renal cell carcinoma (ccRCC). Whether this association also exists in papillary renal cell carcinoma (PRCC) is unknown. Studying ERV expression in PRCC and its impact on the tumor microenvironment (TME) may help elucidate its role in PRCC response to immunotherapy. Methods: We quantified ERV expression on human PRCC tissue samples using real-time quantitative PCR (RT-qPCR). ERV4700 was selected due its correlation with response to immunotherapy when expressed in ccRCC. In addition, we stained matched human FFPE tissue with 31 antibodies using multiplex immunohistochemistry (mxIHC) to investigate the TME. Using mxIHC protein expression levels, we generated a probabilistic cell classification algorithm to quantify immune cells. We investigated associations between ERV expression data, clinicopathologic variables, and immune cell proportions in the tumor samples using linear regression. Results: We performed ERV expression and mxIHC analysis on 104 PRCC nephrectomy samples from 1997-2016. After quality control, 78 unique patient tumor samples had results from both pipelines. Median patient age was 65 (IQR 56-71), 74.4% were male, and Fuhrman grade was 1 in 3.9%, 2 in 5.9%, 3 in 50.0%, and 4 in 9.0% of patients. Over a median follow-up of 3.03 years (IQR 0.61-6.99 years), 11.5% had recurrence after definitive local therapy, and 7.7% had an RCC-related death. Increased ERV expression correlated with increasing Fuhrman grade (r = 0.057, p &lt;0.001), but not with disease recurrence or RCC-related death. Increased ERV expression was also associated with an increased TME proportion of cytotoxic T cells, memory T cells, and CD20+ B cells, and with a decreased TME proportion of macrophages (see Table 1). Conclusions: Higher expression of ERV4700 correlates with increased proportions of cytotoxic T cells in the TME of PRCC samples. Given its association with immunotherapy response in ccRCC, further studies are warranted to study ERV expression as a prognostic and predictive biomarker in PRCC. [Table: see text]
SWOG S2200 (PAPMET2): A phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC).
Authors: Benjamin L. Maughan, Melissa Plets, Sumanta Kumar Pal, Yasser Ged, Catherine Tangen, Ulka N. Vaishampayan, Seth P. Lerner, Ian M. Thompson
Journal: Journal of Clinical Oncology (2024)

TPS493 Background: The role of immune therapy is not established in PRCC. The S1500 (PAPMET) clinical trial established single agent cabozantinib as the standard of care for PRCC (PMID 33592176) with a median progression free survival (PFS) of 9.0 months compared to 5.6 months with sunitinib. Trials have shown activity of PD-(L)1 antagonists as monotherapy (PMID 33529058) or in combination with targeted therapy (PMID 34491815). In a single arm study of cabozantinib/nivolumab the median PFS was 12.5 months (PMID 35298296). There are no prior randomized studies of immune therapy in PRCC. Single arm trials often overestimate the true effect size (PMID 31218346), highlighting the unmet clinical need for a randomized clinical trial in PRCC. We hypothesize that the combination will have higher clinical activity than single agent cabozantinib. Methods: This is a prospective randomized phase II clinical trial conducted through the NCTN and led by SWOG. The primary endpoint is a comparison of PFS between cabozantinib and cabozantinib/atezolizumab. Secondary endpoints include comparison of objective response rate, overall survival and safety. Patients are treated with cabozantinib 60mg/day versus cabozantinib 60mg/day + atezolizumab 1200 mg q3 weeks. 200 patients will be enrolled and randomized 1:1. Key inclusion criteria include a pathologic confirmation of PRCC; presence of metastasis; 0-1 prior systemic lines of therapy for metastatic disease; and measurable disease as defined by RECIST 1.1 criteria. Prior treatment with adjuvant pembrolizumab is allowed if completed greater than 6 months before enrollment. Key exclusion criteria include clinically significant autoimmune disease; ongoing use of strong CYP3A4 inhibitors, strong CYP3A4 inducers. Planned correlatives include stool microbiome testing and genomic/transcriptomic analysis from blood and baseline tissue assays. Clinical trial information: NCT05411081 .
Identification and characterization of prognostic isoforms associated with bladder cancer outcomes.
Authors: Christopher Patsalis, Armand Bankhead, Phillip Lee Palmbos
Journal: Journal of Clinical Oncology (2024)

683 Background: Alternative splicing events can represent driver aberrations in cancer the same way as mutations, copy number changes, and gene fusions. We previously identified TP63 isoforms that were associated with prognosis in patients with bladder cancer and other tumor types. However, little is known about how isoform expression heterogeneity in other genes contributes to outcomes in bladder cancer. We hypothesized that expression of alternative isoforms in bladder cancer would be associated with clinical outcomes in a manner distinct from previously seen gene level associations. Methods: To examine this, we developed a high-throughput approach to identify and characterize prognostic gene isoforms that are associated with worse prognosis using RNA-sequencing data from The Cancer Genome Atlas (TCGA) bladder cancer cohort (BLCA). To identify gene isoforms that associate with bladder cancer outcomes, we aligned patient reads using HISAT2 and quantified expression for 69,272 isoforms using the Refseq isoform definitions from NCBI and the Stringtie algorithm. We filtered our quantifications to isoforms that belong to a gene with two or more isoforms, and those that had &gt;0.1 Log2 TPM expression. The remaining 42,798 isoforms were tested for association with overall survival using cox regression and based on the following criteria: an isoform had to have a Hazard Ratio greater than 1 with a p-value &lt; 0.05, an FDR adjusted p-value &lt; 0.2 for a log-rank survival statistic using 3 quantile expression thresholds (25, 50 and 75 th ), and no significant gene-level association with disease prognosis. We validated our quantifications by confirming read coverage at the unique splice junctions for each isoform and by RT-PCR. We then performed differential expression and pathway enrichment analyses for tumors with or without expression of each pathogenic isoform. Results: 34 individual isoforms (from 30 genes) fit the criteria for association with survival. Several isoforms identified by our screen, such as FLNB, AXL, and COL6A3 isoforms, were previously shown to be associated with cancer outcomes in other tumor types. Expression of 7 isoforms were confirmed in human bladder cancer (2 isoforms of COL6A1, APLP2, TIAL1, and 1 isoform of FLNB) using RT-PCR. Expression of 21 of these prognostic isoforms were enriched in the aggressive basal squamous molecular subtype. Pathway analysis of TCGA BLCA tumors expressing these isoforms revealed enrichment of gene pathways associated with invasive cancer phenotypes, such as epithelial to mesenchymal transition and MYC targets. Conclusions: Specific isoforms are significantly associated with bladder cancer patient survival and suggest that splicing events in certain genes may act as driver aberrations in bladder cancer. Further work will need to be done to establish the regulatory mechanisms as well as how these isoforms contribute to cancer progression.
Serum IgG: A potential biomarker for predicting the efficacy of systemic therapy in metastatic renal cell carcinoma.
Authors: Honglei Cui, Jie Wu, Rui-Yang Xie, Gan Du, Bing-Qing Shang, Xin Dong, Yan Song, Wang Qu, Hongsong Bai, Youyan Guan, Hongzhe Shi, Xin-Gang Bi, Ai-Ping Zhou, Jianzhong Shou
Journal: Journal of Clinical Oncology (2024)

442 Background: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) and tyrosine kinase inhibitor (TKI) are the main treatment strategies that have significantly improved outcomes of metastatic renal cell carcinoma (mRCC) patients. However, there are no effective biomarkers available to predict the efficacy of these regimens. We aim to explore the predictive value of serum immunoglobulin G (IgG) in systemic treatment. Methods: The study consisted of 292 mRCC patients who received TKI or IO-TKI therapy. Serum IgG in the pre-treatment baseline, 1 month, and 3 months after systemic treatment were measured using the immunoturbidimetric method. The Wilcox test was used to compare baseline serum IgG levels and paired t-test was utilized to compare serum IgG levels between baseline and 3 months after treatment. Kaplan-Meier curve were used to evaluate the PFS and Cox proportional hazard regression analysis was conducted to identify independent determinant factors for PFS. Results: The baseline level of IgG was not associated with objective response rate (ORR) in the overall patient cohort. However, there was a significant decrease in IgG in patients achieving CR/PR and an increase in patients with SD/PD after 3 months of treatment (p&lt;0.05). In the TKI cohort, the estimated 9-month PFS was significantly higher in the IgG-decrease group versus the IgG-increase group (HR 2.5, 95%CI 1.8-3.4, p&lt;0.001). The results were similar in the IO-TKI cohort. The predictive value of alteration of IgG after 1-month treatment was demonstrated in terms of the estimated 9-month PFS (HR 1.5, 95%CI 1.0-2.3, p=0·048). The ROC curve showed outstanding performance of alteration of serum IgG in predicting PFS. Conclusions: Alteration of serum IgG after systemic treatment is a reliable biomarker to predict the efficacy in mRCC patients. The change of IgG after 1-month treatment could serve as indicator of treatment efficacy and improve individualized drug selection. Further validation is warranted.
Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d’Etude des Tumeurs Uro-Genitales) study.
Authors: Florian Carneiro, Armelle Vinceneux, Mathieu Larroquette, Maelle Rony, Lucia Carril, Brigitte Laguerre, Ilfad Blazevic, Philippe Barthelemy, Diego Teyssonneau, Morgan Goujon, Claude Linassier, Antoine Thiery-Vuillemin, Guilhem Roubaud, Loic Mourey, Laurence Albiges, Gwenaelle Gravis, Marine Gross-Goupil, Mathilde Cancel
Journal: Journal of Clinical Oncology (2024)

391 Background: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. Objectives: To report clinical presentations, patients’ characteristics, therapeutic strategies, and prognosis of GIMs from RCC. Methods: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. Results: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of the patients already had other metastases. GIMs occurred after a median of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. The management of GIMs consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. Conclusions: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether they are symptomatic.
Role of geriatric assessment and oncological multidimensional prognostic index (Onco-MPI) in a real-world cohort of elderly patients with advanced urothelial carcinoma.
Authors: Davide Bimbatti, Nicolò Cavasin, Eleonora Bergo, Chiara De Toni, Eleonora Lai, Elisa Erbetta, Salim Jubran, Francesco Pierantoni, Camilla Ruffini, Antonella Brunello, Umberto Basso, Marco Maruzzo
Journal: Journal of Clinical Oncology (2024)

563 Background: At least 75% of bladder cancer (BC) are diagnosed in adults aged ≥65 years, with a median of 72 years. Older adults have poor outcomes but are also an heterogeneous population in which the functional status often does not reflect the chronological age. ASCO and SIOG recommend the use of geriatric assessment (GA) to guide management of these patients (pts) but very few data are present to date. Methods: We investigated the role of GA and an oncological version of MPI in pts ≥70 years old affected by advanced/metastatic urothelial carcinoma. Data were retrieved from a prospectively maintained database from 2010 to 2022. Comprehensive GA (CGA) is a multidimensional tool used to classify pts as fit, vulnerable and frail according to Balducci’s criteria. Onco-MPI was calculated by a validated algorithm derived from different GA domains and tumour characteristics. We also collected characteristics of pts, tumors and treatment regimens. Correlation between GA and treatments used and oncological outcomes were analysed. Results: Complete data and follow up were available for 181 patients. Pts characteristics are reported in Table 1. According to Onco-MPI all the pts but 7 were at high risk. The mFU was 46.2 months, while mOS was 8.2 months. Balducci’s CGA and Bellmunt groups had a concordance of 58%, p&lt;0.01. Strong correlations between these scores and type of treatment received were found (pts fit or 0 score received more often a platinum-based treatment without reduction dose while frail or 2-3 score received more often treatment with a reduced dose or no treatment at all, p&lt;0.01). The two scores have a strong prognostic value (18.5 vs 10.8 vs 3.8 months, p&lt;0.01; 21.9 vs 8.5 vs 4.1 months, p&lt;0.01, respectively for CGA and Bellmunt subgroups). At univariate analysis also timing of mets, number of sites, type of treatment and dose were good prognostic variables. All these variables retained their prognostic value at a multivariate analysis incorporating each of the two scores separately. Conclusions: CGA has a great prognostic value in older adults with metastatic urothelial cancer. This tool could help in decision making and patients stratification but validation in prospective cohort is needed. Onco-MPI could also be useful but new cut offs must be set in this specific population.[Table: see text]
Hypoxia-inducible factor-2 alpha (HIF-2α) target activation and clinical outcomes in 942 patients with clear cell renal cell carcinoma.
Authors: Sahil D Doshi, Fengshen Kuo, Andrea Knezevic, Ritesh R Kotecha, Robert J. Motzer, A. Ari Hakimi, Martin H Voss
Journal: Journal of Clinical Oncology (2024)

445 Background: Von Hippel Lindau ( VHL) gene function is uniformly lost in clear cell renal cell carcinoma (ccRCC) with consequent accumulation of hypoxia inducible factor 2 alpha (HIF-2α). HIF-2α inhibitors have entered the clinical arena as a new class of agents, alone and in combinations. While VHL loss is thought to result in broad increase of HIF-2α activity, preclinical data suggests that HIF-2α target activation varies across patients. Xenograft response to HIF-2α inhibition helped define an RNA-based HIF-2α target signature (SIG) comprising 277 genes downregulated with treatment (Courtney et al. CCR 2020). We applied this signature in our analysis of two large cohorts. Methods: Retrospective analyses were conducted using two cohorts: 533 tumors from the Cancer Genome Atlas Project (TCGA) with emphasis on early-stage disease and 409 archival tumors collected from patients receiving pazopanib or sunitinib on the phase 3 COMPARZ trial in metastatic RCC. Using single-sample gene set enrichment analysis (ssGSEA), enrichment scores were calculated for HIF-2α-SIG and a previously validated 6 gene tumor angiogenesis SIG (McDermott et al. Nat Med 2020). Individual patients were classified as “high” vs “low” for each (enrichment scores &lt; vs ≥ median). We tested associations of HIF-2α and angiogenesis scores with overall survival (OS) using the Kaplan Meier Method and log-rank comparison. Results: In the TCGA cohort, patients with “high” HIF-2α-SIG had inferior median OS compared to those with “low” levels (69 months [95% CI 53-117] vs 'not reached', log-rank p&lt;0.0001). In the metastatic COMPARZ cohort, “high” HIF-2α-SIG associated adversely with median OS (27 months [95% CI 21-32] vs 36 months [95% CI 28-not reached], log-rank p=0.0240) while angiogenesis scores associated favorably. In both cohorts the majority of HIF-2α “high” patients categorized “low” for angiogenesis and vice versa. Associations amongst HIF-2α-SIG, angiogenesis-SIG, and OS are summarized below (Table). Conclusions: HIF-2α target activation was adversely associated with survival in early and late stage ccRCC while angiogenesis scores correlated favorably. HIF-2α targets other than VEGF appear to have clinical impact and should be explored. HIF-2α-SIG may prove helpful for clinical development of targeted HIF-2α inhibitors and deserves further study.[Table: see text]