bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance characteristics of a tumor-informed circulating tumor DNA (ctDNA) minimal residual disease (MRD) assay in invasive bladder cancer in clinical practice.
Authors: Mehler Shoshana , Guilbeau Seth , Somer Shmuel , Reed Kevin , Greene Heather , Vaena Daniel A. , Grothey Axel , Somer Brad
Published: March 2023

542

Background: Detection of minimal residual disease (MRD) is emerging as a potential risk stratification and surveillance tool in patients with resected bladder cancer to potentially direct adjuvant therapy and early intervention. Recently, the sensitivity of MRD testing for early detection of recurrence has been questioned. We sought to evaluate the real world diagnostic performance characteristics of the Signatera ctDNA assay in patients with stage 1-4 bladder cancer who either had transurethral resection of bladder tumor (TURBT) in addition to either chemoradiation or radical cystectomy. Methods: Patients with bladder cancer who underwent ctDNA MRD testing after resection for stage 1-4 disease from 03/2021 to 09/2022 were evaluated retrospectively. Both patients with single and serial ctDNA assays were included. Individual chart review was performed to collect demographic and clinical variables such as diagnosis, stage, pathology, imaging results, and treatment course. Results: MRD results from 19 patients were available, 9 of which had serial assays. 13/19 patients were found to have ctDNA positive results at any time point. The positivity rate at initial testing was associated with stage: Stage 1: 3/5 patients, of which 2 had TURBT and 1 Radical cystectomy, stage 2: 2/5, stage 3: 6/8, and stage 4: 0/1. Notably, of the 9 patients with serial assays, one patient’s result converted from negative to highly positive during surveillance, with subsequent decrease to low positive after adjuvant therapy. One patient had a result of 2 consecutive low positives initially, which was converted to negative after systemic therapy and radiation. 7/19 patients completed testing 3 or more times over a span of approximately 4-13 months, 2 of whom had negative results throughout. Most patients who were found to have positive ctDNA did demonstrate radiographic recurrence within 2-3 months of ctDNA detection. Conclusions: Positive ctDNA MRD after resection is common in bladder cancer. Tumor-informed ctDNA MRD testing has very high sensitivity, but a one-time negative test result does not exclude the presence of metastatic disease. The above data shows an association between cancer stage and positivity results, particularly for advanced stages. Stage I cases with positive results can likely be explained by inadequate resection. Increases in ctDNA may represent early recurrence and can potentially be salvaged with early systemic therapy reverting to negative ctDNA. Prospective randomized and non-randomized studies are evaluating the clinical utility of ctDNA MRD testing in bladder cancer, and analysis of Signatera ctDNA assays will largely contribute to these efforts.
Evaluation of PD-L1 and B7-H3 expression as a predictor of response to adjuvant chemotherapy in bladder cancer.
Authors: Mahmoud Ahmed , Frank Igor , Ahmed Mohamed E. , Orme Jacob , Lavoie Roxane , Thapa Prabin , Costello Brian Addis , Cheville John , Gupta Sounak , Dong Haidong , Lucien Fabrice
Published: March 2023

548

Background: PD-L1 and B7-H3 have been found to be overexpressed in urothelial carcinoma (UC) of the urinary bladder. Recent studies have also demonstrated that B7-H3 and PD-L1 can promote resistance to platinum-based drugs but the predictive value of B7-H3 expression in patients treated with platinum-based chemotherapy is unknown. This study aims to investigate the association of PD-L1 and B7-H3 tumor expression with oncological outcomes in patients who underwent radical cystectomy (RC) and received subsequent adjuvant chemotherapy. Methods: Immunohistochemistry was performed on paraffin-embedded sections from bladder and lymph node specimens of 81 patients who had RC for bladder cancer. PD-L1 and B7-H3 expression on tumor cells was assessed by immunohistochemistry in both primary tumors and lymph node specimens. Association with clinicopathologic outcomes was determined using Fisher’s exact test and postoperative survival using Kaplan–Meier survival curves and Cox regression model. Results: B7-H3 expression in cystectomy specimens was more common than PD-L1 expression (72.8% vs. 35.8%). For both markers, no association was found with pathologic tumor stage, lymph node (LN) status, and histological subtype. Similar findings were observed for double-positive tumors (PD-L1+B7-H3+). Concordance between the primary tumor and patient-matched lymph nodes was found in 76.2% and 54.1% of patients for PD-L1 and B7-H3, respectively. PD-L1 tumor expression was not associated with oncologic outcomes. However, B7-H3 expression was associated with recurrence-free survival (HR: 2.38, 95% CI 1.06–5.31, p = 0.035) and cancer-specific survival (HR: 2.67, 95% CI 1.18–6.04, p = 0.019). Conclusions: In our single institutional study, B7-H3 is highly expressed in patients with UC treated with adjuvant chemotherapy and it was associated with decreased recurrence-free survival and cancer-specific survival. Pending further validation in larger cohorts, B7-H3 expression may function as a predictor of response to adjuvant chemotherapy and thus be useful in patient and regimen selection.
Distinct gene expression patterns identify patients who relapse after neoadjuvant pembrolizumab and radical cystectomy in the PURE-01 study.
Authors: Reike Moritz Johannes , Raggi Daniele , Marandino Laura , Patanè Damiano Alfio , Crupi Emanuele , Padua Tiago Costa de , Black Peter C. , Gibb Ewan , Necchi Andrea
Published: March 2023

549

Background: The PURE-01 clinical trial reported the use of neoadjuvant treatment with pembrolizumab prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC; cT2–3N0M0; PMID 30343614). We have previously reported that specific molecular subtypes (i.e. basal or claudin-low) and immune signatures are associated with more favorable survival. However, reports on the detailed tumor biology of patients (pts) who relapsed after neoadjuvant pembrolizumab are lacking. Herein, we provide a detailed characterization of relapsing pts and identify distinct gene expression patterns with potential utility as novel biomarkers. Methods: Microarray data from transurethral resection of the bladder tumor (TURBT; N=102) and matched RC (N=25) tissue from the PURE-01 trial were analyzed. Gene expression signatures and molecular subtypes were assigned as previously described (PMID 32165065). The Kaplan-Meier method was used to estimate differences in patient outcomes. Immune-signatures were split by median for survival analysis. All significance testing used a two-sided t-test at a threshold of 0.05. Results: Differential gene expression analysis identified KRT20 and H19 to be enriched in relapsing patients (both p<0.001). Expression below the median was predictive of favourable 3-year overall (OS) and recurrence-free (RFS) survival (OS, 37.3% vs. 21.6%, p=0.118; RFS, 35.3% vs. 21.6%, p<0.01 and OS, 41.2% vs. 17.6%, p=0.03; RFS, 39.2% vs. 17.6%, p=0.012, respectively). Distribution of molecular subtypes showed tumors with neuronal character (NE-like) were enriched in pts who relapsed. Low immune-signatures, including Interferon-gamma and -alpha, were predictive of relapse (3-year RFS, 31.4% vs. 25.5%, p<0.001 and 31.4% vs. 25.5%, p<0.01, respectively), whereas Immunophenoscore for CD4 was not. None of these markers were predictive for relapse in matched RC-samples. Conclusions: Relapsing patients demonstrated distinct biological patterns in pre-therapy tumor samples that show prognostic value, potentially making an earlier identification and therefore adapted treatment possible. Low expression of immune-related signatures was associated with relapse.
Complimentary genomic, pathologic, and artificial intelligence analysis on low-grade noninvasive bladder cancer to predict downstream recurrence.
Authors: Rose Kyle M. , Vosoughi Aram , Borjas Gustavo , Huelster Heather L , Spiess Philippe E. , Berglund Anders E. , Sexton Wade J. , Joshi Anirudh , Kumar Nagi B. , Li Roger
Published: March 2023

553

Background: Low-grade noninvasive (LGTa) bladder cancer is a relatively quiescent but heterogenous malignancy, characterized by downstream recurrences requiring repeated transurethral resections and frequent surveillance. Investigations to elucidate drivers of recurrence have been sparse, but will help risk-stratify patients with LGTa and allow augmentation of follow up protocols. Methods: Patients with LGTa index tumors were stratified by those with no downstream recurrences (nonrecurrent) vs. those with later recurrences (recurrent). RNA sequencing identified differentially expressed genes (DEGs), deconvoluted for cell-type using xCell. Pathologic analysis was performed by a genitourinary pathologist, then a deep-learning artificial intelligence (AI) platform was leveraged to correlate recurrence risk and recurrence-free survival (RFS) based on deep-learning algorithm of segmented nuclei. Results: Thirty index bladder tumors/patients were identified, 18 (60%) of which had later recurrence (Table). There were 238 DEGs recognized, with recurrent tumors expressing signatures for epithelial mesenchymal transition, myogenesis, TNFα signaling via NFκB, and angiogenesis. Recurrent tumors also demonstrated a higher tissue micoenvironment, stroma, and cancer-associated fibroblast score. Pathologic TME analysis validated these findings, with recurrent tumors demonstrating a higher frequency of inverted growth pattern and a higher median stroma percentage. Finally, the AI-derived signature was predictive of recurrence and risk-stratified the cohort (HR= 5.43 [95% CI 1.1-26.76]) for predicting high vs. low risk of recurrence. Patients in the high risk group had a 87.5% recurrence rate while those in the low risk group had a 28.5% recurrence rate (p<0.01). Conclusions: Using a multi-disciplinary approach, we identified key signatures in recurrent LGTa bladder cancer. Characterization of these factors is a critical first step in the risk-stratification of LGTa tumors, and may allow risk-stratification of surveillance protocols and identification of possible targets for chemoprevention trials. [Table: see text]
Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts.
Authors: Bahlinger Veronika , Branz Annalena , Strissel Pamela , Strick Reiner , Lange Fabienne , Geppert Carol-Immanuel , Klümper Niklas , Hölzel Michael , Wach Sven , Taubert Helge , Sikic Danijel , Wullich Bernd , Angeloni Miriam , Ferrazzi Fulvia , Diehl Lauri , Kovalenko Maria , Elboudwarej Emon , Juergensmeier Juliane Margarete , Hartmann Arndt , Eckstein Markus
Published: March 2023

554

Background: Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved in recent years. Besides immunomodulative therapeutic options like anti-PD-(L)1 inhibitors and inhibitors targeting FGFR alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved for treatment. However, little is known about associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. This study characterizes associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 gene and protein expression with morphomolecular and clinico-pathological characteristics of aUC in two large independent cohorts. Methods: The TCGA BLCA (n=405) and the CCC-EMN (n=247) cohorts were retrospectively analyzed. Expression of mRNA and protein for TACSTD2/TROP2 and NECTIN-4/NECTIN-4 was measured and correlated with clinico-pathological characteristics, molecular subtypes, FGFR3 alterations and PD-L1 expression. Results: TACSTD2/TROP2 and NECTIN-4/NECTIN-4are highly expressed at protein and transcript level in aUC, and their expression status did not correlate with patient survival in two independent cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumors and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-Score < 15). TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double negative tumors. TROP2 and NECTIN-4 negative tumors (protein level) included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumor and immune cells did not associate with TROP2 or NECTIN-4 expression. Conclusions: TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression. Expression loss is associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC. TROP2 and NECTIN-4 are widely expressed in aUC thus representing suitable targets for novel ADC treatment for the majority of aUC patients.
Characterization and impact of Wnt5A signaling on outcomes of urothelial carcinoma.
Authors: Salmasi Amirali , Krause Harris , Elliott Andrew , Farrell Alex Patrick , Antonarakis Emmanuel S. , Bastos Bruno R. , Heath Elisabeth I. , Jamieson Christina , Stewart Tyler F. , Bagrodia Aditya , Nabhan Chadi , Oberley Matthew James , Korn W. Michael , McKay Rana R.
Published: March 2023

560

Background: Active Wnt signaling via WNT5A through ROR1 and its partner, ROR2, or WNT5A/frizzled 2 (FZD2) is linked to processes driving tumorigenesis, disease progression and therapy resistance. The role of this pathway in the pathogenesis of urothelial carcinoma (UC) is not fully elucidated. In adult tissue, ROR1 is largely absent, which makes it ideal for targeted therapies, with several ROR1 targeting agents in early clinical development. We utilized a large dataset of molecularly characterized UC tumors to investigate the significance of Wnt5a/ ROR1, ROR2 or FZD2 transcriptional expression. Methods: NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4743 UC tumors submitted to Caris Life Sciences (Phoenix, AZ). PD-L1 expression (SP142; Positive (+): ³2+, ³%5) was tested by IHC. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed; Bao, 2020). WNT5a, ROR1, ROR2, and FZD2-high and -low expression were defined as ³ top and < bottom quartile of transcripts per million (TPM), respectively. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( q < .05). Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan Meier estimates were calculated for molecularly defined cohorts. Results: We observed similar expression of these WNT5A signaling pathway genes between upper (N=795) and lower tract UC (N=3,204): WNT5A (22.7 v. 22.2 median TMP (mTPM), q = .18), FZD2 (3.4 v 3.5, q = .93), ROR1 (2.0 v. 1.7, q = .05), and ROR2 (2.1 v 2.5, q < .01). WNT family gene expression varied significantly between primary (N=2,756) and metastatic sites (N=1,361): WTN5A (25.2 v 16.8 mTPM), FZD2 (3.2 v 4.05), ROR1 (1.7 v 2.1), and ROR2 (2.4 v 2.6) for primary vs. metastatic sites respectively ( q < .05 for all). Comparison of high- and low-expression subgroups revealed variation in the prevalence of TP53, FGFR3 and RB1 mutations, as well as PDL1+ staining and T cell-inflamed scores (Table). High gene expression for ROR2 (HR 0.66, 95% CI 0.56-0.78, p < .001) and FZD2 (HR 0.75, 95% CI 0.63-0.89, p < .001) was associated with worse OS compared to low gene expression. No significant difference in OS was observed for WNT5A (HR 0.97, 95% CI 0.82-1.15, p < .76) and ROR1 (HR 0.86, 95% CI 0.72-1.01, p < .068). Conclusions: Distinct genomic and immune landscapes for the four investigated WNT pathway components were observed and should be leveraged to identify combination therapies that complement the current pipeline of WNT pathway-targeting drugs. [Table: see text]
Characterization of the tumor transcriptomic differences by smoking history in locally advanced or metastatic urothelial carcinoma (UC).
Authors: Sahu Kamal Kant Kant , Tripathi Nishita , Chigarira Beverly , Sayegh Nicolas , Mathew Thomas Vinay , Li Haoran , Jo Yeonjung , Gebrael Georges , Iyer Puja , Nussenzveig Roberto , Agarwal Neeraj , Maughan Benjamin L. , Gupta Sumati , Swami Umang
Published: March 2023

561

Background: Understanding the influences of cigarette smoke exposure at the gene expression level may have clinical significance and therapeutic implications. Investigating variations in the gene expression patterns could provide insights into differences in disease progression, survival, and therapeutic response based on smoking history amongst smokers vs. non-smokers (PMID: 29050337). Our objective was to correlate smoking with the gene expression of pts with locally advanced or metastatic UC. Methods: In this IRB-approved retrospective study, eligibility criteria included pts with locally advanced or metastatic UC with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on smoking history. DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Statistical significance was predetermined at p < 0.05. Results: 38 pts were eligible and included: Smokers (n=18) and non-smokers (n=20). The median age at diagnosis for smokers vs. non-smokers (67 vs.71 years). The three most upregulated significant pathways amongst smokers (vs. non-smokers) were the MYC, E2F target, and cholesterol homeostasis pathways (q for all <0.01) [Table]. The three most downregulated significant pathways were interferon-alpha, interferon-gamma, and inflammatory response pathways (q for all <0.01). Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with advanced UC with smoking history demonstrated a different transcriptomic profile than those without smoking. Increased expression of proto-oncogene MYC and E2F could explain an aggressive disease amongst smokers. Future trials could utilize these transcriptomic differences by smoking history in guiding drug development. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with UC. [Table: see text]
Oncologic outcomes following post-cystectomy recurrence of bladder cancer based on metastatic site and role of salvage immunotherapy.
Authors: Ladi Seyedian Seyedeh Sanam , Doshi Chirag , Santos Molina Luis , Wood Erika , Cai Jie , Miranda Gus , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak
Published: March 2023

574

Background: To evaluate how the location of bladder cancer recurrence after radical cystectomy (RC) affects survival and assess the role of salvage immunotherapy in this setting. Methods: On retrospective review of 4093 patients from our institutional IRB approved cystectomy database from January 1971 to December 2021, we identified 889 patients who underwent RC with curative intent and have been detected with recurrence of bladder cancer. Patients with urethral and ureteral recurrence were excluded. The data was then stratified based on the site of recurrence. Results: In this cohort of 889 patients (median age of 68, 77% male), the most common sites of metastases were widespread (48%), local (15%), lung (10%), bone (8%), retroperitoneal nodes (5.5%), liver (5%) and brain (1.5%) in order. With a median of 8.4 months, bone metastasis had shortest length from cystectomy to recurrence, while liver metastasis had shortest post recurrence survival (median of 4 months). For distant recurrence alone, only 33% survived past the first year. Salvage immunotherapy was administered in 8% of the patients and 47% received salvage chemotherapy. On multivariate analysis, liver metastasis (HR 2, 95%CI 1.4-2.9), widespread metastasis (HR 1.9, 95%CI 1.5-2.4), pathological staging>T3 (HR 1.3, 95%CI 1.1-1.6) and nodal involvement at the time of RC (HR 1.5, 95%CI 1.2-1.7) were significantly associated with worse survival after the recurrence. Salvage immunotherapy provided a significant improvement in post-recurrence survival (HR 0.2, 95% CI 0.1-0.3). Conclusions: Liver, brain, and widespread metastases predominantly showed the lowest chance of survival past one year from recurrence; however, more than half of all patients with recurrence did not live past the first year. Salvage immunotherapy may lead to a better prognosis in recurrence post-cystectomy. [Table: see text]
Prognostic value of C-11 choline PET/CT scan in patients with metastatic castration resistant prostate cancer (m-CRPC) undergoing treatment with radium-223.
Authors: Lee Matthew , Ahmed Mohamed E. , Kwon Eugene D. , Kendi Ayse T.
Published: March 2023

59

Background: Radium-223 (Ra-223) has been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with predominantly osseous metastases. PSA flare phenomenon with Ra-223 limits the use of PSA as a prognostic tool to predict treatment response. Currently, there is a lack of diagnostic tools to predict treatment response to Ra-223. Therefore, we sought to investigate the role of mid-treatment C-11 choline PET/CT scan in predicting overall response to Ra-223. Methods: In a single institute retrospective study, we identified 32 patients who were treated with a full course of 4-6 cycles of Ra-223 and were evaluated with both PSA and C-11 choline PET scan before treatment, at mid-treatment, and after a complete course of Ra-223 between 2013 – 2018. Ra-223 was used as salvage therapy for their predominant bone disease after failing chemotherapy and 2nd generation hormone therapy. Blind repeat radiographic evaluation of patients’ scans was performed by a radiologist specialized in nuclear radiology. Favorable response was defined by achieving partial response or stable disease on imaging, while unfavorable response was defined by showing progressive disease on imaging. Results: Mean age (±SD) at starting Radium223 was 67.6 (±7.1) years, median (IQR) primary Gleason score was 9 (8-9), and median (IQR) pretreatment PSA was 13.5 (5.4-39.6) ng/ml. 78% of the patients (n=25) completed 6 cycles of Ra-223, 15% of the patients (n=5) completed 5 cycles, and 6% (n=2) received only 4 cycles. At mid-treatment scanning, 25% of the patients (n=8) showed favorable response (Group A), while 75% of the patients (n=24) showed unfavorable response (B). After a complete course of treatment, 62.5% of patients (n=5) in Group (A) continued to show favorable response, while only 8.3% of patients (n=2) in Group (B) showed favorable response (p-value= 0.0023). Conclusions: Mid-treatment evaluation with C-11 choline PET/CT scan can predict overall response to Radium 223. Patients with progressive disease at mid-treatment evaluation are very likely not going to respond to further treatment. Further studies and clinical trials are warranted.
Factors associated with poor survival outcomes in patients with prostate cancer (PCa) with radiographic disease progression in the setting of low PSA.
Authors: Ahmed Mohamed E. , Mahmoud Ahmed , Andrews Jack R. , Lee Matthew , Childs Daniel S , Kendi Ayse T. , Johnson Geoffrey , Tollefson Matthew K. , Boorjian Stephen A. , Karnes R. Jeffrey , Kwon Eugene D.
Published: March 2023

60

Background: Recent studies, including a post-hoc analysis of the ARCHES trial, highlight radiographic disease progression (rDP) occurring without concordant rise in prostate specific antigen (PSA). In a previous study by our group, we reported that almost 40% of patients on 2nd generation hormone therapy experience rDP with non-rising PSA and have poor survival outcomes. The current analysis more specifically focuses on the subgroup of patients with rDP occurring at low PSA (<0.5 ng/dL) and describes factors associated with poorer survival outcomes in this patient population. Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET registry for patients treated between 2011 and 2021, who experienced rDP at low PSA (value < 0.5 ng/mL). Disease progression on C-11 choline PET was confirmed by either tissue biopsy or subsequent response to therapy. We investigated factors associated with poor cancer-specific survival outcomes in univariable and multivariable cox regression analyses. Results: In total, 220 (16%) patients experiencing rDP at low PSA were identified. Median (IQR) age at rDP was 67.91 (61.10 – 73.87) yrs., median (IQR) primary Gleason score was 9 (7-9), and median (IQR) PSA was 0.17 (0 – 0.32) ng/ml. 75% of the patients (n=166) had CRPC disease status at time of rDP. Prior systemic treatments included 2nd generation HT in 18% (n= 40) and chemotherapy in 31% (n=70). Sites of rDP were divided into 7% local (n=16), 42% lymph nodes (n=91), 43% bone (n=95), and 8% visceral metastases (n=18). Over a median follow-up duration of 55 months, 46% of patients (n=100) reported death. Factors associated with poor survival outcomes are demonstrated in the table and include age at rDP, CRPC status, and disease location (P-value <0.05). Conclusions: We found that radiographic disease progression commonly occurs at low PSA (<0.5 ng/mL). CRPC-disease status and the development of visceral metastases are associated with particularly poor survival outcomes. To identify early progression, monitoring with imaging may be warranted, even in the patients with low PSA. [Table: see text]
Effect of treatment of residual disease after immunotherapy-based combinations on complete response rate in metastatic renal cell carcinoma.
Authors: Moinard-Butot Fabien , Oriel Marine , Tricard Thibault , Cazzato Roberto Luigi , Pierard Laure , Gaillard Victor , Werle Pierre , Lindner Veronique , Martin Sophie , Schuster Caroline , Roy Catherine , Burgy Mickael , Anthony Anne , Bigot Cecile , Boudier Philippe , Fritsch Aurelie , Malouf Gabriel G. , Lang Herve , Barthelemy Philippe
Published: March 2023

601

Background: Immunotherapy (IO) has revolutionized the management of metastatic renal cell carcinoma (mRCC) by improving survival, overall response and complete response (CR) rates. CR is achieved in 11 to 17% with the different PD-1-based IO combinations in first-line setting of mRCC. However, local treatment of residual disease after systemic treatment exposure may improve CR rates. We performed a retrospective study to characterize patients (pts) in CR with systemic therapy alone or combined to an ablative approach of residual disease. Methods: We included all consecutive mRCC pts treated with mRCC in first-line treatment with IO combination with IO or TKI, either alone or with local treatment at the Institut de Cancérologie Strasbourg Europe. Pts were characterized according to IMDC risk group. Radiologic response was defined according to RECIST v1.1. Results: We enrolled 80 pts with mRCC between 5/2015 and 5/2022; median age was 68 (41-89) years; 75% male; 36 pts (45%) had prior nephrectomy; IMDC risk group: 12 favorable (15%), 50 intermediate (63%), 18 poor risk pts (22%), respectively; 47 pts (59%) received IO + IO, 24 (30%) received IO + TKI and 9 pts (11%) received another IO-based therapy; 35 pts (44%) achieved partial response, 23 pts (29%) stable disease, 13 pts progressive disease and 9 pts achieved CR (11%) as best response with systemic therapy alone; 10 pts out of 35 PR pts achieved CR by adding local treatment on residual disease. Among CR pts: 5 out of 19 pts had a component of sarcomatoid histology; median age was 60 years. Characteristics of pts with CR are reported in the table. Median duration of IO exposure before local therapy was 13 months. Residual disease resected sites included kidney (N = 6), lymph node (N = 4), lung metastasis (N = 2) and liver metastasis (N = 1). Local treatment was surgery for 9 pts and liver thermoablation for 1 patient. Conclusions: The resection of residual disease after first line IO-based therapy in mRCC improves CR rates (from 11% up to 24%). This approach should be considered as an option for a selected population. Prospective trials assessing this strategy should be performed in the future. Characteristics of patients in CR. [Table: see text]
Effect of race-free estimated glomerular filtration rate equations (eGFR) on oncology clinical trial eligibility for Black patients.
Authors: Schmeusser Benjamin , Palacios Arnold Raul , Midenberg Eric , Nabavizadeh Reza , Patil Dattatraya H , Harvey R. Donald , Bryksin Janetta , Connor Michael J. , Ogan Kenneth , Bilen Mehmet Asim , Master Viraj A.
Published: March 2023

611

Background: Race is no longer recommended in estimated glomerular filtration rate (eGFR) equations. The resulting lower eGFR may positively impact black patients, such as with earlier nephrology referral. However, the impact of race-free equations on black oncology patients–a cohort more likely to experience inferior cancer outcomes and underrepresentation in clinical trials–has not been fully examined. Here, we analyze removal of race from eGFR in black patients with cancer, specifically with regards to clinical trial eligibility. Methods: Self-identified black patients undergoing nephrectomy at a referral center from 2009-2021 were identified. Patients with end-stage renal disease were excluded. Using preoperative creatinine, height, and weight, eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation with and without race (CKD-EPI-WithRace; CKD-EPI-WithoutRace, respectively), and the Modification of Diet in Renal Disease equation with and without race (MDRD-WithRace; MDRD-WithoutRace, respectively). Distribution of patients and changes within CKD stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated based on utilization of the race coefficient. Subgroup analysis was completed on patients with stage III-IV disease only. Results: 459 self-identified black patients that underwent nephrectomy at our institution were identified, 135 of which had stage III-IV disease. On average, eGFR decreased around 10-13ml/min/1.73m2 with removal of the race coefficient (Table). 13-22%, 6-12%, and 2-3% more black patients would fall under common clinical trial cutoffs of 60, 45, or 30ml/min cutoffs, respectively, depending on the equation used (Table). Subanalysis of stage III-IV patients only were similar. Conclusions: Race free renal function equations may inadvertently result in increased exclusion of black patients from clinical trials. [Table: see text]
Impact of race and payor status on patterns of utilization of partial and radical nephrectomy in patients with localized renal cell carcinoma (RCC).
Authors: Barragan-Carrillo Regina , Dallas Kai , Tripathi Abhishek , Govindarajan Ameish , Zengin Zeynep Busra , Meza Luis A , Philip Errol James , Castro Daniela V. , Chehrazi-Raffle Alexander , Chawla Neal , Hsu Joann , Dizman Nazli , Eilber Karyn , Bergerot Cristiane Decat , Pal Sumanta Monty
Published: March 2023

614

Background: Racial minorities experience intersecting forms of marginalization and suffer significant healthcare disparities. Prospective trials have shown similar outcomes with partial and radical nephrectomy among patients with localized RCC (Van Poppel et al Eur Urol 2011), and multiple studies suggest increasing use of the former technique (Breau et al Can J Urol 2020). We hypothesize that patients from minority groups, as well as those with non-private insurance, will have less access to this specialized procedure and therefore have a higher rate of radical nephrectomy. Methods: We utilized the California Office of Statewide Health Planning and Development (OSHPD) database that collects information from all inpatient admissions, emergency room visits and inpatient/outpatient procedures in the state. All patients undergoing nephrectomy (both partial and radical) were identified from Jan 1, 2012 to Dec 31, 2018 using CPT and ICD-9/10 codes to identify patients. Demographic data was collected with specific attention to race and payor status. Univariate and multivariate analyses were conducted to determine the association between demographic data and procedure type. Results: In total, 31,093 patients were identified; 57% were males, with a mean age of 58 years. Among these, 16,142 (51.9%), 8,645 (27.8%), 2,795 (9.0%), 2,032 (6.5%) and 1,479 (4.8%) were characterized as White, Hispanic, Asian, Black and other, respectively. Partial nephrectomy and radical nephrectomy were performed in 15,840 (50.9%) and 15,253 (49.1%) of patients. By race, partial nephrectomy was performed in 8,576 (53.1%), 4,107 (47.5%), 1,286 (46.0%), 1,124 (55.3%) and 747 (50.5%) of White, Hispanic, Asian, Black and other patients, respectively (p<0.001). Use of partial nephrectomy also differed among patients based on payor status, with rates of 6,800 (56.4%), 5,036 (43.9%), 1,817 (38.3%) and 2,187 (77.7%) among patients with private, Medicare, indigent coverage (e.g., MediCal or Medicaid) and other insurance, respectively (p<0.001). On multivariate analysis controlling for age, gender, comorbidities and frailty, race was independently associated with type of nephrectomy procedure. Conclusions: Our study confirms that race and payor status may have an influence on utilization of partial versus radical nephrectomy, with the highest rate of partial nephrectomies among Whites and patients with private insurance. Although there are multiple potential confounders (e.g., latency of diagnosis and resulting tumor size/complexity), it is possible that access to care may be an important driver of these disparities.
Validating the Palacios’ future glomerular filtration rate equation with and without race.
Authors: Schmeusser Benjamin , Ali Adil , Patil Dattatraya H , Palacios Arnold Raul , Armas-Phan Manuel , Ogan Kenneth , Master Viraj A.
Published: March 2023

616

Background: Accurate prediction of future glomerular function rate (fGFR) following nephrectomy in renal cell carcinoma (RCC) patients is of interest. A postoperative estimated glomerular filtration (eGFR) rate ≥ 45 mL/min/1.73m2 is considered favorable, with guidelines reflecting these findings. Though nephron sparing surgery is preferable, radical nephrectomy is often the preferred oncologic surgery. Various models to predict postoperative renal function have been proposed, with a new 2021 equation by Palacios et al. exhibiting strong performance in predicting fGFR. We aim to validate this fGFR equation in a large institutional cohort using both the Chronic Kidney Disease Epidemiology (CKD-EPI) 2009 equation with race, used in the creation of the formula, as well as the CKD-EPI 2021 equation without race, which is currently the recommended CKD-EPI creatinine equation. Methods: Using an institutional database, patients that underwent partial or radical nephrectomy for RCC from 2005-2021 were identified. Patients with creatinine values preoperatively and 3-12 months postoperatively were included, with end stage renal disease serving as exclusion criteria. Correlation/bias/accuracy/precision of the fGFR equation (fGFR=35+ [preoperative eGFR x 0.65]- 18 [if radical] - [age x 0.25]+ 3 [if tumor >7cm]-2 [if diabetes]) with observed postoperative eGFR was determined by both the CKD-EPI-2021 and CKD-EPI 2009 equations. Results: 1,443 patients were included in our analysis. 71% (1,024) and 22.9% (331) patients were white and black, respectively. A majority of patients underwent radical nephrectomy (60.3%). 40% of patients had T3-T4 RCC, with 14.8% of patients having M1 disease. Median observed vs predicted fGFR was 58.0 vs 58.7 ml/min/1.73m2 for CKD-EPI 2021 and 56.0 vs 57.5 for CKD-EPI 2009. The correlation/bias/accuracy/precision of the fGFR equation was 0.805/-0.5/81.7/7.9-9.0 for CKD-EPI 2021 and 0.809/-0.8/81.3/-8.1-8 for CKD-EPI 2009 equations (Table). Conclusions: The fGFR equation accurately predicted renal function in our large and diverse institutional cohort using both the CKD-EPI 2009 including race and CKD-EPI 2021 excluding race equations. [Table: see text]
Natural history of patients with muscle metastases from renal cell carcinoma: Results of the French national ARTEMIS study.
Authors: Wespiser Mylene , Carril-Ajuria Lucia , Ilfad Blazevic , Thibault Constance , Flechon Aude , Martin Sophie , Laramas Mathieu , Borchiellini Delphine , Simon Camille , Mahammedi Hakim , Linassier Claude , Goujon Morgan , Zaibet Sonia , Rolland Frederic , Albiges Laurence , Meurisse Aurelia , Falcoz Antoine , Thiery-Vuillemin Antoine
Published: March 2023

618

Background: Muscle metastases (MM) are among rare secondary locations in renal cell carcinoma (RCC). Current guidelines do not provide specific advice on the management of these patients. There is a lack of scientific literature on the subject, mainly based on case reports or small retrospective monocentric cohorts. To date, therefore, there remains uncertainty about the clinical history, prognosis, and appropriate management of patients with MM. Methods: ARTEMIS is an ambispective national French multicenter, non-interventional study. It was opened to patients with metastatic RCC who had MM. The study was designed to assess overall survival (OS), progression-free survival (PFS), describe diagnostic and treatment modalities, and treatment-related serious adverse events in case of local treatments (TR-SAEs). Results: Median follow-up was 74.4 months IC95% [38.7-84.1]. The 146 enrolled patients were 73.6% male, with a median age of 57.6 years at diagnosis. They were initially diagnosed with stage IV RCC for 40.4% of them and had a favorable (36.2%), intermediate (45.7%), or poor (18.1%) IMDC risk score at the onset of metastases. Initially, metastases were mainly located in the lungs (55.5%), lymph nodes (26.7%), and bones (24.0%). Patients had a history of partial or total nephrectomy in 78.8% of cases. There were 30.0% of patients with synchronous MM. The median times from initial diagnosis or metastatic status to MM discovery were 25.5 [16.8-35.7] months and 8.4 [5.0-13.5] months, respectively. The majority (69.0%) of MM were discovered on conventional injected CT scans, whereas 8.3% were diagnosed clinically. Survival data are displayed on the table. Thirty-seven (25.3%) patients received local treatment of their MM which consisted of: external radiotherapy (48.6%), surgery (27.0%), cryotherapy (27.0%), stereotactic radiotherapy (5.4%), embolization (2.7%). Among them, local treatments prevented local relapse of MM in 28 patients (75.7%). Local TR-SAEs were seen in two patients (5.4%). Conclusions: ARTEMIS is the largest published cohort describing the disease history of patients with RCC suffering from MM. To our knowledge, this is the first study reporting the diagnostic and treatment modalities, also survival data. Despite its low incidence, the issue of these patients is not so rare in physicians’ practice. This work thus allows a greater understanding of clinical features and treatment of this pathology. [Table: see text]
Predictive accuracy of computer-generated C-index nephrometry scores compared with human-generated scores in predicting oncologic and perioperative outcomes.
Authors: Wood Andrew , Benidir Tarik , Abdallah Nour , Heller Nicholas , Isensee Fabian , Tejpaul Resha , Suk-ouichai Chalairat , Curry Caleb , You Alex , Remer Erick M. , Haywood Samuel , Campbell Steven , Papanikolopoulos Nikolaos , Weight Christopher J.
Published: March 2023

623

Background: The Centrality index (C-index) score is a validated nephrometry scoring system that requires precise measurements and mathematical calculations of cross sectional imaging. Like other nephrometry scores, its implementation has been slowed by required time investment and interobserver variability. We sought to automate this score on preoperative computerized tomography scans by developing an artificial intelligence-generated C-index score. We then aimed to evaluate its ability to predict meaningful oncologic and perioperative outcomes as compared to human-generated C-index nephrometry scores. Methods: 300 patients with preoperative computerized tomography with early arterial contrast phase were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer. A deep neural network approach was used to automatically segment kidneys and tumors, and then programed to generate the measurements and calculate C-index score. Human C-index scores were independently calculated by medical personnel blinded to AI-scores. AI- and Human score agreement was assessed using bivariate linear regression correlation and their predictive abilities for both oncologic and perioperative outcomes were assessed using logistic regression and compared with receiver operating characteristic (ROC) curve analyses with measurements of areas under the curve (AUC). Results: Median age was 60 years (IQE 51–68), and 40% were female. Median tumor size was 4.2 cm and 91.3% had malignant tumors. 27% were high stage, 37% high grade, and 63% underwent partial nephrectomy. There was significant agreement between Human scores and AI-scores on linear regression analysis (R2 = 0.738, p <0.0001). Both AI- and Human generated C-index scores similarly predicted meaningful oncologic outcomes, with lower levels of either C-index score associated with increased risk of malignant histology (H-score p = 0.018, AI score p =0.014) high-grade disease (both p <0.0001), and high stage disease (both p <0.0001). Lower levels of either AI or human generated C-index scores also predicted a radical nephrectomy rather than partial nephrectomy surgical approach (both p <0.0001). AUC measurements (Table) were similar but consistently superior for AI generated C-index scores. Conclusions: Fully automated AI-generated C-index scores are comparable to human-generated C-index scores and predict a wide variety of meaningful patient-centered outcomes. Once validated in additional populations, our results suggest that our AI generated C-index could be delivered automatically from a preoperative CT scan to a clinician and patient at the point of care to aid in decision making. [Table: see text]
Clinical outcomes of patients with metastatic renal cell carcinoma who discontinued nivolumab +/- ipilimumab therapy electively or due to toxicity.
Authors: Yoo Jessica Heejin , Hussey Duncan , Gross Evan , Psutka Sarah P. , Tykodi Scott S. , Thompson John A. , Hall Evan Thomas
Published: March 2023

625

Background: Immune checkpoint inhibitor (ICI) based regimens are the standard of care for patients with metastatic renal cell carcinoma (mRCC). In other tumor types such as melanoma, there is evidence that cancer control can persist long after discontinuation of ICI therapy. Outcomes after ICI discontinuation for mRCC are less characterized. Our aim is to characterize the durability of treatment response in mRCC patients who discontinued ICI therapy electively or due to toxicity. Methods: We identified patients with mRCC who responded to nivolumab +/- ipilimumab and then discontinued ICI therapy either for elective reasons or due to toxicity. Patients who discontinued therapy due to progressive disease or who died within 3 months of their last ICI dose were excluded. Complete response (CR) duration was calculated from last ICI dose to the most recent documentation of CR status. Time to progression was defined as the time from last ICI dose to documentation of disease progression or initiation of next-line therapy. Durability of treatment response was calculated from the date of last ICI dose to the most recent follow up date at which sustained response was noted. Results: We identified a total of 56 patients treated with nivolumab +/- ipilimumab therapy who discontinued treatment for toxicity (n=30) or for elective reasons (n=26) and achieved CR or partial response/stable disease (PR/SD). Of the entire cohort, 19 patients (34%) achieved CR, and the majority (95%) were still alive and disease-free with a median follow up of 906 days (range 86-2143 days). Among all patients who discontinued treatment with best response of PR/SD, 49% experienced disease progression, with a median progression-free survival of 382 days (range 77-1267). 42% of patients who stopped ICI electively achieved CR and all (100%) were still alive with sustained CR (median follow-up = 735 days) at data collection. Among those with best response of PR/SD after elective discontinuation, about half (53%) maintained disease control while the rest had disease progression or death (47%). Conclusions: Patients with mRCC who achieve CR with nivolumab +/- ipilimumab and then subsequently discontinue therapy for reasons other than disease progression have excellent long-term cancer outcomes. Recurrence and subsequent progression are rare in this group. These results are similar to the durability of ICI treatment response observed in complete responders in melanoma. Outcomes were less favorable for patients who obtained PR/SD as best response prior to ICI discontinuation, although some patients had ongoing and durable cancer control for up to several years. More research is indicated to ascertain which disease/patient features predict long-term disease control after ICI discontinuation in patients who respond favorably to ICI therapy.
Cabozantinib + nivolumab in adult patients with advanced or metastatic renal cell carcinoma: A retrospective, non-interventional study in a real-world cohort.
Authors: Hilser Thomas , Darr Christopher , Niegisch Guenter , Schnabel Marco Julius , Foller Susan , Haeuser Lorine , Zschaebitz Stefanie , Lewerich Jonas , Anders-Meyn Merle , Ivanyi Philipp , Schlack Katrin , Grünwald Viktor
Published: March 2023

628

Background: Standard treatment for 1st-line mRCC are IO-combinations. Data from real-world collectives are rare. In this multicenter study, we therefore evaluated safety and effectiveness of cabozantinib/nivolumab in Germany. Methods: Data were collected retrospectively from eight GU cancer centres in Germany. Patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) were eligible. Treatment with cabozantinib 40 mg orally + nivolumab 240 or 480 mg i.v. was mandatory and administered according to routine care. Adverse events (AEs) were reported according to CTCAE 5.0. Objective response rate per RECIST 1.1 and Progression Free Survival (PFS) were calculated from start of treatment to progression or death. Descriptive statistics and KM-plots were utilized, where appropriate. Results: 67 suitable pts (62.7% male) with median age of 67.6 years were included. The most common histology was clear cell RCC (ccRCC) in 67.2% (n=45). Nephrectomy was performed in 56.7% (n=38). ECOG 0-1 was 76.1% (n=51). IMDC scores were: 0 in 11 (16.4%), ≥ 1 in 45 (67.1%), missing in 11 pts (16.4%). 29.9% (n=20) required dose reductions or interruptions. Partial response was documented in 46.3% (n=31), stable disease in 32.8% (n=22), and progressive disease in 4.5% (n=3) as best overall response. Data were missing in 14.9% (n=10). Median Follow-up was 8.3 mo, median treatment duration was 6.0 months, PFS rate at 6 month was 81.9% overall (79.3% for ccRCC; 85.9% for non-ccRCC). AEs (all grades) were reported in 82.1% (n=55) and 47.8% (n=32) for grade 3-5. Elevated liver enzymes (40.3%), diarrhea (22.4%) and hand-foot-syndrome (20.9%) were the 3 most frequent AEs of any grade and causality. Conclusions: In this real-world cohort of mRCC pts. cabozantinib + nivolumab was shown to be safe and feasible. While no new safety signals were reported, a reduced dose was frequently utilized. Our data support the use of cabozantinib + nivolumab as a first-line standard. Major limitations were the retrospective data capture and short follow-up of our study.