High-grade Upper Tract Urothelial Carcinoma Research Articles

Abstract 1028: Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma

Abstract Introduction and Objective: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with upper tract urothelial carcinoma (UTUC). The application of a robust urine-based multiplex assay, Oncuria-Detect®, to aid in the detection of UTUC has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis. Methods: To evaluate the performance of Oncuria-Detect®, a multiplex immunoassay capable of querying a voided urine sample for 10 protein biomarkers associated with urothelial carcinoma (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA). Its application to UTUC was evaluated in a multi-institutional cohort of 35 prospectively collected subjects presenting for evaluation of upper tract mass along with 46 prospective collected matched controls (i.e., non-tumor bearing). The ability of the test to identify patients harboring UTUC was assessed. UTCU status was confirmed by endoscopy and tissue biopsy or definitive surgery. Diagnostic performance was assessed using ROC curves. Results: Oncuria-Detect® provided an AUC of 0.886 (95% CI: 0.807-0.964) with an overall sensitivity of 91.4%, specificity of 73.9%, NPV 91.9% and PPV 72.7%. Sensitivity values of the diagnostic panel for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 86.7%, 90.9%, 88.9% and 94.1%, respectively. Urinary cytology or selective ureteral washing/cytology was associated with an overall sensitivity of 54.2%, specificity of 100%, NPV 63.3% and PPV 100%. Sensitivity values of cytology for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 100%, 100%, 100%, and 77.8%, respectively. Conclusions: Urinary levels of a biomarker panel enabled the accurate discrimination of UTUC and controls non-tumor bearing individuals. The multiplex Oncuria-Detect® test can achieve the efficient and accurate detection of UTUC in a non-invasive patient setting. Citation Format: Toru Sakatani, Sunao Tanaka, Kazutoshi Fujita, Jennifer Linehan, Kaoru Murakami, Riko Lee, Ian Pagano, Charles J. Rosser, Hideki Furuya. Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1028.

Comparative outcomes of radical nephroureterectomy and kidney-sparing surgery in the treatment of high-grade upper tract urothelial carcinoma.

607 Background: Patients with upper tract urothelial carcinoma (UTUC) can be managed with either radical nephroureterectomy (RNU) or kidney sparing surgery (KSS) depending on the pathology and patient specific characteristics. Due to the rarity of this disease, high-level evidence is lacking with regard to clinical and oncologic outcomes after surgery. This study aims to compare outcomes of RNU with KSS for patients with high-grade (HG) UTUC. Methods: We retrospectively reviewed patients with >1 year follow-up who were treated for HG UTUC at our institution from 2015-2021. Oncologic and clinical outcomes were recorded. Procedure-related burdens, including total number of procedures under anesthesia, anesthesia time, and days hospitalized were collected. Results: 65 patients were analyzed, with 46 patients treated via RNU and 19 treated via KSS. There were no differences in the ASA or CCI between patients in the two groups. The 5-year overall survival (OS) was 65.2% (95% CI, 52.8%-80.5%) for RNU and 44.4% (95% CI, 26.5%-74.5%) for KSS. The 3-year metastasis-free survival was 78.3% for RNU and 78.9% for KSS. The 3-year recurrence-free survival, including recurrences in the bladder, was 47.8% (95% CI, 35.4%-64.7%) for RNU and 43.8% (95% CI, 25.1%-76.3%) for KSS. A decline of GFR <10 2 years after surgery occurred in 97.1% of patients treated with RNU and 100.0% of those treated with KSS. The total number of procedures under anesthesia was higher for KSS than RNU at 3.4 +/- 1.7 vs 2.1 +/- 1.7, respectively (p = 0.0155). The total number of TURBTs for KSS and RNU was similar at 0.6 +/- 0.7 vs 1.1 +/- 1.7, respectively (p = 0.9538). The total number of days hospitalized for KSS was similar to RNU at 5.5 +/- 4.3 vs 6.8 +/- 4.6, respectively (p = 0.3579). The total anesthesia time for KSS was 400 +/- 218 min and was 474 +/- 185 min for RNU (p = 0.2561). Conclusions: There were similar oncologic and clinical outcomes in patients with HG UTUC treated with either KSS or RNU. Patients treated with KSS saw a higher procedural load. There was a trend towards lower OS for patients treated with KSS but this was not statistically significant, likely due to the small sample size. Larger datasets are needed to further evaluate outcome and treatment burdens of RNU vs KSS as treatment options for patients with HG UTUC. [Table: see text]

Sequential endoluminal gemcitabine and docetaxel versus bacillus Calmette–Guérin for the treatment of high-grade upper tract urothelial carcinoma.

Sequential endoluminal gemcitabine and docetaxel versus bacillus Calmette–Guérin for the treatment of high-grade upper tract urothelial carcinoma.

Preoperative Systemic Inflammation Score Predicts the Prognosis of Patients with Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy

Background: To investigate the prognostic significance of systemic inflammation score (SIS) in upper tract urothelial carcinoma (UTUC) in patients undergoing radical nephroureterectomy (RNU). Methods: A total of 313 UTUC patients who underwent RNU at West China Hospital from May 2014 to June 2019 were retrospectively analyzed. The predictive value of SIS for relevant endpoints, including overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS), was assessed by Kaplan–Meier curves and the Cox proportional hazards model. Results: According to inclusion and exclusion criteria, 218 UTUC patients were ultimately included in this cohort study. Statistical analysis shows that increased SIS was significantly associated with higher TNM stage (p = 0.017), lower BMI (p = 0.037), absence of hemoglobin (p < 0.001), and pathologic necrosis (p = 0.007). Kaplan–Meier survival curves clearly visually stratified survival for the three outcomes. After adjusting for tumor grade, the multivariate Cox proportional hazards model results showed that SIS was an independent risk factor for poor OS and CSS (HR = 1.89, 95% CI: 1.11–3.21, p = 0.0183, HR = 1.89, 95% CI: 1.07–3.33, p = 0.0285) in the advanced group. Conclusions: SIS was an independent risk factor for OS and CSS after RNU in patients with high-grade UTUC. It may be a novel and conducive tool for preoperative risk stratification and guiding individualized therapy for high-risk UTUC patients.

Management of Upper Tract Urothelial Carcinoma in a Double Collecting System Kidney.

Upper tract urothelial carcinoma (UTUC) in a duplex collecting system (DCS) is a relatively uncommon presentation with unclear management guidelines. Herein, we retrospectively reviewed all published cases of DCS with UTUC aiming to suggest personalized clinical care options for future cases. We conducted a systematic search for all cases of UTUC in DCS from published literature using the following keywords: UTUC, urothelial carcinoma (UC), collecting duct carcinoma, and DCS. The cases were summarized based on demographics, clinical presentation, predisposing risk factors, tumor location, management, and follow-up. We present an additional case based on our experience with a 69-year-old female with high-grade (HG) UTUC of the upper moiety in complete DCS. The patient underwent a robotic upper pole hemi-nephroureterectomy (hemi-NU) with a common sheath distal ureterectomy and a bladder cuff, followed by lower pole ureteral reimplantation. Overall, 34 patients with 35 renal units of UTUC in DCS were included and analyzed. To conclude, UTUC of DCS is rare and underreported. Hence, it is difficult to define a standard treatment. Although hemi-NU has been previously described, to the best of our knowledge, this is the first case report of robot-assisted hemi-NU for complete DCS with single-moiety UC.

Invasiveness of Upper Tract Urothelial Carcinoma: Clinical Significance and Integrative Diagnostic Strategy.

In this study, we aimed to determine the clinicopathologic, radiologic, and molecular significance of the tumor invasiveness to further stratify the patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) who can be treated less aggressively. Clinicopathologic and radiologic characteristics of 166 surgically resected HG UTUC (48 non-invasive, and 118 invasive) cases were evaluated. Six non-invasive UTUC cases with intra-tumoral tumor grade heterogeneity were selected for whole exome sequencing (WES) to understand the underlying molecular pathophysiology. Barcode-tagging sequencing (BTSeq) was done for validation of the target genes from WES data. Patients with non-invasive UTUC showed no cancer-specific death with better cancer-specific survival (p<0.001) and recurrence-free survival (p<0.001) compared to the patients with invasive UTUC. Compared to the invasive UTUC, non-invasive UTUC was correlated to a low grade on the preoperative abdominal computed tomography (CT) grading system (p<0.001), histologic intratumoral tumor grade heterogeneity (p=0.018), discrepancy in preoperative urine cytology diagnosis (p=0.018), and absence of urothelial carcinoma in situ (p<0.001). WES of the heterogeneous components showed mutually shared HRAS and FGFR3 mutations shared between the HG and LG components. HRAS mutation was associated with the lower grade on preoperative abdominal CT and intratumoral tumor grade heterogeneity (p=0.045 and p<0.001, respectively), whereas FGFR3 mutation was correlated to the absence of carcinoma in situ (p<0.001). According to our comprehensive analysis, HG non-invasive UTUC can be preoperatively suspected based on distinct preoperative radiologic, cytologic, histologic, and molecular features. Non-invasive HG UTUC shows excellent prognosis and thus should be treated less aggressively.

The influence of the initial clinical presentation of upper tract urothelial carcinoma on histopathological tumor features.

To investigate the influence of the initial clinical presentation (symptomatic vs. asymptomatic) on histopathological tumor features in patients with upper tract urothelial carcinoma (UTUC). We conducted a single-center, cross-sectional, and retrospective study that enrolled 72 adults with primary UTUC who underwent radical nephroureterectomy at our institution over a period of 4 years (April 2019-April 2023). Symptomatic patients exhibited significantly higher frequencies of high-grade UTUC (73.6% vs. 36.8%, p = 0.006), ≥ T2 stage UTUC (60.4% vs. 26.3%, p = 0.007), and larger tumor sizes (median 5 vs. 4cm, p = 0.015) compared to asymptomatic patients. Multiple regression analyses demonstrated significant associations between symptomatic presentation and the presence of high-grade UTUC (OR 6.35, 95% CI 1.81-22.27, p = 0.004), ≥ T2 stage UTUC (OR 5.98, 95% CI 1.62-22.08, p = 0.007), and larger tumor size (B 3.14, 95% CI 0.62-5.66, p = 0.015). A subset of patients with hematuria was separately analyzed to assess the influence of hematuria severity (gross vs. microscopic) on UTUC characteristics. Patients with gross hematuria exhibited significantly higher frequencies of high-grade UTUC (72.9% vs. 33.3%, p = 0.048) and ≥ T2 stage UTUC (58.3% vs. 22.2%, p = 0.001). Multiple regression analyses showed significant associations between gross hematuria and the presence of high-grade UTUC (OR 6.34, 95% CI 1.15-34.95, p = 0.034) and ≥ T2 stage UTUC (OR 6.54, 95% CI 1.11-38.93, p = 0.039). Initial symptomatic presentation was independently associated with adverse histopathological UTUC characteristics, potentially attributed to earlier detection of UTUC in asymptomatic patients, before the onset of symptoms.

Sequential endoluminal gemcitabine and docetaxel for the treatment of clinically non-invasive high-grade upper tract urothelial carcinoma

PurposeThere is an unmet need for effective renal sparing treatments for upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown favorable efficacy in nonmuscle invasive bladder cancer. We report the outcomes of patients treated with endoluminal Gem/Doce for noninvasive high-grade UTUC. MethodsA retrospective review of patients treated with Gem/Doce for clinically noninvasive high-grade UTUC with no radiographic or endoscopically visible disease, either at diagnosis or following ablation, was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks, followed by 6 monthly instillations if disease-free. Recurrence was defined as biopsy-proven disease or high-grade (HG) cytology. Progression was defined by development of muscle invasion, metastases, or death due to cancer. Survival was assessed with the Kaplan-Meier method. ResultsThe final cohort included 31 patients with 41 upper tract units, 51% of which would have been dialysis dependent with nephroureterectomy. Median (IQR) age was 74 years (68–81). Median follow-up was 29 months (IQR 20–58). Prior to treatment, 37 (90%) units presented with a localizing HG cytology (presumed occult CIS), and 4 (9.8%) with HG biopsy-proven disease. Sixteen (52%) patients reported any side effects; 5 were Grade 3 and 1 was Grade 5. Recurrence-free survival was 76%, 54%, and 40% at 1, 2, and 3 years, respectively. Five patients died from urothelial carcinoma. The 3-year progression-free and overall survival were 75% and 75%, respectively. ConclusionsGem/Doce demonstrates promising safety and efficacy as a renal-sparing treatment option for high-grade UTUC in appropriately selected patients.

PD46-07 URINARY COMPREHENSIVE GENOMIC PROFILING AIDS IN DETECTION AND RISK PROGNOSIS OF UPPER TRACT UROTHELIAL CARCINOMA: A CASE-CONTROLLED COHORT STUDY

You have accessJournal of UrologyCME1 Apr 2023PD46-07 URINARY COMPREHENSIVE GENOMIC PROFILING AIDS IN DETECTION AND RISK PROGNOSIS OF UPPER TRACT UROTHELIAL CARCINOMA: A CASE-CONTROLLED COHORT STUDY Paul Yonover, Robert Kaplinsky, Keyan Salari, Adam Feldman, Debasish Sundi, Kevin G. Phillips, Daniel Fisher, Ava Cherry, Brian C. Mazzarella, Vincent T. Bicocca, Joe Gray, Theresa M. Koppie, Trevor G. Levin, and Justin Cohen Paul YonoverPaul Yonover More articles by this author , Robert KaplinskyRobert Kaplinsky More articles by this author , Keyan SalariKeyan Salari More articles by this author , Adam FeldmanAdam Feldman More articles by this author , Debasish SundiDebasish Sundi More articles by this author , Kevin G. PhillipsKevin G. Phillips More articles by this author , Daniel FisherDaniel Fisher More articles by this author , Ava CherryAva Cherry More articles by this author , Brian C. MazzarellaBrian C. Mazzarella More articles by this author , Vincent T. BicoccaVincent T. Bicocca More articles by this author , Joe GrayJoe Gray More articles by this author , Theresa M. KoppieTheresa M. Koppie More articles by this author , Trevor G. LevinTrevor G. Levin More articles by this author , and Justin CohenJustin Cohen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003359.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A urine test capable of detecting upper tract urothelial carcinoma (UTUC) that provides diagnostic and prognostic information might aid diagnosis and improve risk stratification, which are major clinical challenges in UTUC. Urinary comprehensive genomic profiling (uCGP) via next-generation sequencing with the CLIA-validated UroAmp assay (Convergent Genomics) was developed to identify mutations, diagnose disease, assess molecular grade and stage, and predict recurrence risk. Here we verify that a urine-based uCGP approach can identify lesions in UTUC patients and we compare these genomic profiles to subjects with bladder cancer. METHODS: uCGP was performed on 69 specimens from individuals with de novo pathology-confirmed UC of the bladder (UCB) and 12 urine specimens from individuals with de novo pathology-confirmed UTUC. Urine DNA was sequenced, comprehensively profiled across 60 genes, and disease classification was predicted by a machine learned algorithm. Differential mutational signals of UTUC and UCB were compared through odds ratio (OR) analysis with statistical significance ascribed by Fisher’s exact test. RESULTS: Among UTUC patients, grade distribution was 83% HG, 17% LG; stage distribution was 25% Ta, 25% T1, 8% T2, 8% T3, 8% T4, 25% unknown; among UCB patients grade distribution was 70% HG, 30% LG; stage distribution was 45% Ta, 22% T1, 20% T2, 7% T4, 4% Tis, 2% unknown. uCGP correctly classified 100% of UTUC subjects and 97% (67/69) of UCB subjects as disease positive. UTUC lesions had a high prevalence of TP53 mutations (70%) and frequently demonstrated genomic instability with large scale aneuploidy (40%), loss of heterozygosity (30%), ERCC2 amplification (30%), and CDKN2A loss (10%). Additional recurrent mutations included KMT2C (40%), KMT2D (40%), FGFR3 (30%), and TERT (30%). OR analysis revealed significant enrichment of promoter mutations in TERT (OR=10.6) among high grade (HG) UCB lesions compared to HG UTUC. Further, mutations in ARID1A, PLEKHS1, were solely observed in HG UCB lesions. CONCLUSIONS: uCGP is a quantitative diagnostic with the ability to profile genomic lesions in UTUC and UCB. While further study is needed, distinct mutational patterns in UTUC could potentially serve to identify urologic origins of urine-based disease signals. Source of Funding: Research support by Convergent Genomics © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1172 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Paul Yonover More articles by this author Robert Kaplinsky More articles by this author Keyan Salari More articles by this author Adam Feldman More articles by this author Debasish Sundi More articles by this author Kevin G. Phillips More articles by this author Daniel Fisher More articles by this author Ava Cherry More articles by this author Brian C. Mazzarella More articles by this author Vincent T. Bicocca More articles by this author Joe Gray More articles by this author Theresa M. Koppie More articles by this author Trevor G. Levin More articles by this author Justin Cohen More articles by this author Expand All Advertisement PDF downloadLoading ...

Role of immune checkpoint inhibitors in non-extirpative treatment of high-grade upper tract urothelial carcinoma. Single referral center experience

Role of immune checkpoint inhibitors in non-extirpative treatment of high-grade upper tract urothelial carcinoma. Single referral center experience

Biological and prognostic implications of biopsy upgrading for high-grade upper tract urothelial carcinoma at nephroureterectomy.

Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated. Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low-grade on URS biopsy) versus same grade (high-grade on URS biopsy) for high-grade UTUC tumors on radical nephroureterectomy (RNU) specimens. This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy-based low- and high-grade tumors, respectively. Median follow-up was 27.3 months. Patients with high-grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high-grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10-2.75; p = 0.018), cancer-specific (HR 1.94; 95% CI, 1.07-3.52; p = 0.03), and recurrence-free survival (HR 1.80; 95% CI, 1.13-2.87; p = 0.013). In subgroup analyses of patients with pT2-T4 and/or positive LN, its significant association retained. Furthermore, high-grade biopsy in clinically non-muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (≥pT2) compared to low-grade biopsy. High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low-grade UTUC that becomes upgraded to high-grade might carry a better prognosis than high-grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high-grade on RNU.

Bilateral nephrolithiasis and upper tract transitional cell carcinoma in horseshoe kidney

Nephroureterectomy is currently the criterion-standard treatment for high-grade upper tract urothelial carcinoma. Current guidelines and expert opinions propose some exceptions to this approach based on patient characteristics, disease status, and function of the contralateral kidney. We present a rare case of a patient with horseshoe kidney, bilateral large nephrolithiasis, high-grade upper tract urothelial carcinoma in one moiety, and relative parenchymal thinning of the contralateral side. The patient was treated with a percutaneous, minimally invasive, nephron sparing approach. The patient also had intracollecting system instillations of gemcitabine and docetaxel. Minimally invasive percutaneous resection of high-grade upper tract urothelial carcinoma is a safe procedure in select cases. Current guidelines may not apply to all patients; unique scenarios with upper tract urothelial carcinoma may require personalized decision-making and treatment at specialized centers.

Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival.

The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC. We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation. Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points. Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.

Novel use of ctDNA to identify muscle-invasive and non-organ-confined upper tract urothelial carcinoma.

4587 Background: Upper tract urothelial carcinoma (UTUC) is an aggressive cancer for which use of neoadjuvant chemotherapy (NAC) is limited by suboptimal clinical staging prior to nephroureterectomy. Detection of circulating tumor DNA (ctDNA) is associated with locally advanced and metastatic urothelial carcinoma of the bladder and may help identify UTUC patients who would benefit from NAC. Here we examine the feasibility and utility of plasma ctDNA in the diagnosis of non-organ confined high-risk UTUC. Methods: Patients with high-grade cTa-T2 UTUC without radiographic evidence of metastatic disease undergoing up-front radical nephroureterectomy (RNU) were prospectively accrued for pre- and post-operative plasma collection. Blood was collected preoperatively on the day of surgery, and plasma and buffy coat were processed for extraction of cell-free DNA and genomic DNA, respectively. FFPE tumor samples from RNU were used for tissue genomic DNA extraction. Targeted next-generation sequencing (NGS) was used for variant profiling. ctDNA positivity was defined as the presence of plasma cell-free DNA variants concordant with tissue-based variants. Results: NGS analyses of matched FFPE and plasma samples were successfully performed for all 19 accrued UTUC patients. Alterations in the TERT promoter (74%), TP53 (58%), FGFR3 (53%), myc amplification (53%), and ATM (42%) were demonstrated in urothelial tumor tissue. Matched plasma ctDNA showed prevalent alterations in the TERT promoter (42%), TP53 (42%), PIK3CA (37%), ATM (32%) and CD274 (26%). Nine patients (47%) had detectable plasma ctDNA mutations concordant with tumor-specific variants using the targeted NGS panel. All patients with detectable preoperative ctDNA had advanced staging (≥pT2 or ≥pN1) and lymphovascular invasion on final pathology, resulting in a 90% sensitivity. The panel was 100% specific with no patients with pTis, pTa, pT1 and pN0 having detectable concordant ctDNA mutations. Concordant plasma ctDNA was detected in four of nine patients postoperatively. Two of three (67%) who developed metastatic disease had detectable ctDNA while neither of the two who developed non-muscle-invasive bladder recurrences did. Conclusions: Prospective ctDNA analysis using a targeted NGS panel can be used to predict muscle-invasive and non-organ-confined UTUC preoperatively. Detectable postoperative ctDNA may indicate residual disease and predate clinical recurrence.

The Role of Prior Bladder Cancer on Recurrence in Patients Treated with Radical Nephroureterectomy.

The prognostic role of prior history of bladder cancer (BCa) among patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) is poorly addressed.We aimed to investigate the role of prior BCa on any recurrence, distant metastases, and bladder recurrence following RNU among low-grade (LG) and high-grade (HG) UTUC patients. We retrospectively analyzed 1,580 UTUC patients treated with RNU at 8 tertiary referral centers between 1992 and 2016. Any recurrence was defined as recurrence in the urinary tract, in theresection bed, or distant metastases (defined as disease outside the urinary tract and regional lymph nodes). Time torecurrence wascomputed from RNU. Multivariable Cox models were generated to predict risk of any recurrence, distant metastases, and bladder recurrence according to prior BCa history, coded as no prior BCa, non-muscle-invasive (NMIBC), and muscle-invasive BCa (MIBC). Median follow-up for survivors was 4 years. Overall, 71%, 25%, and 4% of patients had no prior BCa, NMIBC and MIBC. 5-year any recurrence-free survival was 61%, 41%, and 19% in LG (P < .001) and 42%, 34%, and 30% in HG patients (P=.1) with no prior BCa, NMIBC, and MIBC. On multivariable models, LG patients with NMIBC and MIBC showed a significantly higher risk of any recurrencecompared to no prior BCa (bothp≤0.005); previous NMIBCwas associated with any recurrence among HG patients (P=0.04). 5-year distant metastases-free survival was 92%, 90%, and 87% in LG (P > .05) and 68%, 75%, and 45% in HG patients (P=.01) with no prior BCa, NMIBC, and MIBC.Previous NMIBC increased the risk of bladder recurrence among LG (P < .001) and HG (P=.003) patients. UTUC patients with prior history of BCa exhibit a higher risk of any recurrence after RNU. Our study provides important information which could address patient's counseling and decision-making process.

PD58-01 PREVALENCE AND SPECTRUM OF GERMLINE MUTATIONS IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyCME1 May 2022PD58-01 PREVALENCE AND SPECTRUM OF GERMLINE MUTATIONS IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA Hong Truong, Rania Sheikh, Yelena Kemel, Manuel Jesus Escano, Andrew Lenis, Peter Reisz, Alvin Goh, Eugene Cha, Bernard Bochner, Maria Carlo, Hikmat Al-Ahmadie, and Jonathan Coleman Hong TruongHong Truong More articles by this author , Rania SheikhRania Sheikh More articles by this author , Yelena KemelYelena Kemel More articles by this author , Manuel Jesus EscanoManuel Jesus Escano More articles by this author , Andrew LenisAndrew Lenis More articles by this author , Peter ReiszPeter Reisz More articles by this author , Alvin GohAlvin Goh More articles by this author , Eugene ChaEugene Cha More articles by this author , Bernard BochnerBernard Bochner More articles by this author , Maria CarloMaria Carlo More articles by this author , Hikmat Al-AhmadieHikmat Al-Ahmadie More articles by this author , and Jonathan ColemanJonathan Coleman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002643.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Deleterious germline mutations confer high cancer risks and require enhanced cancer screening, yet the prevalence and spectrum of germline mutations among patients with upper tract urothelial carcinoma (UTUC) are unknown. We sought to determine the frequency of germline mutations in cancer susceptibility genes in patients with UTUC and identify clinical and pathologic factors associated with the presence of germline mutations in DNA mismatch repair (MMR) genes. METHODS: We retrospectively reviewed patients with UTUC who underwent germline sequencing with a targeted panel of >75 cancer-associated genes as part of an institutional protocol of matched tumor-germline sequencing initiative from 04/2015 to 04/2021. Prevalence and spectrum of pathogenic/likely pathogenic variants were determined. Clinicopathologic characteristics were assessed by mutation status. All statistical computations were performed using STATA version 12.1. RESULTS: Of 232 patients, 70% were male, 85% had high grade UTUC, 12% had bilateral tumors, and 11% had metastasis at diagnosis. Germline mutations were identified in 37 (16%) patients. 21 (9%) had mutations in Lynch syndrome (LS) associated MMR genes (13 MSH2, 4 MSH6, 4 MLH1) and 11 (5%) had mutations in moderate/high penetrance non-MMR genes (3 BRCA1, 3 BRCA2, 2 ATM, 1 BARD, 1 BRIP1, and 1 CHEK2). In 21 patients with MMR mutations, 3 (14%) had bilateral UTUC, 10 (48%) and 15 (71%) had personal and family history of LS-associated cancers, respectively. Only 10 (48%) of patients with MMR mutations met current NCCN guideline for genetic testing. UTUC tumor analyses of patients with MMR mutations revealed 15/16 (94%) had MMR-deficiency, and 12/18 (67%) had microsatellite instability. CONCLUSIONS: In our cohort of patients with UTUC identified to have pathogenic germline variants in MMR gene, half did not qualify for germline testing based on current genetic guideline for Lynch syndrome. Importantly, most patients with MMR mutations had microsatellite unstable or MMR-deficient UTUC tumors which would qualify patients for immunotherapy. Our findings support germline testing, especially for MMR genes, for all patients with UTUC. Source of Funding: NIH T32 Ruth L. Kirschstein National Research Service Award 2020 - 2022 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1011 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hong Truong More articles by this author Rania Sheikh More articles by this author Yelena Kemel More articles by this author Manuel Jesus Escano More articles by this author Andrew Lenis More articles by this author Peter Reisz More articles by this author Alvin Goh More articles by this author Eugene Cha More articles by this author Bernard Bochner More articles by this author Maria Carlo More articles by this author Hikmat Al-Ahmadie More articles by this author Jonathan Coleman More articles by this author Expand All Advertisement PDF DownloadLoading ...

LBA01-10 INTERIM RESULTS FROM A PHASE 1B CLINICAL TRIAL EVALUATING TOLERABILITY AND ACTIVITY OF FGFR INHIBITION IN LOCALIZED UPPER TRACT UROTHELIAL CARCINOMA (UTUC)

You have accessJournal of UrologyCME1 May 2022LBA01-10 INTERIM RESULTS FROM A PHASE 1B CLINICAL TRIAL EVALUATING TOLERABILITY AND ACTIVITY OF FGFR INHIBITION IN LOCALIZED UPPER TRACT UROTHELIAL CARCINOMA (UTUC) Surena Matin, Mehrad Adibi, Amishi Shah, Omar Alhalabi, Paul Corn, Charles Guo, Rhenita Amirtharaj, Marisa Lozano, Lianchun Xiao, Sumanta Pal, and Matthew Campbell Surena MatinSurena Matin More articles by this author , Mehrad AdibiMehrad Adibi More articles by this author , Amishi ShahAmishi Shah More articles by this author , Omar AlhalabiOmar Alhalabi More articles by this author , Paul CornPaul Corn More articles by this author , Charles GuoCharles Guo More articles by this author , Rhenita AmirtharajRhenita Amirtharaj More articles by this author , Marisa LozanoMarisa Lozano More articles by this author , Lianchun XiaoLianchun Xiao More articles by this author , Sumanta PalSumanta Pal More articles by this author , and Matthew CampbellMatthew Campbell More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002669.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Infigratinib is a potent oral inhibitor of FGFR1-3 with activity in metastatic urothelial cancer (response rate [RR], 25.4%), particularly in patients with metastatic UTUC (RR 50%) (Dizman et al ASCO 2020). We initiated a biomarker-informed preoperative study of infigratinib in patients with localized UTUC. METHODS: Patients with low-grade, or localized cis-platin ineligible high-grade UTUC, undergoing either ureteroscopic (URS) management or nephroureterectomy/ureterectomy (NU/U), were enrolled on a preoperative phase 1b trial (NCT04228042). Enrollment required a GFR of 30 or greater, sufficient biopsy tissue for mutational analysis, and a tumor map of all residual tumors after endoscopic biopsy and any ablation. Treatment consisted of once-daily infigratinib 125 mg (21 days of 28-day cycle) for 2 cycles. A second tumor map based on URS or NU/U was completed after cycle 2. Tolerability was assessed by ongoing monitoring and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, with a total planned enrollment of 20 patients. Targeted sequencing was performed using a NovaSeq 6000 solid tumor panel covering 610 somatic alterations including 33 fusions. RESULTS: From May 2021 until Feb 2022, 12 patients were enrolled (Table). Of 11 evaluable patients, 9 completed therapy and 2 continue on treatment. Of the 9 patients completing therapy, 2 had toxicities preventing the full duration of treatment. 4 of 9 (44%) patients had a response with tumor reduction (range 25-83%); all responders had FGFR3 mutations. Most non-responders had a prior history of bladder cancer and 1 had FGFR3-TACC3 fusion. CONCLUSIONS: Infigratinib shows substantial activity in patients with localized UTUC bearing FGFR3 mutations, consistent with previous data in the metastatic setting. Enrollment continues, and based on these promising initial results, a phase 2 expansion evaluating additional cycles is planned. Source of Funding: The trial was sponsored by QED Therapeutics. Sponsor had no involvement with data acquisition, analysis, or drafting of abstract © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1039 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Surena Matin More articles by this author Mehrad Adibi More articles by this author Amishi Shah More articles by this author Omar Alhalabi More articles by this author Paul Corn More articles by this author Charles Guo More articles by this author Rhenita Amirtharaj More articles by this author Marisa Lozano More articles by this author Lianchun Xiao More articles by this author Sumanta Pal More articles by this author Matthew Campbell More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP40-19 HOW TO IDENTIFY PATIENTS SUITABLE FOR CONSERVATIVE MANAGEMENT OF UPPER TRACT UROTHELIAL CARCINOMA (UTUC) ACCORDING TO TUMOR SIZE: IMPLICATIONS FOR CLINICAL GUIDELINES

You have accessJournal of UrologyCME1 May 2022MP40-19 HOW TO IDENTIFY PATIENTS SUITABLE FOR CONSERVATIVE MANAGEMENT OF UPPER TRACT UROTHELIAL CARCINOMA (UTUC) ACCORDING TO TUMOR SIZE: IMPLICATIONS FOR CLINICAL GUIDELINES Eugenio Ventimiglia, Christian Corsini, Margherita Fantin, Mario de Angelis, Pietro Dioni, Marco Moschini, Daniele Raggi, Maurilio Ponzoni, Umberto Capitanio, Andrea Necchi, Roberta Lucianò, Olivier Traxer, Alberto Briganti, Francesco Montorsi, Luca Villa, and Andrea Salonia Eugenio VentimigliaEugenio Ventimiglia More articles by this author , Christian CorsiniChristian Corsini More articles by this author , Margherita FantinMargherita Fantin More articles by this author , Mario de AngelisMario de Angelis More articles by this author , Pietro DioniPietro Dioni More articles by this author , Marco MoschiniMarco Moschini More articles by this author , Daniele RaggiDaniele Raggi More articles by this author , Maurilio PonzoniMaurilio Ponzoni More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , Roberta LucianòRoberta Lucianò More articles by this author , Olivier TraxerOlivier Traxer More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Luca VillaLuca Villa More articles by this author , and Andrea SaloniaAndrea Salonia More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002600.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tumor size <2 cm is the upper dimensional limit for conservative management of upper tract urothelial carcinoma (UTUC). Within this indication, we aimed to analyze the risk of adverse oncological outcomes of this approach according to specific tumor size. METHODS: Data from 151 consecutive ureteroscopies (n=39 patients) performed for UTUC at a single academic center between 2015 and 2021 were included in this analysis. Two experienced endo-urologists performed all the procedures. Ureteroscopies were performed using a digital flexible ureterorenoscope (Flex XC, Karl-Storz). Ureteroscopic biopsy forceps (3 Fr Piranha, Boston Scientific) were used in every case. Biopsy specimens were assessed by a dedicated uro-pathologist according to 2016 WHO grading classification and classified into low- vs high-grade. Tumor Ho:YAG laser ablation was performed in any case whenever feasible (VersaPulse PowerSuite 100W, Lumenis) using 1 J and 10 Hz. Tumor size was evaluated at pre-operative contrast-enhanced CT-scan; for non-CT visible lesions, size was endoscopically estimated by comparing with a 0.038” nitinol guidewire. We analysed the association between tumor size and histopathological grade according to different size cut-offs (≥1 and <1.5, ≥1.5, and ≥2 cm). Moreover, we explored the graphical relationship between tumor size and the multivariable adjusted probability of having high-grade tumor at biopsy (LOWESS curve). RESULTS: Mean [IQR] tumor size was 1.5 [0.8-2.0] cm. High grade disease was found in 34 cases (23%). At multivariable logistic regression analysis tumor size ≥1.5 cm (OR 2.46 [1.06-5.88], p=0.04) and ≥2.0 cm (OR 2.90 [1.24-6.93]) were associated to increased risk of having high-grade disease, whereas tumor size between 1 and 1.5 cm was not (p=0.80). We then graphically modelled the multivariable adjusted risk of high-grade disease according to different tumor size cutoffs. The risk of high-grade disease (∼20%) remained stable for tumors <1.5 cm, then linearly increased up to 30% for tumors >2 cm. CONCLUSIONS: The probability of diagnosing high-grade UTUC during fURS marginally increases for tumor size ≥ 1.5 cm as compared to smaller lesions. These patients need to be accurately counselled regarding the risk of not being enrollable in conservative management protocols. Source of Funding: none © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e682 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eugenio Ventimiglia More articles by this author Christian Corsini More articles by this author Margherita Fantin More articles by this author Mario de Angelis More articles by this author Pietro Dioni More articles by this author Marco Moschini More articles by this author Daniele Raggi More articles by this author Maurilio Ponzoni More articles by this author Umberto Capitanio More articles by this author Andrea Necchi More articles by this author Roberta Lucianò More articles by this author Olivier Traxer More articles by this author Alberto Briganti More articles by this author Francesco Montorsi More articles by this author Luca Villa More articles by this author Andrea Salonia More articles by this author Expand All Advertisement PDF DownloadLoading ...

Randomized phase II trial of gemcitabine, avelumab and carboplatin versus no neoadjuvant therapy preceding surgery for cisplatin-ineligible muscle-invasive urothelial carcinoma (MIUC): SWOG GAP trial (S2011).

TPS591 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). An unmet need exists in cisplatin-ineligible pts with MIUC who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) have been demonstrated to be safe and active although the benefit may not extend to the majority of pts. The combination of GCa and an ICI has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and an ICI may improve outcomes across a broad group of MIUC by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and long-term outcomes compared to upfront surgery for MIUC (S2011, NCT04871529). Methods: This multicenter, randomized (1:1), open-label phase II trial is comparing the combination of GCa and avelumab (Arm A) as neoadjuvant therapy vs. upfront surgery (Arm B) for pts with cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma (UTUC). Adjuvant therapy following radical cystectomy, nephroureterectomy or ureterectomy is deferred to investigator discretion in both arms. Eligible pts include those with MIBC or high-grade UTUC with a predominant urothelial component who are cisplatin-ineligible (≥1 of: Zubrod performance status [PS] = 2, creatinine clearance [CrCl] 30 to &lt; 60 ml/min, neuropathy &gt; grade 1, hearing loss &gt; grade 1, congestive heart failure &gt; grade 2). The primary objective is pCR. The stratification factors include clinical stage (cT2N0M0 vs cT3-4aN0M0), Zubrod-PS (0-1 vs 2), CrCl (30 to &lt; 60 vs ≥ 60 ml/min). With 178 evaluable pts, the trial will have a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival (EFS) and overall survival (OS). Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics. Arm A receives gemcitabine 1000 mg/m2 IV days 1, 8 every 3 weeks x 4 cycles, carboplatin AUC 4.5 (escalated to AUC 5 from cycle 2 if tolerated in cycle 1) IV day 1 every 3 weeks x 4 cycles and avelumab 800 mg IV day 1 every 2 weeks x 6 cycles. Surgery is performed 4-8 weeks after the last neoadjuvant administration. The trial is funded by NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868, and in part by EMD Serono, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Clinical trial information: NCT04871529.

Defining hereditary upper tract urothelial carcinoma: Implications for genetic testing and clinical management.

523 Background: Despite being a rare cancer, upper tract urothelial carcinoma (UTUC) is the third most common core cancer associated with Lynch syndrome (LS) after colorectal and endometrial cancers. Yet, there is no established guideline to identify patients with UTUC who are at risk of carrying germline mutations in LS-associated genes. The objective of this study is to define selection criteria for patients with UTUC for LS screening. Methods: We retrospectively identified patients with UTUC who underwent germline sequencing of ≥77 cancer susceptibility genes using next generation sequencing (NGS) as part of a prospective matched tumor-normal genomic profiling initiative from 04/2015 to 04/2021. Mismatch repair protein status was evaluated by immunohistochemical (IHC) staining for MMR genes MSH2, MSH6, MLH1, and PMS2. Microsatellite instability (MSI) status was determined using NGS. Diagnostic performance of clinical and tumor-based screening criteria was assessed by the presence of germline pathogenic/likely pathogenic variants (PGVs) in MMR genes. Results: A total of 232 patients with UTUC underwent germline testing; median age of diagnosis was 67 years (interquartile range 59 – 73). Of these patients, 70% were male, 43% had UTUC diagnosed before the age of 65, 85% had high grade UTUC,12% had bilateral UTUC, 11% had metastasis at diagnosis, 10% and 31% had personal and family history of LS-associated cancers, respectively. PGVs in moderate or high-penetrance genes were identified in 31 (13%) patients including 6 (3%) in BRCA1/ 2 and 21 (9%) in MMR genes (13 MSH2, 4 MSH6, 4 MLH1). A total of 10/21 (48%) patients with MMR PGVs developed UTUC as their first cancer diagnosis. Of patients with MMR PVGs, 15/16 (94%) had MMR-deficient tumors and 12/18 (67%) had MSI-high tumors. Personal and family history of LS core cancers (p &lt; 0.001), age of diagnosis &lt; 65 (p = 0.008), MSI-high (p &lt; 0.001), and MMR-deficiency (p &lt; 0.001) were associated with MMR carrier status. Female gender (p = 0.7), HG UTUC (p = 0.5), and bilateral UTUC (p = 0.7) were not associated with MMR PGVs. Current NCCN genetic referral criteria for Lynch syndrome has high specificity in identifying patients with LS (100%) but missed 11/21 (52%) patients with UTUC and MMR PGVs. Conclusions: Current genetic referral guidelines for Lynch syndrome may miss a significant portion of patients with LS-associated UTUC. UTUC tumor should be investigated for MMR protein and MSI status with IHC or next generation sequencing methods to augment LS-screening of patients with UTUC and inform systemic treatment selection.