bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell analysis of CD8+ T-cells by sex in renal cell carcinoma.
Authors: Kang Ning
Published: June 2023

e16501

Background: Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC patients and explored a promising combination drug regimen to enhance the efficacy of immunotherapy. Methods: Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments. Results: By analyzing the scRNA-seq data of 220,156 cells and MxIF and FCM assays, we found that CD8+ T-cells infiltrated highly in the TME of male RCC, but mainly presented an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo. Conclusions: We delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Clinically, androgen receptor inhibitors plus immunotherapy can be a promising combination regimen in RCC patients.
Detection of progression and regression of genitourinary cancers by circulating tumor DNA (ctDNA).
Authors: Karki Ujjwal , Ghimire Bipin , Herrman Emma , Chisti Mohammad Muhsin
Published: June 2023

e16508

Background: Circulating tumor DNA (ctDNA) are short DNA sequences shed by tumor cells into systemic circulation. The sensitivity and specificity of single ctDNA test to predict relapse or recurrence in solid tumor vary widely and the utility of monitoring serial ctDNA trends has not been well-described in genitourinary cancers. Methods: We conducted a retrospective study including adult patients with genitourinary cancers at the hematology-oncology clinic at William Beaumont - Royal Oak and Troy Hospitals, Michigan from, August 2021 to May 2022, who had ctDNA testing done with imaging available for comparison. We evaluated the correlation between ctDNA test, both single test as well as dynamic trends in value over time, with imaging findings. We also calculated lead time for uptrending ctDNA to detect disease progression compared to imaging. Results: 21 total ctDNA test results from eight patient were included in the study; five had renal cell cancer, two had urothelial cancer and one had prostate cancer. The median age at diagnosis was 62 years (Range: 45-82); 90% were Caucasian and 50% were female. Majority (87.5%) had Stage III or IV disease. Out of the 21 total ctDNA samples, all 16 positive ctDNA results had evidence of disease on corresponding imaging: 13 showed progression while 3 showed regression with residual disease compared to prior imaging. Of the 5 negative ctDNA test results, 2 showed no evidence of disease and 3 showed regression with residual disease on corresponding imaging. Sensitivity and specificity of a single positive ctDNA test to detect evidence of disease on imaging was 84.2% and 100%, respectively. Six patients had multiple ctDNA test results with 12 pairs of serial ctDNA values, of which 9 were up-trending, and 3 were down-trending. Both sensitivity and specificity of up-trending ctDNA values to detect progression and down-trending ctDNA values to detect regression on imaging were 100%. Uptrending ctDNA values predicted disease progression with a median lead time of 55.5 days compared to imaging. Conclusions: Given the high sensitivity and specificity of serial ctDNA monitoring to detect disease progression and regression in our study, we conclude that this may be a valid way to reliably monitor for changes in disease status in genitourinary cancers before they become evident on imaging studies. Further clinical studies are needed to prove its utility in detecting immediate changes in disease status and guide therapeutic intervention in genitourinary cancers. [Table: see text] [Table: see text]
Nivolumab as second-line treatment of patients with metastatic renal cell carcinoma with high or normal fibrinogen levels: A prospective, cohort study.
Authors: Tsimafeyeu Ilya , Volkova Maria , Utyashev Igor A. , Gerk Ivan , Zakurdaeva Kristina
Published: June 2023

e16510

Background: In a number of coagulation-related studies, elevated fibrinogen levels were found in patients with renal cell carcinoma (RCC) and correlated with more advanced disease. The impact of hyperfibrinogenemia on the clinical outcomes of immunotherapy remains uncertain. Methods: In this prospective cohort study, fibrinogen levels were measured one week prior to the second-line nivolumab therapy (240 mg or 480 mg every 2 or 4 weeks) and then monthly until disease progression or unacceptable toxicity. High fibrinogen level was defined as ≤5 g/L. Key eligibility criteria included metastatic clear cell RCC resistant to the first-line targeted therapy, ≤3 MSKCC risk factors, ECOG PS 0-2, platelet count <400×10(9)/L, no heart diseases, no anticoagulation therapy, and age 40-65 years. The primary endpoint was overall survival (OS) in cohorts with high (H) and normal (N) fibrinogen levels. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and fibrinogen levels during therapy. Results: Between November 2018 and January 2021, 82 patients were enrolled, of whom 41 and 41, respectively, were recruited in H and N cohorts. The groups were well balanced at baseline. The median follow-up time was 32.4 months. Compared to patients in N cohort, patients in H cohort had shorter OS (P=0.001), shorter PFS (P<0.01), and lower ORR (P=0.012). In H cohort, a below-median fibrinogen level was associated with longer observed OS (median, 23.7 vs. 19.4 months; P=0.03). In N cohort, 6 (15%) patients with stable disease had an increase in fibrinogen levels during nivolumab therapy. Patient characteristics and clinical outcomes are summarized. Conclusions: High fibrinogen levels affect the clinical outcomes in patients with metastatic renal cell carcinoma treated with second-line nivolumab. These findings require large-scale prospective validation. Clinical trial information: KCRB0181209 . [Table: see text]
Uncovering LAG-3 related tumor immunology in renal cell carcinoma and pan-cancer evaluation.
Authors: Takamatsu Kimiharu , Tanaka Nobuyuki , Matsumoto Kazuhiro , Kosaka Takeo , Mizuno Ryuichi , Oya Mototsugu
Published: June 2023

e16517

Background: LAG-3 (lymphocyte activation gene 3) is of interest as a target molecule for next-generation immune checkpoint inhibitors in several solid tumors, including renal cell carcinoma (RCC). The aim of this study is uncovering the tumor immune microenvironment (TIME) of the LAG-3-dominant RCC. Methods: Firstly, we performed an automated single-cell count for immunolabelled LAG-3, TIM-3 and TIGIT and TIME evaluation panel molecules (CD3, CD8, CD39, PD1, PDL1, Ctla4, CD68, CD163, CD47, Ki67, CD73, IDO1, GLUT1, CD34 and D2-40) to 105 primary ccRCC tumor samples and created the new classification model. The TIME and clinical value of LAG-3-dominant RCC were evaluated. Secondly, The TIME features of LAG-3 dominant RCC in metastatic sites was evaluated in 47 metastatic samples. Lastly, mRNA seq data from the public cohort and clinical trial data (RCC, n = 1144, other solid cancers, n = 3691) was analyzed with the digital cytometry and evaluated whether the TIME features of LAG-3 dominant RCC are RCC-specific or applicable to other solid tumors. Results: In our cohort and our validated cohort (n = 96), the LAG-3 group had significantly shorter OS (p = 0.037 and p = 0.003). The LAG-3 high expression RCC also showed shorter OS in the TCGA RCC cohort (p = 0.016). As the result of TIME evaluation, LAG-3 dominant RCCs had statistically high level of CD8, high CD39+CD8+, and high M2 macrophages. In metastasis samples, LAG-3 dominant RCCs preserved high level of CD8, high CD39+CD8+. In public mRNA seq analysis, LAG-3 dominant RCCs showed high level of CD8, high CD8+Tregs and high M2 macrophages. High Tregs in LAG-3 dominant tumor were seen in melanoma, HCC and prostate cancer. High M2 macrophage TIME in LAG-3 dominant tumor was unique to RCC, not seen in other solid cancer. Conclusions: LAG-3 dominant RCC had poor prognosis and could exhibit a unique, immunosuppressive TIME.
Outcomes and safety of subsequent treatments after immune- and anti-VEGF therapy in patients with metastatic clear-cell renal cell carcinoma: Outcomes from a tertiary referral hospital.
Authors: Tapia Jose Carlos , Toms Charlotte , Wang Yishen , Jovaisaite Agne , Young Matthew Nicholas , Jackson-Spence Francesca , Powles Thomas , Szabados Bernadett
Published: June 2023

e16533

Background: Immune checkpoint inhibitors (ICIs) and anti-VEGFs, either in combination or sequentially, are the standard of care in first- and second-line (2L) setting for metastatic clear-cell renal cell carcinoma (mRCC); however, there is uncertainty about the subsequent lines. We describe real-world outcomes and safety of using anti-VEGFs such as cabozantinib (CABO), axitinib (AXI), and sunitinib (SUN) after ICIs and anti-VEGF therapies in patients (pts) with mRCC. Methods: A retrospective audit was performed on pts with mRCC treated between June 2014 and June 2022 at the St Bartholomew’s Hospital, London, UK. Baseline patient and treatment characteristics, best response, dose modifications and survival outcomes were collected. Kaplan-Meier methods were used to evaluate the progression-free survival (PFS) and overall survival (OS). Results: Overall, 188 pts with mRCC were treated. We analysed 69 pts of whom 45 (65%), 16 (23%) and 8 (12%) pts received CABO, AXI, and SUN, respectively, as subsequent treatment after prior ICIs and anti-VEG. Baseline characteristics are described. Median follow-up was 36 months (95% CI: 31.6 - 55.3). Overall, the partial response (PR) and stable disease (SD) rates were 9% and 45%, respectively. Eleven percent, 12% and 0% pts achieved PR and 53%, 25% and 31% achieved SD on CABO, SUN and AXI, respectively. In general, the median PFS was 9.9 months (95% CI: 6.5-14.2) and the median OS was 16.5 months (95% CI: 11.6-23.5). One-year PFS and 1-year OS was 36% and 51%, respectively. PFS and OS by treatment are reported. The number of pts who experienced toxicities that required dose reductions was higher with CABO (58%) and SUN (37%) than with AXI (6%). The median time to dose reduction was 2.4, 1.4, and 1.4 months for CABO, SUN and AXI. Conclusions: In our centre, CABO was the most common subsequent treatment after previous ICIs and anti-VEGF. Taking into account the retrospective and single-centre nature of the collected data these results support the activity of CABO, AXI and SUN in this setting. AXI was well tolerated with less dose modifications. [Table: see text]
Efficacy of subsequent immunotherapy-tyrosine kinase inhibitor combinations after TKI monotherapy failure in patients with intermediate/poor risk metastatic clear cell renal cell carcinoma: A real-world retrospective study.
Authors: Wu Jie , Qu Wang , Hu Linjun , Zhou Aiping , Shou Jianzhong
Published: June 2023

e16537

Background: The randomized phase 3 trials KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated the efficiency of immunotherapy-based drug combinations as first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). Immunotherapy-tyrosine kinase inhibitor (IO-TKI) has shown significant benefits over sunitinib monotherapy with respect to overall survival in mccRCC patients with intermediate/poor international metastatic database consortium (IMDC risk group). However, most of the patients received second-line TKI or immune checkpoint inhibitors therapy after TKI monotherapy failure in those clinical trials. The role of IO-TKI after disease progression in sunitinib monotherapy cohort was not fully investigated. We sought to evaluate the efficacy of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk who had previously received at least one line of TKI monotherapy. Methods: We conducted retrospective analysis of IMDC intermediate/poor risk mccRCC patients treated with IO-TKI during any treatment line at our center from June 2019 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The primary end point was overall survival (OS), defined as the time from initiation of treatment to death from any cause or last follow-up. The secondary end point was progression-free survival (PFS), defined as the time to the first documented disease progression. Results: Overall, 81 IMDC intermediate/poor risk mccRCC patients were enrolled, with a median follow-up of 17 months. 49 patients received first-line IO-TKI therapy, 32 patients who had previously received at least one line of TKI monotherapy received second-line IO-TKI after disease progression. The objective response rate (ORR) and median PFS of second-line IO-TKI after TKI monotherapy failure was 28.6% and 9 months, respectively. OS between first-line IO-TKI therapy and second-line IO-TKI after TKI monotherapy failure was not statistic significant (30 months vs. 26 months, p = 0.630). Conclusions: In this real-world retrospective study, we observed antitumor activity of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk after disease progression. Notably, first-line IO-TKI therapy did not have superior OS when TKI monotherapy patients received second-line IO-TKI therapy. Randomized trials are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.
Urine-based epigenetic profiling for detection of clear cell renal cell carcinoma: A prospective study.
Authors: Kong Wen , Zhang Jin , Dong Hang , Tang Haoran , Du Pan , Jia Shidong
Published: June 2023

e16545

Background: Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that poses a significant challenge in early detection and differentiation from other subtypes in clinical practice. Liquid biopsy using epigenomic signatures represents a potential solution for non-invasive cancer detection and disease surveillance. Methods: In this prospective study, aiming to collect matched tissue-plasma-urine samples from 200 ccRCC patients and 50 non-tumor donors, we enrolled 14 patients with ccRCC and 10 patients with benign kidney lesions. Matched samples (tissue, blood, and urine) were collected and analyzed using the DNA methylation assay, PredicineEPIC. An in-house developed bioinformatics algorithm was used to investigate the genome-wide epigenomic profiles, and a machine-learning model was built for tumor prediction based on tumor-specific methylation patterns. Further enrollment is ongoing. Results: In the exploratory cohort, tissue-based differential methylated regions (DMRs) profiling differentiated tumors from normal renal tissues with high accuracy. The ccRCC-specific methylation patterns were constructed with 637 optimized methylation features, and the machine learning classifier was trained. The prediction efficacy was tested in a larger-scale TCGA-KIRC dataset, which demonstrated high sensitivity and specificity (AUC = 0.985). Compared with the use of blood, urinary cell-free DNA-based methylation profiling allowed for the differentiation of ccRCC patients from healthy controls and patients with benign kidney lesions. Conclusions: The current preliminary study demonstrates the technical feasibility of urine-based methylation study in the identification of patients with ccRCC. Our findings highlight the potential of urine-based methylation profiling in kidney cancer detection and disease surveillance.
Immunotherapy-related toxicities: A retrospective analysis of barriers to prompt detection and initiation of treatment in renal cell carcinoma.
Authors: Zeter Daniel , Patel Ina J
Published: June 2023

e16547

Background: In 2021, there was an estimated 76,000 patients diagnosed with kidney cancer in the United States, and 90% of these patients were diagnosed with renal cell carcinoma (RCC). The current treatment for RCC is the use of immune checkpoint inhibitors (ICIs), which allow the body to naturally fight against cancer cells without impedance. A common side effect of this therapy, however, is immunotherapy-related adverse events (irAE), which are toxicities where the bodies overactive immune system attacks noncancerous organs. When irAEs arise, the patient’s immunotherapy is stopped, and a steroid regiment is begun to dampen the immune system before re-starting immunotherapy. Time is crucial when treating irAEs, and this study is aimed to identify barriers in the onset of steroid treatment and identify interventions that can help providers and patients identify toxicities and begin steroid treatment as soon as possible. Methods: We conducted a retrospective study analyzing adult patients (ages 18-75) being treated for RCC at UT Southwestern Medical Center and Moncrief Cancer Institute (MCI). We specifically looked at patients being treated with ipilimumab, nivolumab, and pembrolizumab. The first portion included a chart review to identify patients and identify barriers to prompt treatment, i.e. fear of worsening hyperglycemia in diabetics, access to healthcare, delay of re-initiating immunotherapy. The second portion of this study will be to identify and test a possible intervention for these patients to ensure timely recognition of toxicities and prompt initiation of steroids. Results: Upon review of 201 patients with RCC stage III/IV, the most common toxicity found was colitis (28.4%), followed by transaminitis (9.0%) and pneumonitis (9.0%). The most common method for identification of toxicities was routine lab work performed before immunotherapy administration (30.4%), check-ins at regularly scheduled appointments (21.7%), and after-hour physician telephone lines (19.6%). Additionally, the average time from irAE identification to steroid administration was 1.45 days. Excluding toxicities found either at office appointments or on routine lab work, the average time to steroids from identification was 3.55 days. Our data collection also demonstrated that routine labs were the most likely factor to identify immunotherapy toxicity in a timely manner. Conclusions: Continuation of current practices can lead to further decreases in time to steroid treatment. This study can be used as a blueprint and expanded to further investigate irAEs in other solid tumors as well as contribute to management of the ever-evolving immunotherapy landscape.
Updated analysis of real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.
Authors: Zakharia Yousef , Vlahiotis Anna , Siu Gordon , Rao Dharanija , Teresi Rosemary , Eccleston Anthony
Published: June 2023

e16553

Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Previous analyses described the demographic and clinical characteristics, as well as outcomes of patients receiving 1L AXI+PEM in a real-world setting. We report updated data with longer follow-up for this cohort. Methods: Electronic medical record data from the Flatiron Health, nationwide de-identified Database (280 cancer clinics across 800 sites in the US) were used to select patients with confirmed Stage IV/metastatic RCC and who initiated 1L AXI+PEM on or after 1/1/2018 to 7/31/2022. Analyses included best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, 12, 18 and 24 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and forty patients received 1L AXI+PEM, with an extended mean follow-up of 19.2 (0.1–41.6) months. Most patients were male (69.1%) and mean age of 64.1 (21.0–83.0) years. At diagnosis, 56.5% of patients had Stage IV RCC and 78.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 24 (6.8%), 123 (34.4%), and 78 (22.1%) patients, respectively (unknown = 125 (36.8%)). At the time of analysis, 192 patients (56.5%) received only 1L therapy with AXI+PEM, while 148 patients (43.5%) received ≥1 subsequent line of treatment. Vascular endothelial growth factor receptor (VEGF-R) inhibitors were the most commonly used second-line (2L) treatment (109 patients, 73.6%), with cabozantinib being the most frequently used VEGF-R inhibitor (84 patients, 77.1%). Median rwPFS was 8.6 (CI: 7.2-9.7) months with 15.0% of patients achieving rwPFS at 2 years. Median rwOS was 29.4 (CI: 24.2-37.3) months with 38.5% of patients alive at 2 years. Best overall response rate to 1L was 54.1% (complete or partial response observed in 184/340 patients). 51.5% of patients required a dose hold, of which 58.3% required it due to an adverse event. Conclusions: This updated analysis supports the use of 1L AXI+PEM in patients with advanced RCC across all IMDC risk groups, providing further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US. [Table: see text]
Clinical-pathological features and treatment outcomes in Hispanic/Latino patients with advanced renal cell carcinoma at a single institution.
Authors: Ocejo Gallegos Jesus Antonio , Murray Abner , Jones Sandra , Frias Rosa Lizeth , Noy Jose , Campoverde Leticia , Merchan Jaime R.
Published: June 2023

e16554

Background: Annually, there are over 400,000 new renal cell carcinoma (RCC) cases and more than 170,000 deaths worldwide. RCC is one of the top ten more prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. Studies demonstrate histologic differences and outcome disparities among Hispanic and Latino patients diagnosed with RCC. Research to date describes earlier and more advanced diseases at diagnosis, higher rates of obesity at presentation, and higher mortality among these cohorts. However, there is limited data on clinical, pathological, molecular, and treatment outcomes in this patient population. This study aims to characterize clinical features and treatment outcomes in this patient population in South Florida. Methods: We conducted a retrospective cohort study to describe the characteristics and rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami (which serves four counties in South Florida) between June 2010 to June 2022. An IRB-approved advanced RCC database was developed on RedCap, where clinical, laboratory, pathological, treatment, and response information were captured. Ethnicity was determined as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical groups were classified based on the last encounter as local RCC after nephrectomy, recurrent metastatic RCC after nephrectomy, and metastatic RCC at diagnosis/de novo. Results: We analyzed a total of 2048 patients aged 18 and older diagnosed with RCC, from which 1008 patients (47.70%) were identified as NHL and 963 (47.92%) as HL. RCC was in over a 2:1 ratio of men to women in both HLs and NHLs. A subtotal of 435 patients (22.87%) had metastatic RCC at diagnosis/de novo, from which 245 (55.59%) were NHL, and 175 (40.32%) were HL. A subtotal of 1613 patients (78.76%) were diagnosed with local RCC and underwent nephrectomy, from which 763 (45.46%) were identified as NHL and 788 (50.15%) as HL. From the NHL group that underwent nephrectomy, 222 patients (28.21%) had recurrent disease, and 541 patients (71.79%) did not. From the HL group, 175 patients (21.69%) had recurrent disease, and 613 (78.31%) did not. Overall, 408 patients had metastasis after nephrectomy, of which 175 (44.31%) were HL, and 203 (52.24%) were NHL. Conclusions: In this cohort of patients with RCC, over 40% of patients diagnosed with metastasis were HL. NHL appeared to have more disease recurrence after nephrectomy and higher rates of metastatic disease at diagnosis compared to Hispanics. Further histopathological differences, clinical outcomes, genomic characterization, and rates of clinical trial participation between the NHL and HL cohorts will be presented at the meeting, along with comparisons between US and foreign-born HLs.
Incidence and risk of peripheral sensory neuropathy with enfortumab vedotin in patients with advanced urothelial cancer: A systematic review and meta-analysis.
Authors: Shah Yousuf , Sher Amna Falak , Wu Shenhong
Published: June 2023

e16556

Background: Enfortumab Vedotin (EV), a first-in-class antibody-drug conjugate directed against Nectin-4, is associated with peripheral sensory neuropathy (SN) in the treatment of advanced urothelial cancers. A systematic literature review and meta-analysis were conducted to assess the overall incidence and risk of SN in patients receiving EV. Methods: A systematic search through mid-2022 of PubMed, Cochrane Library, and recent ASCO annual and genitourinary meetings was conducted to identify relevant studies. Eligible studies were clinical trials of patients with urothelial cancer receiving single-drug EV at the standard dose with data on SN available. Incidence and relative risk (RR) of SN were calculated using both a fixed-effects and a random-effects model. Results: Of the 93 initial publications identified, there were 5 trials that met the eligibility criteria and included a total 996 patients with 630 patients receiving EV at the standard dose. The summary incidence of all-grade SN was 42.3% (95% CI: 38.5-46.2%) with the incidence of high-grade SN being 3.1% (95% CI: 1.9-4.9%). In comparison with standard chemotherapy, there was no significant difference for EV in all-grade SN (RR = 0.95, 95% CI: 0.77-1.18, p = 0.66) and high-grade SN (RR = 1.69, 95% CI: 0.40-7.21, p = 0.48). In some cases, SN also led to discontinuation of EV (4.4%, 95% CI: 2.1-6.7%). Conclusions: EV is associated with a substantial toxicity of peripheral sensory neuropathy, and its risk may be comparable to that of standard chemotherapy. Further studies are needed to assess and reduce the risk of severe neuropathy.
Real-world use, dose intensity, and adherence to enfortumab vedotin (EV) in locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Tsingas Konstantinos , Parikh Ravi Bharat , Elsouda Dina , Mucha Lisa , Fuldeore Rupali , Hubbard Rebecca A. , Mamtani Ronac
Published: June 2023

e16567

Background: EV, the first antibody drug conjugate approved for la/mUC, received accelerated approval in the US in 2019 as later-line therapy (post-immunotherapy and platinum-chemotherapy) and regular approval in 2021 with label expansion to include earlier-line therapy (cisplatin-ineligible, ≥1 prior therapy). Because EV delivery per current labelling (1.25 mg/kg, D1, 8, 15 of a 28D cycle) may differ from routine practice, we examined real-world EV use, dose intensity and adherence across 280 US cancer clinics. Methods: This descriptive post-marketing retrospective cohort study used the Flatiron Health longitudinal database derived from EHR records of US patients with la/mUC initiating EV on or after December 19, 2019. We summarized EV use, including but not limited to: % cisplatin-ineligible, and median duration of use and number of cycles administered. We computed metrics of dose intensity: average treatment rate (mean number of treatments per patient-month), dosing frequency (mean number of treatments per cycle), dose (mean dose, mg/kg), and % change in dose (mg) from baseline (difference in dose between last recorded treatment in last cycle and first recorded treatment in first cycle). Finally, we measured treatment adherence, defined as % of cycles across all patients where a patient had > 2 treatments per 28D cycle. Results: Among patients with la/mUC, we identified 416 EV users (mean [SD] age 71 [9] years, 27.4% female, 24.8% non-white, 70.2% prior smokers, 17.5% ECOG 2+, 81.5% from community sites). EV use, dose intensity, and adherence are shown (table). Most were cisplatin-ineligible (55%). Average dosing frequency (2.4 [0.5] treatments per cycle) and dose (1.1 [0.2] mg/kg) were lower than label indication guidelines; 58.8% received > 2 treatments per 28D cycle. Conclusions: Among la/mUC patients treated with EV in contemporary practice, treatment frequency and dosing were lower than recommended in the product labelling. Further research is required to understand clinical factors and outcomes associated with the differences observed. [Table: see text]
Identification of biomarkers for early progression in muscle invasive bladder cancer (MIBC) using real-world data.
Authors: Singh Neeraj , George Rohini , Agrawal Smita
Published: June 2023

e16568

Background: MIBC accounts for ~25% of all newly diagnosed bladder cancers and is associated with a high rate of recurrence despite radical treatment. The time to progression (TTP) can vary significantly between patients and can affect their prognosis. We leveraged a real world clinico-genomics database to classify patients as early vs late progressors, understand its impact on their outcomes and identify genetic drivers of early progression. Methods: This retrospective study was executed using the deeply curated ConcertAI Genome360 bladder cancer dataset. Only patients with confirmed MIBC status with reported tumor progression after initial treatment were considered. Based on the distribution of TTP from MIBC diagnosis of this patient cohort, we subdivided the patients into early vs late progressors. Overall survival (OS) and progression free survival (PFS) analyses were performed between these 2 cohorts. The underlying deleterious genomic mutations were identified in each cohort and differential genomic enrichment analysis was performed to identify statistically significant biomarkers correlated with early progression (p-value < = 0.05). Additionally, identified biomarkers were analyzed in the context of administered therapies. Results: The TTP exhibited a bimodal distribution with a break at around 500 days, so we chose this as the cut-off to define early (N = 203) vs late progressors (N = 51). As expected, there was a significant difference in the median PFS of early vs late progressors (0.62 vs 2.41 years (p < 1e-6)). The OS was also significantly different (1.98 vs 4.36 years (p = 6e-6)). We further identified mutations in 6 biomarkers which were enriched in early vs late progressors. These were CDK12 (p = 0.05), EGFR (p = 0.034), LRP1B (p = 0.05), MET (p = 0.045), PTEN (p = 0.026) and SMAD4 (p = 0.047). These patients were primarily treated with platinum-based therapies +/- gemcitabine/PD-L1 therapies in-line with MIBC treatment guidelines. The identified driver genes activate PI3K-AKT-MTOR, JAK-STAT3, b-catenin and ERK pathways which are known to interfere with the mechanism of action of platinum-based therapies, thus potentially forming the basis of early progression. Conclusions: Using our Genome360 bladder dataset, we have identified prognostic biomarkers for early progression in MIBC. This may provide clinicians with a tool to identify and modify treatment for a subset of MIBC patients who are at risk of early progression on standard of care therapies.
Effects of treatment and patterns of metastases in upper tract and bladder urothelial cancer and non-urothelial cancer based on the national cancer database (NCDB) analysis.
Authors: Yu Eun-mi , Wang Hongkun , Aragon-Ching Jeanny B.
Published: June 2023

e16571

Background: Upper tract Urothelial cancer (UTUC) and bladder urothelial and non-urothelial cancers can have varying patterns of metastases and response to treatment. Given worse response of visceral metastases to current immune checkpoint inhibitors (ICI) and worse outcomes of non-urothelial cancers, understanding the incidence, characteristics and survival for different metastatic presentation would be informative. Methods: The primary objective is to describe characteristics, treatment patterns, evaluate trends and differences in metastatic presentation and survival according to NCDB between upper tract urothelial cancers (UTUC) versus non-urothelial (nUTUC) histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and bladder urothelial cancer (UC) and bladder non-urothelial cancer (nUC). Results: Extraction of data from diagnosis between year 2004 – 2017 from the NCDB was performed. A total of 649939 cases of whom UC = 630423 and nUC = 19516 for both bladder and upper tract cancers, respectively, were identified. Median age was 71.4 years (UC) and 70.1 years (nUC), with majority made up of men (62% of UTUC and 75% of bladder UC). Stage distribution at diagnosis was higher in nUC with Stage III at 1711 (8.8%, nUC) compared to 15725 (2.5%, UC) and Stage IV the nUC group (21.9%) compared to UC at 4.6%. Overall survival (OS) was worse with nUC for stage IV cancers with median OS (mOS) of 6.14 mos (95% CI 5.78-6.47) for nUC vs 7.92 mos (95% CI 7.75-8.08) for UC; logrank p < 0.001. Metastatic sites evaluated included bone, brain, liver, lung, and distant lymph nodes. mOS of Patients with visceral metastatic sites of disease are as follows: distant lymph nodes: UC: 7.59 mos (95% CI 6.6- 8.8); nUC: 5.62 mos (95% CI 4.1-7); log-rank p = 0.0372; liver: UC: 3.5 mos (95% CI 2.89-4.1); nUC: 4.1 mos (95% CI 2.6-6.83); p = 0.1874; lung: UC: 5.7 mos (95% CI 5.09-6.37); nUC: 4.27 mos (95% CI 2.99-6.74); p = 0.1567; Brain: UC: 3.06 mos (95% CI 2.1-4.24); nUC: 2.34 (95% CI 1.1-5.3), p = 0.5464. Use of chemotherapy resulted in improved OS in the UC group with mOS of 73.53 mos (95% CI 72.61-74.41) compared to nUC at 17.28 mos (95% CI 16.59-17.87), p < 0.0001 and use of ICI similarly yielded improvement in the UC group with mOS of 115.98 mos (95% CI 114.33-117.65) compared to nUC at 64.49 mos (95% CI 45.67-88.51); p < 0.0001 although radiation therapy resulted in less profound treatment effect with UC at 16.39 mos (95% CI 16.07-16.69) and nUC: 13.01 (95% CI 12.32-13.63); p < 0.0001. Conclusions: While treatment using chemotherapy and ICI has led to improvement in OS in higher stages of disease, patterns of metastases reveals visceral presentation portends a poor prognosis in both urothelial and non-urothelial cancers with slightly better mOS in those with distant lymph nodes as main presentation of metastases.
CDH12 and the development of the neuronal subtype in MIBC.
Authors: Chen Xingyu , Basu Mukta , Knott Simon , Theodorescu Dan
Published: June 2023

e16579

Background: We discovered a novel cell epithelial cell population we termed “C3” in muscle-invasive bladder cancer (MIBC) that is negatively prognostic for surgery and chemotherapy. This cell population shares similarities with the neuronal subtype MIBC (NEBC) which has limited treatment options and is driven by unclear molecular mechanisms. The objective of the study was to determine if NEBC is driven by some of the genes that are overexpressed in C3 cells. A top overexpressed and C3 cell specific gene that is also enriched in normal neuronal tissue is Cadherin 12 (N-Cadherin 2, CDH12). Hence, we initiated a study of this gene. Methods: We overexpressed CDH12 in two murine MIBC cell lines (NA13 and MB49) and then inoculated them into mice. Tumor growth kinetics were studied, and single-nucleus RNA sequencing (snRNA-seq) and bulk RNA sequencing were then used to evaluate the tumors. Tissue samples from patients with MIBC were also analyzed using snRNA-seq and Co-detection by Indexing (CODEX) multiplexed immunofluorescence, and our bioinformatics analysis combined transcriptomic profiles from > 2000 MIBC samples from published datasets, to characterize the transcriptional programs induced by enforcing CDH12 expression. Results:Enforced expression of CDH12 led to enhanced tumor growth and the appearance of the neuroendocrine tumor phenotype. NEBC from human samples showed the highest expression of CDH12, and snRNA-seq results showed that NEBC also has the highest proportion of CDH12 epithelial cells and demonstrated co-expression of CDH12 and neuronal markers (NCAM1, CHGA, and SYP). RNA velocity analysis in murine and human tumors implicated CDH12 as a driver for the development of the neuronal subtype. Conclusions: To our knowledge, this study provides the first identification of a genetic driver leading to NEBC and implicates a novel gene, CDH12 in this process.
Prediction of 6-year risk of bladder cancer using the HUNT Lung Cancer Risk Model in ever-smokers: A HUNT study.
Authors: Røe Oluf D. , Nguyen Olav Toai Duc , Fotopoulos Yannis , Lagani Vincenzo , Tsamardinos Ioannis
Published: June 2023

e16581

Background: Bladder cancer is the 6th most common cancer in men and 17th most common cancer in women and the mortality is high when detected in advanced stage. Previous or current cigarette smoke is the main risk factor. There is no screening program for bladder cancer. Given the pathophysiological similarity with lung cancer, we postulated that a lung cancer risk model could work for bladder cancer. The validated HUNT Lung Cancer Risk Model (HUNT LCM) predicts lung cancer in 6 years with an area under the ROC curve (AUC) of 0.87. Here we aimed to test the performance of the HUNT LCM in the prospective HUNT2 cohort for a 6-year prediction of bladder cancer. Methods: The HUNT2 cohort from Norway, a prospective population study of 65 200 individuals 19-100 years of age, was followed up for a median of 15 years. This population was linked with the Norwegian Cancer Registry and all cases diagnosed with bladder cancer were registered. The HUNT Lung Cancer Model was used to predict risk of bladder cancer within 6 years. Results: In the HUNT2 cohort 38 846 ever-smokers were identified. 82.6% of those developing bladder cancer were ever-smokers. 31 269 had all the variables needed for the model and of those, 191 developed bladder cancer in six years. The HUNT Lung Cancer Model prediction of bladder cancer in 6 years AUC was 0.751. Conclusions: To our knowledge, this is the first time a lung cancer risk prediction model has been applied to predict bladder cancer. The performance of the model is lower than for lung cancer but still has a good performance. This may open a path for screening and early detection of bladder cancer.
Characterizing immune-genomic signatures associated with response to immune checkpoint inhibitors (ICI) in patients with metastatic urothelial carcinoma (mUC).
Authors: Pramod Nikhil , Dawsey Scott , Pavicic Paul G. , Lodha Roshan , Patgunarajah Ubenthira , Nair Monica , Ornstein Moshe Chaim , Gilligan Timothy D. , Wee Christopher Eing , Mian Omar Y. , Nizam Amanda , Nguyen Jane , Diaz-Montero C. Marcela , Gupta Shilpa
Published: June 2023

e16582

Background: Response rates with ICI are modest at around 20% in mUC and there is a lack of validated biomarkers to select pts who are likely to derive benefit from ICI. There is an unmet need to develop biomarkers of response and resistance to avoid unnecessary treatment (Tx) and spare physical and financial toxicity. Here we report tumor immune-genomic characteristics associated with response and resistance to ICI in mUC. Methods: We selected 58 mUC pts who received at least 2 cycles of ICI (atezolizumab or pembrolizumab) between 2015-2020 and had pre-Tx archival formalin fixed paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as responders (R) (Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) (N = 30) or non-responders (NR) (Progressive Disease (PD)) (N = 28). Tumor was macrodissected from FFPE slides and RNA extraction was done using Qiagen Rneasy FFPE kit. 100ng of RNA was used for transcriptomic analysis using the Nanostring PanCancer IO 360 panel. Data normalization and analysis was carried out using nSolver 4.0. Results: Differential expression analysis comparing (R) vs (NR) displayed upregulation of gene signatures associated with Immunoproteasome, Antigen presenting machinery (APM), IFN Gamma, PD-L1, and IFN downstream. Additionally, the tumor inflammation signature (TIS), which is trained to predict response to ICI, was upregulated in (R) vs (NR) (Table 1). Single gene analysis showed trend towards upregulation of ISG15 (logFC = 0.7821, p = 0.00337), TAP1(logFC = 0.7649, p = 0.00422), and STAT1 (logFC = 0.6053, p = 0.00510) in (R), P-values, were above significance threshold after adjustment for multiple comparisons. Receiver operator characteristic (ROC) analysis with area-under the curve (AUC) scores assess capacity of gene signatures to predict response to ICI (Table 1). In our cohort, the median overall survival for (R) was 44.1 months compared to 24.5 months in NR (p = 0.0100). Conclusions: In our cohort of mUC pts treated with ICI, we found an association between signatures of tumor immunogenicity (APM and Immunoproteosome) and anti-tumor immune activity (IFN Gamma, IFN Downstream, TIS) in pre-Tx tissue with favorable response to therapy (including SD). These findings are hypothesis generating and need to be further validated in prospective trials. Ongoing genomic and immunologic correlative studies in our cohort will further help understand comprehensive biomarkers of response and resistance to ICI in pts with mUC. [Table: see text]
Immune checkpoint inhibitors therapy in advanced bladder carcinoma: A meta-analysis of phase III randomized controlled trials.
Authors: Patel Rushin , Chitkara Akshit , Patel Zalak , Patel Mrunal , Anamika Fnu , Trivedi Shivang , Ramaswamy Bhuvaneswari
Published: June 2023

e16584

Background: Currently, platinum-based chemotherapy is the standard treatment for advanced bladder cancer. Immune checkpoint inhibitors (ICIs) have been evaluated in these patients with clinical trials. There is no meta-analysis available of phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in these patients. In this article, we write about the meta-analysis of ICIs use in advanced bladder cancer. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google scholar, and ClinicalTrials.gov were searched for relevant studies with prespecified terms. We included only phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in patients with advanced bladder carcinoma. Outcomes studied were Overall survival (OS), Progression-free survival (PFS), Objective response rate (ORR), and Grade 3 or higher adverse events (AE). We used a random effects model via RevMan 5.4 software to perform the meta-analysis. Results: 8 phase III RCTs met the inclusion criteria with a total of 5041 patients (immune checkpoint inhibitors = 2481 patients, Chemotherapy/placebo = 2560 patients) and a median follow-up of 24 months. Compared to the chemotherapy/placebo group, immune checkpoint inhibitors showed higher OS [HR = 0.83 (0.73-0.93) P = 0.002]. No significant differences were observed in PFS [HR = 0.84(0.68-1.05) P = 0.13] and ORR [HR = 2.15(0.51-9.09) P = 0.30] between the two groups. Compared to the chemotherapy group, immune checkpoint inhibitors showed significantly fewer severe adverse events [HR = 0.21 (0.14-0.32) P < 0.00001]. Conclusions: The use of immune checkpoint inhibitors in patients with advanced bladder carcinoma is associated with favorable overall survival and fewer severe adverse events. The two groups observed no significant differences between progression-free survival and objective response rates.
Radiogenomics of muscle invasive bladder cancer.
Authors: Chen Xingyu , Qureshi Touseef , Xie Yibin , Knott Simon , Li Debiao , Rosser Charles Joel , Furuya Hideki
Published: June 2023

e16587

Background: Accurate staging of Muscle Invasive Bladder Cancer (MIBC) is essential to ensure optimal treatment (e.g., radical cystectomy vs. bladder preservation). However, currently about 1/3 of patients are overstaged and 1/3 are understaged. There is a pressing need of accurate noninvasive staging for MIBC to assist clinical decision making. Methods: In this preliminary study, an extensive radiogenomic analysis of MIBC cases was performed to identify potential indicators of MIBC stages, and to automate the staging process. A total of 28 MRI scans and their matched transcriptomic profiles were obtained from subjects diagnosed with MIBC at different stages. In the genomics, a bulk RNA-seq from FFPE tissues was performed that identified 3 major clusters, high, intermediate, and low infiltrating immune cells and fibroblasts. This was followed by a bioinformatic analyses, such as pathway enrichment and gene set enrichment analyses, 15 most significant signatures were identified for stage categorization of MIBC (Fig. 1). In the radiomics, several hundred image-based features from bladder tumor in MRI were extracted and analyzed. The tumors were manually outlined and grouped into lower-stage (stage I and II) and higher-stage (stage III and IV) by the trained radiologists. Using various statistical tests, several radiomic features (e.g., heterogeneity, inverse contrast, entropy) were inferred as significant at discriminating the two groups (Fig. 2). A naïve Bayes machine learning model was then used to integrate such features and perform automated binary classification of cases into their true class. A 4-fold cross validation was performed in which a unique 75% and 25% of 28 cases were used for training and testing of the model respectively. Results: The model performance was assessed in terms of prediction (binary classification) of stages as mean sensitivity, specificity, and accuracy, reaching 84%, 86%, and 86% respectively. Conclusions: The radiogenomics of MIBC provides insight into features associated with cancer stages. Assisted with AI, the discriminative features can accurately stage MIBC. Source of Funding: Cedars-Sinai Cancer Internal Funds: Developmental Funds for Investigator Initiated Trials Using Advanced Imaging Methods.