PURPOSE:To determine whether carcinoma in situ (CIS) is a sufficient measure of minimal residual disease (MRD) in non-muscle-invasive bladder cancer (NMIBC) and evaluate alternative measures of MRD. EXPERIMENTAL DESIGN:We evaluated the concordance of CIS on transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) to determine eradication rates of clinical CIS (cCIS) by TURBT alone and rates of occult pathologic CIS (pCIS) seen only in RC specimens. We studied a prospective cohort of patients with BCG-naïve high-grade NMIBC to evaluate pretreatment urinary cytology and urinary tumor (ut)DNA as alternative biomarkers. RESULTS:Eradication of CIS was seen in 20% of patients (78/383). Positive urinary cytology, but not cCIS, was associated with pCIS. In our prospective cohort (n = 173), abnormal pre-BCG urine cytology, but not pre-BCG cCIS, had worse high-grade recurrence-free survival [HG-RFS; hazard ratio, 3.56; 95% confidence interval (CI), 1.74-7.31, P < 0.001]. The median follow-up was 1.8 years (95% CI, 1.3-2.2). Among those with utDNA available, 84% (56/67) had sufficient DNA for genomic profiling. The 2-year HG-RFS rate in patients without an oncogenic alteration (n = 17) in their pre-BCG urine was 100% versus 60% (95% CI, 46%-78%) in patients with detectable oncogenic alterations (n = 38; P = 0.004). Area under the curve values for predicting 2-year HG-RFS were 0.52 for cCIS, 0.68 for cytology, and 0.74 for utDNA. CONCLUSIONS:We found ∼20% eradication of cCIS from TURBT alone. cCIS was a poor metric of MRD, performing worse than abnormal pretreatment urinary cytology and utDNA. These urine biomarkers are more objective MRD measures than cCIS for NMIBC risk stratification and treatment assessment.

OBJECTIVES:To evaluate the benefit of neoadjuvant chemotherapy (NAC) for patients with high-risk upper tract urothelial carcinoma (UTUC) using a large, well-curated multi-institutional database. PATIENTS AND METHODS:This study was a multi-institutional retrospective analysis conducted by the UTUC Collaborative Network (UCAN), combining data from 2276 patients with UTUC who underwent radical nephroureterectomy at seven high-volume tertiary care centres in the United States. The UCAN data were analysed to evaluate the impact of response to NAC on survival outcomes in patients with UTUC. RESULTS:A total of 378 patients in the UCAN database underwent NAC. On final surgical pathology, 101 patients (26.8%) had ≤ypT1N0 disease and were defined as NAC treatment responders. Patients who responded to NAC had significantly longer overall survival (OS) and progression-free survival (PFS) compared to non-responders. At 5 years post-surgery, 81.5% of responders were alive compared to 59.8% of non-responders. The median OS and PFS times among non-responders were 7.0 years (95% confidence interval [CI] 5.6-9.7) and 6.0 years (95% CI 4.6-9.3) respectively, while the median OS and PFS were not reached among responders. Limitations of this study include its retrospective design, heterogeneity in chemotherapy regimens, and the absence of clearly defined patient selection criteria for treatment. CONCLUSION:These data suggest that NAC can play a pivotal role in the treatment of well-selected UTUC patients who respond positively. Non-responders had clearly inferior outcomes. More work is needed to find predictors of response which can improve patient selection.

Introduction The AUA/SUO guidelines for upper tract urothelial carcinoma (UTUC) recommend endoscopic evaluation as part of the diagnostic workup with grade of tissue as the driving factor for risk stratification. In addition to being a risk factor for intravesical recurrence, ureteroscopic biopsy has a poor concordance with final pathologic stage. Because of this, patients and clinicians must make uninformed decisions regarding various aspect of treatment such as the use of neoadjuvant chemotherapy and intraoperative lymph node dissection. As such, we sought to create a genomic model that was predictive of stage in patients with UTUC. Methods A retrospective cohort of patients that underwent nephroureterectomy and next generation sequencing with MSK-IMPACT, a targeted sequencing panel covering up to 505 genes were included. Diagnoses were dichotomized into low (<T2) or high (≥T2) stage based on final pathology. Genes mutated with ≥5% prevalence and oncogenic or likely oncogenic based on OncoKB annotation were considered for inclusion. Five-fold cross validation was used to compare the following logistic regression models: (1) including only known predictors of stage, TP53 and FGFR3; (2) including only genes significant in univariable analyses after adjustment for TP53 and FGFR3; and (3) logistic regression with stepwise selection. The median and interquartile range (IQR) for sensitivity, specificity, and the area under the curve (AUC) are reported, where sensitivity refers to the proportion of high stage tumors that were predicted to be high stage, and specificity refers to the proportion of low stage tumors that were predicted to be low stage. Results 242 chemotherapy naïve patients were included in the discovery cohort, of which 152 (63%) were stage ≥T2. Stage based on biopsy was only 32% concordant with pathologic stage, with 7% sensitivity and 100% specificity for distinguishing high versus low stage disease (Figure 1). HRAS mutations were significantly associated with increased likelihood of low stage disease after adjustment for TP53 and FGFR3. The multivariable logistic regression model with TP53, FGFR3, and HRAS was selected as the optimal model. Using these three genes in a logistic model resulted in a median AUC of 0.79 (IQR 0.76-0.85). The sensitivity and specificity of the model were 0.60 (IQR 0.50-0.70) and 0.78 (IQR 0.74-0.83), respectively. Conclusions We developed a three-gene model that was predictive of high stage disease. Our model significantly outperforms the accuracy of uretereoscopic biopsy in a development set but is yet to be validated in this population. Ultimately, the clinical utility of this model may be seen not only in improving ureteroscopic biopsy accuracy, but also as applied to sequenced urinary tumor DNA as a non-invasive biomarker. The candidate model is supported by previously published feasibility and concordance studies; validation of this prediction model is planned.

PURPOSE:After radical nephroureterectomy for upper tract urothelial carcinoma, 25% of patients experience distant metastasis within 5 years. Nonurothelial recurrence is associated with poor prognosis and survival, with ∼80% of patients dying within 2 years. We evaluated predictors, patterns, and timing of recurrences after radical nephroureterectomy, and the association between recurrence location and cancer-specific survival. MATERIALS AND METHODS:Separate competing risk regression models were conducted with each site as the outcome and all other recurrence sites as the competing risk. A Cox proportional hazards model was used to evaluate predictors and the association between cancer-specific survival and recurrence site, adjusting for time from surgery to recurrence. A separate model including multiple sites (yes/no) was used to evaluate the association with cancer-specific survival, also adjusting for recurrence sites. RESULTS:Two thousand one hundred seventy-seven patients with upper tract urothelial carcinoma underwent radical nephroureterectomy between January 2000 and February 2021 in 7 institutions, with 454 developing nonurothelial recurrence (survivor median follow-up, 34 [IQR 11-70] months). Improved cancer-specific survival rates were seen in lung and lymph node metastasis compared with other sites (HR 0.60, 95% CI 0.37-0.97, P = .038; HR 0.65, 95% CI 0.41-1.02, P = .063, respectively). Recurrence to multiple concurrent nonurothelial sites was associated with worse cancer-specific survival rates (HR 1.68, 95% CI 1.30-2.17, P < .001). Significant recurrence associations included tumor size, high stage/grade, and tumor location. There were no statistically significant survival differences based on timing of recurrence. CONCLUSIONS:Recurrences were common within 2 years. Lung/lymph node recurrences portended the most favorable cancer-specific survival rates. Understanding the timing and location of recurrence can tailor surveillance strategies.

BACKGROUND AND OBJECTIVE:Molecular classification of upper tract urothelial carcinoma (UTUC) can provide insight into divergent clinical outcomes and provide a biological rationale for clinical decision-making. As such, we performed multi-omic analysis of UTUC tumors to identify molecular features associated with disease recurrence and response to immune checkpoint blockade (ICB). METHODS:Targeted DNA and whole transcriptome RNA sequencing was performed on 100 UTUC tumors collected from patients undergoing nephroureterectomy. Consensus non-negative matrix factorization was used to identify molecular clusters associated with clinical outcomes. Gene set enrichment and immune deconvolution analyses were performed. Weighted gene co-expression network analysis was employed for unsupervised identification of gene networks in each cluster. KEY FINDINGS AND LIMITATIONS:Five molecular clusters with distinct clinical outcomes were identified. Favorable subtypes (C1 and C2) were characterized by a luminal-like signature and an immunologically depleted tumor microenvironment (TME). Subtype C3 was characterized by FGFR3 alterations and a higher tumor mutational burden, and included all tumors with microsatellite instability. Despite higher rates of recurrence and inferior survival, subtypes C4 and C5 harbored an immunologically rich TME favoring response to ICB. Limitations include extrapolation of molecular features of tumors from the primary site to determine response to systemic immunotherapy and the limited resolution of bulk sequencing to distinguish gene expression in the tumor, stroma, and immune compartments. CONCLUSIONS AND CLINICAL IMPLICATIONS:RNA sequencing identified previously underappreciated UTUC molecular heterogeneity and suggests that UTUC patients at the highest risk of metastatic recurrence following surgery include those most likely to benefit from perioperative ICB.

PURPOSE Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

AbstractPurpose: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI [TMB-H/microsatellite stable (MSS)]. Experimental Design: We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test. Results: Sixty-three (2.8%) men had MSI-H/dMMR, and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel, and neoantigen burden compared with TMB-H/MSS. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders. Conclusions: MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB.

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP38)1 May 2024MP38-02 PATTERNS OF NON-UROTHELIAL RECURRENCE AFTER NEPHROURETERECTOMY FOR UPPER TRACT UROTHELIAL CARCINOMA (UCAN COLLABORATION) Andrew B. Katims, Amy L. Tin, Patrick Hensley, Roger Li, Vitaly Margulis, Surena Matin, Maximilian Pallauf, Jonathan Pham, Jay D. Raman, Nirmish Singla, Philippe E. Spiess, and Jonathan Coleman Andrew B. KatimsAndrew B. Katims , Amy L. TinAmy L. Tin , Patrick HensleyPatrick Hensley , Roger LiRoger Li , Vitaly MargulisVitaly Margulis , Surena MatinSurena Matin , Maximilian PallaufMaximilian Pallauf , Jonathan PhamJonathan Pham , Jay D. RamanJay D. Raman , Nirmish SinglaNirmish Singla , Philippe E. SpiessPhilippe E. Spiess , and Jonathan ColemanJonathan Coleman View All Author Informationhttps://doi.org/10.1097/01.JU.0001008700.92603.b1.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: After radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), 25% of patients will experience distant metastasis in the first 5 years. Non-urothelial recurrence is associated with worse prognosis and survival, with ∼80% of patients dying from disease within 2 years. We evaluated the timing and pattern of recurrences after RNU as well as the association of cancer specific survival (CSS) and location of recurrence. METHODS: We identified patients with UTUC who underwent RNU between 01/2000-02/2021 from seven institutions. We categorized recurrences based on site and used competing risk regression models with each site as the main outcome (vs. all other recurrence sites as the competing risk). Cox proportional hazards regression model with time from recurrence to death from disease was created to evaluate the association between CSS and location of recurrence, adjusted for time from surgery to recurrence. A separate model including an indicator for multiple sites was used to assess its association with CSS, after adjusting only for the sites found to be significant in the previous model. RESULTS: 2177 patients were included, among whom 454 developed non-urothelial recurrence (median follow up among survivors was 34 (IQR 11, 70) months). The cumulative incidence of recurrence per site is seen in Figure 1. Risk of CSS based on location of recurrence (p<0.001) is seen in Table 1. Better rates of CSS were seen in lung and lymph node (LN) metastasis (HR 0.60, 95% CI 0.37, 0.97, p=0.038; HR 0.65, 95% CI 0.41, 1.02, p=0.063, respectively). Recurrence to multiple concurrent non-urothelial sites was associated with worse rates of CSS (HR 1.68, 95% CI 1.30, 2.17, p<0.001). CONCLUSIONS: Recurrences mostly occurred within the first 2 years located in the LN or lung which portended the most favorable CSS. These data can be used to inform surveillance strategies after RNU. Download PPT Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e640 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Andrew B. Katims More articles by this author Amy L. Tin More articles by this author Patrick Hensley More articles by this author Roger Li More articles by this author Vitaly Margulis More articles by this author Surena Matin More articles by this author Maximilian Pallauf More articles by this author Jonathan Pham More articles by this author Jay D. Raman More articles by this author Nirmish Singla More articles by this author Philippe E. Spiess More articles by this author Jonathan Coleman More articles by this author Expand All Advertisement PDF downloadLoading ...

Importance With the ongoing bacillus Calmette-Guerin (BCG) shortage, alternate therapeutic options for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are needed. Objective To report the 5-year outcomes of a cohort from a prospective phase 2 trial of patients with high-risk NMIBC who underwent 12 instillations of induction BCG without maintenance. Design, Setting, and Participants Between November 2015 and June 2018, patients at Memorial Sloan Kettering Cancer Center with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without carcinoma in situ) were prospectively enrolled to receive 2 induction courses (12 intravesical instillations) of BCG without maintenance therapy. The analysis itself took place on July 28, 2023. Main Outcomes and Measures Recurrence-free survival (RFS) and cancer-specific survival (CSS) was assessed by landmark analysis at 7.5 months. Recurrence was defined as pathologic high-grade disease. Results Among 81 patients (65 men [84%] and 12 women [16%] with a median [IQR] age of 72 [64-77] years) who consented to participate in the study, 75 remained evaluable for long-term follow-up analysis. Twenty-one patients experienced high-grade recurrence, yielding a 5-year RFS rate of 69% (95% CI, 58%-81%), with a median (IQR) follow-up of 4.4 (3.8-5.3) years for patients without recurrence. Three patients died of bladder cancer, corresponding to a CSS rate of 97% (95% CI, 93%-100%) with a median (IQR) follow-up of 4.9 (4.2-5.7) years for survivors. Using 2 induction courses reduced the amount of BCG per patient from 27 vials to 12 vials. Conclusion and Relevance Twelve induction instillations of BCG without maintenance for patients with high-risk NMIBC reduced the number of vials needed per patient while providing acceptable oncologic outcomes. Given the ongoing BCG shortage, this modified regimen may provide a suitable alternative in this setting.

Importance:With the ongoing bacillus Calmette-Guèrin (BCG) shortage, alternate therapeutic options for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are needed. Objective:To report the 5-year outcomes of a cohort from a prospective phase 2 trial of patients with high-risk NMIBC who underwent 12 instillations of induction BCG without maintenance. Design, Setting, and Participants:Between November 2015 and June 2018, patients at Memorial Sloan Kettering Cancer Center with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without carcinoma in situ) were prospectively enrolled to receive 2 induction courses (12 intravesical instillations) of BCG without maintenance therapy. The analysis itself took place on July 28, 2023. Main Outcomes and Measures:Recurrence-free survival (RFS) and cancer-specific survival (CSS) was assessed by landmark analysis at 7.5 months. Recurrence was defined as pathologic high-grade disease. Results:Among 81 patients (65 men [84%] and 12 women [16%] with a median [IQR] age of 72 [64-77] years) who consented to participate in the study, 75 remained evaluable for long-term follow-up analysis. Twenty-one patients experienced high-grade recurrence, yielding a 5-year RFS rate of 69% (95% CI, 58%-81%), with a median (IQR) follow-up of 4.4 (3.8-5.3) years for patients without recurrence. Three patients died of bladder cancer, corresponding to a CSS rate of 97% (95% CI, 93%-100%) with a median (IQR) follow-up of 4.9 (4.2-5.7) years for survivors. Using 2 induction courses reduced the amount of BCG per patient from 27 vials to 12 vials. Conclusion and Relevance:Twelve induction instillations of BCG without maintenance for patients with high-risk NMIBC reduced the number of vials needed per patient while providing acceptable oncologic outcomes. Given the ongoing BCG shortage, this modified regimen may provide a suitable alternative in this setting.

Introduction Carcinoma in situ (CIS) is a distinct entity in non-muscle invasive bladder cancer (NMIBC) that has both important clinical and research implications. For NMIBC trials, the FDA considers CIS as a “marker lesion” that can be used to determine drug efficacy and allows for approval based on the 3- or 6-month complete response (CR) in patients with BCG-unresponsive CIS. The classification of CIS +/- papillary cohorts and papillary only cohorts, implies that CIS is a surrogate for minimal residual disease (MRD),;despite having limited supporting evidence. Within the context of a prospective clinical protocol, we sought to determine whether the presence of pre-treatment CIS or a pre-treatment positive urinary cytology are indicators of MRD in NMIBC and whether they are associated with treatment outcomes with BCG. Methods Patients with BCG-naive high grade NMIBC (HGTa, HGT1, Tis) were prospectively enrolled onto a biospecimen protocol developed to identify predictors of response/resistance to BCG (IRB #19-015). Patients routinely underwent;repeat TURBT 4-6 weeks following the initial resection, unless not clinically indicated. Pre-treatment CIS status was based on consensus review of the initial and/or repeat TURBT as determined by a GU pathologist. Pre-treatment urinary cytology was collected after the patient's last TURBT but prior to the initiation of BCG and reported based on the Paris System for Reporting Urinary Cytology.;All patients were treated with a standard induction course of BCG +/- maintenance. Patients were monitored for recurrence with cystoscopy and urinary cytology every 3 months for the first 2 years, then every 6 months or as indicated. Recurrences were defined as any high-grade recurrence after BCG treatment. We performed Kaplan Meier survival estimates to compare recurrence free survival (RFS). Results Among 177 patients identified, 174 (98%) completed 6 instillations of induction BCG and 76 (44%) had at least one course of maintenance. Overall, 56 (32%) patients had high grade recurrence and 17 (10%) underwent cystectomy. The overall median follow up was 25.5 months. 68 (46%) patients had CIS on either initial or repeat TURBT. There was no difference in HG-RFS between those that had CIS compared to those that did not (p=0.85) (Figure 1a). 121 patients had cytology results after TURBT but prior to BCG of which 63 (52%) were negative, 26 (21%) were atypical, 13 (11%) were suspicious, and 19 (16%) were positive. Patients with a negative urinary cytology had significantly improved RFS compared to the other groups (p<0.001) (Figure 1b). Abnormal cytology, irrespective of CIS, had the worst RFS (Figure 2). Conclusions Pre-treatment CIS on TURBT is currently considered an indicator of MRD for patients with NMIBC and it is assumed by FDA that CIS cannot be eradicated through TURBT alone. However, utilizing a prospective cohort of high grade NMIBC patients, we found that pre-treatment CIS was not predictive of RFS. Contrarily, patients that had either a positive, suspicious, or atypical cytology after TURBT but prior to BCG had significantly worse RFS compared to those with a negative urinary cytology. Our results suggest that CIS on pre-treatment TURBT is a poor surrogate for MRD and pre-treatment urinary cytology is more predictive of disease recurrence. Using this same cohort, we are evaluating whether urinary tumor DNA sequencing is an even better indicator of MRD for NMIBC.

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma III (PD41)1 May 2024PD41-02 IMPACT OF KMT2 GENE ALTERATIONS ON SURVIVAL OUTCOMES IN UPPER TRACT UROTHELIAL CARCINOMA Muneeb Alam, Andrew B. Katims, Jacob E. Tallman, Wesley Yip, Eugene J. Pietzak, Hikmat Al-Ahmadie, Bernard H. Bochner, Kwanghee Kim, David B. Solit, and Jonathan A. Coleman Muneeb AlamMuneeb Alam , Andrew B. KatimsAndrew B. Katims , Jacob E. TallmanJacob E. Tallman , Wesley YipWesley Yip , Eugene J. PietzakEugene J. Pietzak , Hikmat Al-AhmadieHikmat Al-Ahmadie , Bernard H. BochnerBernard H. Bochner , Kwanghee KimKwanghee Kim , David B. SolitDavid B. Solit , and Jonathan A. ColemanJonathan A. Coleman View All Author Informationhttps://doi.org/10.1097/01.JU.0001008568.76803.f1.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The histone-lysine N-methyltransferase family encompasses proteins that impart epigenetic modifications through lysine methylation of histone H3. These proteins are encoded by the KMT2 family of genes, which are frequently altered in upper tract urothelial carcinoma (UTUC). The purpose of this study is to evaluate the association between KMT2 alterations and outcomes in UTUC. METHODS: Patients diagnosed with UTUC who underwent targeted exome sequencing of up to 505 genes were identified. Patients whose sequencing was performed on a co-occurring bladder tumor were excluded. Tumor mutational burden (TMB) was determined based on the rate of non-synonymous mutations (mut/mB) and compared between groups using the Wilcoxon rank-sum and one-way ANOVA tests. Gene enrichment was evaluated using the false discovery method with q<0.05 considered statistically significant. Survival analysis was performed with the Kaplan-Meier method using the log-rank test to evaluate metastasis-free (MFS) and overall survival (OS) starting at the date of diagnosis. RESULTS: A total of 285 patients were identified for analysis. Median age was 67.5 years (IQR 60.8, 73.7) and 112 (39.3%) patients were female. Median follow-up was 37.9 months (IQR 21.8, 60.5). Definitive surgery was performed in 252 patients, and final pathology demonstrated pT0 (2.4%), pTis (1.6%), pTa (16.3%), pT1 (12.7%), pT2 (11.1%), pT3/4 (35.1%), and pTanyN1-3 (19.8%) disease. Metastatic disease occurred in 52.2% of the cohort. KMT2 alterations included KMT2A (9%), KMT2B (14%), KMT2C (18%), and KMT2D (43%). Median TMB was higher in patients with at least one KMT2 alteration (10.5 vs. 5.9 mut/mB, p<0.001) and was highest for those with alterations in KMT2A (28.1 mut/mB) (Figure 1A). Alterations in KMT2C were associated with superior MFS (HR 0.37, 95% CI 0.25-0.56) and OS (HR 0.51, 95% CI 0.31-0.85). KMT2C-altered tumors were enriched in FGFR3 alterations (60.4% vs. 34.5%, q=0.13), and KMT2C/FGFR3 co-altered tumors demonstrated superior MFS compared to both FGFR3 (HR 0.15, p<0.01) and KMT2C alteration alone (HR 0.17, p<0.01) (Figure 1B). CONCLUSIONS: UTUC demonstrates a high frequency of KMT2 gene alterations, which are associated with increased TMB and metastasis. Further evaluation is warranted to better understand the association between KMT2C and outcomes in UTUC. Download PPT Source of Funding: Ruth L. Kirschstein T32 National Research Service Award © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e886 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Muneeb Alam More articles by this author Andrew B. Katims More articles by this author Jacob E. Tallman More articles by this author Wesley Yip More articles by this author Eugene J. Pietzak More articles by this author Hikmat Al-Ahmadie More articles by this author Bernard H. Bochner More articles by this author Kwanghee Kim More articles by this author David B. Solit More articles by this author Jonathan A. Coleman More articles by this author Expand All Advertisement PDF downloadLoading ...