Lower Tract Urothelial Carcinoma Research Articles

The Genomic Landscape of Urothelial Carcinoma with High and Low ERBB2 Expression.

Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented by ERBB2 expression. NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data. ERRB2-high and -low tumors were defined by ≥75th and <25th percentiles of ERBB2 expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH). Of the patients who were ERBB2-high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), p < 0.001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = 0.95). ERBB2-high tumors had a higher prevalence of pathogenic mutations in pTERT, ERBB2, and ELF3 versus ERBB2-low tumors, p < 0.001. ERBB2-high tumors had higher expressions of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) versus ERBB2-low (p < 0.001), as well as better overall survival from time of tissue sampling than ERBB2-low (HR 1.71, p < 0.001). Our study demonstrated a high concordance between HER2 expression by IHC and ERBB2 gene expression by WTS in UC. Differences in ADC target expression between ERBB2-high vs. ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high ERBB2 expression and survival advantage warrants further investigation.

Characterization and impact of Wnt5A signaling on outcomes of urothelial carcinoma.

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 &lt; 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 &lt; .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 &lt; .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 &lt; .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 &lt; .001) and FZD2 (HR 0.75, 95% CI 0.63-0.89, p &lt; .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 &lt; .76) and ROR1 (HR 0.86, 95% CI 0.72-1.01, p &lt; .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]

The genomic landscape of urothelial carcinoma with high and low ERBB2/HER2 expression.

555 Background: Human epidermal growth factor receptor 2 (HER2) expression has been associated with poor prognosis in urothelial carcinoma (UC). Recent data suggests that HER2-targeted antibody-drug conjugate (ADC) treatment is efficacious. Here, we explore the role of ERBB2/ HER2 expression in UC by analyzing genomic and clinical outcomes in a large database of real-world patient samples. Methods: NextGen Sequencing (NGS) of DNA (592 genes or whole exome sequencing; WES)/RNA (whole transcriptome sequencing; WTS) was performed for 4,743 UC tumors submitted to Caris Life Sciences (Phoenix, AZ). PD-L1 (SP142; Positive (+): ≥ 2+, ≥ %5) and HER2 (4B5; +: ≥3+ and &gt;10%) expression was tested by IHC. High tumor mutational burden (TMB-high) was defined as ≥10 mutations/MB. ERBB2-high and -low expression were defined as ≥ top and &lt; bottom quartile of ERBB2 transcripts per million (TPM), respectively. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( p &lt; .05). Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patients. Results: 2.5% (120/4743) of tumors had HER2 IHC and WTS data available, 97% (61/63) of HER2+ tumors were ERBB2-high, and 98% (51/52) were ERBB2-amplified by DNA NGS (copy number ≥4; 77% with copy number ≥6). Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), p &lt; .001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = .95) but significantly higher in lung metastases (59 v 47 mTPM, p &lt; .001). Mutation rates of ERRB2 (12%), pTERT (76%) and ELF3 (14 %) were higher in ERBB2-high compared to ERBB2-low tumors (5%, 60%, 5%, all p &lt; .001). The opposite pattern was observed for CDKN2A (4% ERBB2-high, 9% ERBB2-low), KMT2D (20%, 35%) and PIK3CA (13%, 23%) (all p &lt; .001). There was a higher incidence of PD-L1+ staining in ERBB2-low (40.3%) compared to ERBB2-high tumors (18%, p &lt; .001). 45.4% of ERBB2-high tumors were TMB-high compared to 35% of ERBB2-low ( p &lt; .001). ERBB2-high tumors had higher expression of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) compared to ERBB2-low (each, p &lt; .001). ERBB2-high tumors were associated with better overall survival from time of tissue sampling than ERBB2-low (HR 1.34, 95% CI 1.14-1.60, p &lt; .001) and from start of anti-PD-L1 therapy (HR 2.26, 95% CI 1.02-5.02, p = .04) but no difference in OS from start of anti-PD1 therapy (HR 1.39, 95% CI 0.75-2.58, p = .30). Conclusions: High concordance between HER2 IHC and ERBB2 expression/amplification was observed. Differences in the genomic landscape and ADC target expression of ERBB2-high vs -low UC may provide rationale for combination treatment strategies with HER2-blocking antibodies. The association between high ERBB2 expression and survival advantage warrants further investigation.

Abstract 5402: Urothelial carcinomas in different anatomical positions exhibit distinct genomic and immunological characteristics

Abstract Background Human bladder cancers were recently suggested to be grouped into different molecular subtypes. However, little is known about the difference in gene landscape between upper tract urothelial carcinoma (UTUC) and lower tract urothelial carcinoma (LTUC) of Chinese patients. Herein, we analyzed the genomic characteristics of primary UTUC and LTUC in China. Methods The formalin-fixed paraffin-embedded specimens of 250 LTUC and 121 UTUC patients have been consecutively collected and have underwent next-generation sequencing (NGS) from 2018 to 2021 in 3DMed Clinical Laboratory Inc. Gene mutation and TMB level were analyzed by NGS, detected PD-L1 expression by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Results NGS analysis showed that, in the samples of UTUC, the top ten gene mutations were CDKN2A/2B 6.6% (8/121), TP53 5.8% (7/121), FGF19 5.8% (7/121), TERT 3.3% (4/121), PREX2 3.3% (4/121), FRS2 3.3% (4/121), KDM6A 2.5% (3/121), PIK3CA 2.5% (3/121), EGFR 2.5% (3/121), MYCL 2.5% (3/121); while in the LTUC, the top gene mutations were TP53 44.4% (111/250), TERT 31.6% (79/250), CDKN2A/2B 25.7% (64/250), FGF3 18% (45/250), KDM6A 17.6% (44/250), PIK3CA 16.4% (41/250), RB1 14.0%(35/250), DGFR3 13.6% (34/250), ARID1A 12.4% (31/250). Furthermore, TMB level and PD-L1 expression in the UTUC and LTUC were also analyzed, and results showed that although the gene mutation was totally different, but no significant difference was found on TMB level (p&amp;gt;0.05). However, among these patients, higher PD-L1 expression level were found in UTUC than LTUC (p&amp;lt;0.05). Conclusion UTUC and LTUC in Chinese patients hold different gene landscape and PD-L1 expression, this suggested these patients may have different prognosis and response differently to targetable therapy and immunotherapy. Citation Format: Ruiqian Li, Hushan Zhang, Qilin Wang, Hong Yang, Yu Bai, Chen Hu, Hongyi Wu, Chongjian Zhang, Ziyong Wang, Qiwei Wang, Pengjie Xu, Jun Li. Urothelial carcinomas in different anatomical positions exhibit distinct genomic and immunological characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5402.

Toripalimab (anti-PD-1) monotherapy as a second-line treatment for patients with metastatic urothelial carcinoma (POLARIS-03): Two-year survival update and biomarker analysis.

4566 Background: Patients with advanced metastatic urothelial carcinoma (mUC) who experience disease progression after standard therapy have limited treatment options. Toripalimab was approved for the 2nd line treatment of mUC based on a phase II clinical study (POLARIS-03) in Chinese patients with mUC (NCT03113266). Here we report the two-year efficacy update and biomarker analysis of the study. Methods: Metastatic UC Patients received toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response was assessed every 8 weeks by independent review committee (IRC) per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 151 patients were enrolled from 15 participating centers. By cutoff date of September 8, 2021, no emergent of new safety signal was identified compared with the previous one-year report. By the cutoff date, 3 CR, 37 PR and 28 SD were observed among the ITT population for an ORR of 26.5% and a DCR of 45.0% as assessed by the IRC. The response was durable as the median duration of response was 25.8 months. The median OS was 14.6 months. Whole exome sequencing (WES) was performed on tumor biopsies and paired PBMCs and the results were available from 135 patients. The median TMB value was 4.1 mutations per million base pairs (Mb) in the cohort. Using 10 mutations/Mb as the cut off, TMB-high patients (n = 27) had better ORR than TMB low patients(n = 108) (48% versus 22%, p = 0.014). The TMB-high group also showed better PFS (12.9 versus 1.8 months, HR = 0.48 [95% CI:0.31-0.74], p &lt; 0.001) and OS (not reached versus 10.0 months, HR = 0.53 [95% CI:0.32-0.88], p = 0.013) than the TMB low group. Patients with mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1 were associated with better responses to toripalimab than patients with wild-type genes. The ORR was 30% (6/20) in patients with FGFR2/FGFR3 mutations or FGFR2/FGFR3 gene fusions, and 42% (5/12) in patients with NECTIN4 genomic alternations. The mutational signature characterized by exposure to aristolochic acid (A:T to T:A transversion) is present in both upper tract urothelial carcinoma (UTUC) and lower tract urothelial carcinoma (LTUC), but enriched in UTUC (p = 0.003). Similar clinical responses were observed in UTUC and LTUC. Conclusions: Toripalimab has demonstrated a manageable safety profile and encouraging clinical activity in metastatic UC patients refractory to 1st line chemotherapy. WES analysis identified divergent mutations in the study. We report the utility of TMB to predict not only the response rate but also the PFS and OS benefits in patients with mUC in response to an ICI monotherapy. Clinical trial information: NCT03113266.

Germline variants across self-reported racial populations with urothelial carcinoma (UC).

4569 Background: Prior studies of the UC germline landscape centered around White patients with minimal representation of other racial populations. Herein, we examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 2,582 patients with UC from various racial populations. Methods: 2,582 patients with UC underwent germline testing of 1 to 126 genes using massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic regions, and copy number alterations (CNAs). P/LP variants including single nucleotide variants, indels and CNAs were reported. Fisher’s Exact test and multivariable logistic regression were used after accounting for the number of genes tested, age at diagnosis, site of disease (upper versus lower tract), gender, family history of UC, and personal history of any cancer. Results: Among the 2,582 patients with UC, median age at diagnosis was 63 years (range, 4-90) and 1158 (44.8%) were female. There were 58 Asians (2.2%), 110 Blacks (4.3%), and 2,414 Whites (93.5%). Overall, 1,639/2,582 (63.5%) patients had a personal history of another cancer and 284/2,393 (11.9%) had history of UC in a family member. 465 P/LP variants were identified in 18% of patients, among whom 286 (11.1%) harbored ≥1 clinically actionable variants. P/LP in cancer-associated genes were most frequently reported in MSH2 (72/2,512, 2.9%), monoallelic MUTYH (45/2,136, 2.1%), BRCA2 (44/2,299, 1.9%) and MSH6 (47/2,511, 1.9%). Patients with upper tract UC had significantly more P/LP (72/247, 29.1%) compared to lower tract UC (332/2,076, 16%, p= 1.3x10-5). Age at diagnosis, gender, personal history of other primary cancers, or family history of UC were not significantly associated with the prevalence of P/LP variants. There were no significant differences ( p= 0.33) in P/LP variants across Asians (11/58, 19.0%), Blacks (14/110, 12.7%), and Whites (440/2,414, 18.2%) although a trend towards lower P/LP in Blacks is notable. Compared to Whites, Blacks and Asians harbored significantly more variants of unknown significance (VUS, Whites vs Blacks: 241/2414 vs 25/110, p= 0.0015; Whites vs Asians: 241/2414 vs 17/58, p= 4e-7). Asians with UC harbored significantly more P/LP variants in ATM (2/50, 4%) compared to Whites (30/2122, 1.4%, OR = 1.1 [95% CI, 1.0-1.2]) and Asian controls from the gnomAD Database. There were no significant differences across racial populations for other highly altered genes ( BRCA1/2, CHEK2, FH, MSH2/6, MUTYH) or for actionable variants. Conclusions: Germline P/LP variants were identified in 18% of patients with UC and were enriched in upper tract tumors. Although no significant differences in P/LP prevalence were noted among patients of different racial populations, a trend towards lower P/LP in Blacks and a higher rate of VUS in Asians and Blacks suggest that ongoing analysis by genetic ancestry may provide richer admixture data and insights.

Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.

567 Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p&lt;0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p&lt;0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]

PD43-06 TUMOR STRATIFICATION OF UPPER TRACT UROTHELIAL CARCINOMA BY GENE EXPRESSION PROFILING AND GENETIC VARIATION

INTRODUCTION AND OBJECTIVE:While lower tract urothelial carcinoma has undergone multiple large gene expression profiling initiatives, upper tract urothelial carcinoma (UTUC) has had relatively litt...

Immune checkpoint inhibitors (ICI) in advanced upper tract and lower tract urothelial carcinoma (UC): A comparison of outcomes.

406 Background: Despite anatomical and biological differences, upper and lower tract UC (UTUC; LTUC) are usually managed similarly. Modern era clinical trial data comparing their outcomes with ICI are conflicting. We hypothesized that response and outcomes would be similar in patients (pts) with advanced UTUC and LTUC. Methods: We performed a retrospective cohort study collecting demographic, clinicopathologic, treatment, and outcome data for pts with advanced UC receiving ICI (2013-2020) across 24 centers (US; Europe). We compared objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between pts with UTUC and LTUC. Uni- / multi- variable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Stratified subgroup analyses were performed according to histology (pure, mixed) and line of treatment (first-line, subsequent). Results: A total of 984 pts were identified, and 707, 717, and 738 were included in ORR, OS, and PFS analyses, respectively. After exclusions, the UTUC group comprised of 130 pts (vs. 616 in LTUC) with median age 71 (40-92) (vs. 70 [32-93]), 62% men (vs. 76%), 41% never smokers (vs. 29%), 62% with history of prior radical surgery for primary tumor (vs. 52%), and 29% with liver metastases (vs. 18%). Table shows results of ORR, OS, and PFS analyses. In the overall population, pts with UTUC and LTUC receiving ICI had comparable ORR, OS, and PFS. Pts with mixed-histology UTUC had significantly lower ORR (adjusted OR 0.20, 95%CI 0.05-0.91) and shorter PFS (adjusted HR 1.66, 95%CI: 1.06-2.59) vs. mixed-histology LTUC. Conclusions: Pts with advanced UTUC and LTUC receiving ICI have similar response and outcomes, except for pts with mixed-histology UTUC vs LTUC. Subset analysis of primary tumor location in ongoing clinical trials can validate our data, while biomarker work is ongoing. [Table: see text]

Site-specific differences in survival among upper and lower tract urothelial carcinoma patients treated with radical surgery.

It currently remains unclear whether the location of primary tumours affects the clinical outcomes of patients with locally advanced urothelial carcinoma in the urinary tract. The aim of the present study was to compare prognostic differences between bladder urothelial carcinoma and upper tract urothelial carcinoma, particularly pT3 or higher tumours. In total, 307 patients with pT3 or higher urothelial carcinoma without distant metastasis who underwent radical cystectomy for bladder urothelial carcinoma (N=127, 41.4%) or radical nephroureterectomy for upper tract urothelial carcinoma (N=180, 58.6%) at Keio University Hospital and three affiliated hospitals between 1994 and 2017 were enrolled. Oncological outcomes were compared between bladder urothelial carcinoma and upper tract urothelial carcinoma using Cox regression analysis. Significantly higher rates of male patients, smokers, neoadjuvant chemotherapy, lymph node involvement and lymphovascular invasion were observed in the bladder urothelial carcinoma group. The incidence of regional lymph node or local recurrence was higher in patients with bladder urothelial carcinoma than in those with upper tract urothelial carcinoma, while that of lung metastasis was lower. In all patients, bladder urothelial carcinoma was independently associated with disease recurrence (hazard ratio (HR) 1.504, P=0.035) in addition to neoadjuvant chemotherapy and lymphovascular invasion. Bladder urothelial carcinoma was also independently associated with cancer death (HR=1.998, P=0.002) as well as lymphovascular invasion. Following the exclusion of patients who received neoadjuvant chemotherapy, bladder urothelial carcinoma remained an independent risk factor for disease recurrence and cancer death (HR=1.702, P=0.010 and HR=1.888, P=0.013, respectively). Bladder urothelial carcinoma may follow worse prognosis compared to upper tract urothelial carcinoma, particularly that with a high pathological stage.

MP61-18 A NATIONWIDE ANALYSIS OF COMPLETE URINARY TRACT EXTIRPATION

INTRODUCTION AND OBJECTIVE: Complete urinary tract extirpation (CUTE) involves bilateral nephroureterectomy and radical cystectomy. This major operation may be necessary for patients with concomitant upper and lower tract urothelial carcinoma (UC) or patients with chronic renal failure and UC. Given the rarity of this operation, descriptions of CUTE are limited to case reports and small case series. However, long−term outcomes following CUTE are not well known, and data regarding oncologic success is limited. METHODS: The United States Renal Data System is a prospective database that includes every hemodialysis (HD) patient in the United States. The database was queried for all patients undergoing radical cystectomy and bilateral nephroureterectomy for UC and resultant need for HD. Post−operative details and complications were assessed. Competing risks analysis was used to estimate overall and cancer−specific survival. Cox regression was used to identify predictors of death. RESULTS: During the study period, a total of 317 patients were identified for analysis, of which 70.9% were male. Mean age was 65.3 ± 12.9 years. Mean length of stay was 16.2 ± 15.3. Overall, 46.0% of patients experienced a complication within 30 days, of which infectious−related complications were most common (13.6%). On multivariable analysis, only female sex was predictive of experiencing a complication (OR 2.37, p<0.01). The 30−day mortality rate was 8.5%. Overall mortality at 1, 3, and 5 years was 45.3%, 69.0%, and 82.7%, respectively. Cancer−specific mortality at 1, 3, and 5 years was 10.0%, 15.7%, and 16.8%, respectively. Predictors of overall mortality were age (subhazard ratio, 1.03; 95%CI, 1.02−1.04) and active smoking status (subhazard ratio, 3.35; 95%CI, 1.50−7.50). CONCLUSIONS: To our knowledge, this represents the largest study evaluating outcomes following CUTE. CUTE is associated with significant morbidity and mortality, with less than 20% of patients surviving 5 years. Complication rate is similar to radical cystectomy, with nearly half of patients experiencing one within 30 days. Source of Funding: None

Blood Myeloid-Derived Suppressor Cells Correlate with Neutrophil-to-Lymphocyte Ratio and Overall Survival in Metastatic Urothelial Carcinoma.

Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC. We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC. MDSCs were measured in blood samples from patientswith mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimatedOS from the time of MDSC collection to last follow-up or date of death. Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS. Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.

Atezolizumab (atezo) therapy for upper tract (UT) urothelial carcinoma (UC): Subgroup analysis of the single-arm international SAUL study in pretreated locally advanced/metastatic urinary tract carcinoma.

488 Background: UTUC is rarer than bladder UC and typically responds poorly to standard chemotherapy. Analysis of 220 biomarker-evaluable atezo-treated patients (pts) in phase II/III trials suggested worse outcomes in UT vs lower tract UC [Galsky, ESMO 2018]. We explored clinical outcomes in pts with UTUC (renal pelvis or ureter) treated with atezo in the SAUL study. Methods: The single-arm SAUL study (NCT02928406) [Sternberg, Eur Urol 2019] enrolled a broader pt population, including pts with poor clinical characteristics and/or immune-mediated conditions, more representative of real-world practice than typically enrolled in randomized phase III immunotherapy trials. Pts with urinary tract carcinoma received atezo 1200 mg q3w until disease progression/unacceptable toxicity. Baseline characteristics, safety and efficacy were analyzed in subgroups of pts with UTUC (subdivided into renal pelvis or ureter UC) vs bladder UC. Results: Baseline characteristics in the 4 subgroups were generally similar, except for a numerically lower proportion of pts with 0 prior lines of therapy for metastatic disease in the UTUC vs bladder UC subgroup (30% vs 41%). Treatment exposure, safety and efficacy are shown below. Conclusions: These exploratory analyses of SAUL showed very similar efficacy and safety in UT vs bladder UC. This provides reassurance that atezo is active and has an acceptable safety profile in pts with UTUC, who are generally expected to have worse outcomes than bladder UC pts. Clinical trial information: NCT02928406 . [Table: see text]

Comparison of Adjuvant Chemotherapy for Upper Tract versus Lower Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis

Introduction: Principles of management for upper tract urothelial carcinoma (UTUC) are mostly derived from knowledge of lower tract urothelial carcinoma (LTUC), however recent research indicates that these may be disparate diseases. In this review, we sought to compare the responsiveness of these tumors to similar treatment, platinum-based chemotherapy used in the adjuvant setting. Materials and Methods: PubMed, EMBASE, and Web of Science were searched using a systematic search strategy. Disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) in patients with LTUC and UTUC treated with adjuvant chemotherapy were compared. Review Manager V 5.3 was used for meta-analyses. Results: Adjuvant chemotherapy was associated with improved DFS (HR 0.41, 95%CI 0.31-0.54), CSS (HR 0.29, 95%CI 0.17-0.50) and OS (HR 0.51, 95%CI 0.38-0.70) rates in LTUC. The effectiveness of adjuvant chemotherapy in UTUC was less pronounced with respect to DFS (HR 0.61, 95%CI 0.1-0.93) and CSS (HR 0.70, 95%CI 0.56-0.90) rates, and there was no effect on OS (HR 0.87, 95%CI 0.69-1.10). Differences in CSS and OS were significant (p < 0.0001) in favor of adjuvant chemotherapy for LTUC versus UTUC Conclusion: Despite similar histology, we found significant differences in responsiveness to adjuvant chemotherapy between LTUC and UTUC. This may add to the already growing knowledge that these are disparate diseases. Newer systemic treatments for urothelial carcinoma may prove more effective than platinum-based chemotherapy in the adjuvant setting for UTUC.

731 - Parallels between immunohistochemical classification of upper and lower tract urothelial carcinoma using markers of urothelial differentiation

731 - Parallels between immunohistochemical classification of upper and lower tract urothelial carcinoma using markers of urothelial differentiation

Distinct genomic hallmarks exist between metastatic upper and lower tract urothelial carcinoma.

371 Background: Although the genomic landscape of LTUC is well studied, less is known about UTUC, including in the metastatic sites. We compared genomic features of metastatic UTUC and LTUC. Methods: We performed whole exome sequencing on 7 rapid autopsy patients with metastatic UC, with matched primary and metastatic tumor samples (N = 37). Single nucleotide variants (SNV) were identified using Mutect and Strelka. Focused analyses were performed on mutations with known significance in UC as well as mutations predicted to have functional impact using 11 mutation assessors. Genome scale copy number aberrations (CNA) were estimated using Sequenza (normalized for ploidy) to derive gene definition restricted copy number estimation outcomes. Multi-dimensional scaling (MDS) was used to visualize how copy number and mutation-derived genomic distances differed between LTUC and UTUC. Results: Three pts with UTUC (3 primary samples, 13 metastases) and four pts with LTUC (4 primary samples, 17 metastases) were examined. The majority of patients were male (5) and received cisplatin-based therapy (5). We found that SNV burden (mean mutation per megabase) was significantly higher in LTUC vs. UTUC overall (6.6 vs. 3.8, p = 0.001) and when stratified by primaries (6.1 vs. 2.9, p = 0.047); or metastases (6.7 vs. 4.1, p = 0.001). Mutational signature analysis revealed higher proportion of APOBEC signature in all LTUC vs. UTUC tumors. Both inter- and intra-individual genomic distances between primary and metastatic tissues were substantially larger in UTUC than LTUC, suggesting a wider spectrum of mutations at the level of individual nucleotides and chromosomal structure. Interestingly, Gene definition-restricted CNA analysis revealed MDM2 amplification exclusively in UTUC tumors which was associated with shallow p53 deletion. Conclusions: Metastatic UTUC appears to have a lower overall mutational burden but greater genomic variability compared to LTUC. Our relatively small dataset suggests that metastatic UTUC displays a greater spectrum of mutational divergence from LTUC which may partially explain differences in clinical behavior.

Diagnostic dilemmas in patients with upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) is a rare condition and recommendations based on a high level of evidence for diagnosis, treatment and follow-up monitoring are lacking. Current decision-making is often based on evidence from trials investigating urothelial carcinoma of the lower tract. Radical nephroureterectomy has been the standard of care for UTUC but kidney-sparing treatment using endoscopic approaches has been established for a select patient group with low-grade and low-stage disease. Optimal treatment choice requires correct tumour characterization. According to available recommendations, diagnostic work-up of UTUC includes evaluation by CT urography or MRI urography, cystoscopy and urine cytology. Ureterorenoscopy and lesion biopsy are grade C recommendations in patients with suspected UTUC. When kidney-sparing treatment is planned, ureterorenoscopy and biopsy should be considered and are the procedures of choice in most cases. These diagnostics have limitations and their accuracy varies in defining tumour characteristics and predicting grade and stage. Urinary tests have higher sensitivity than cytology for detection of lower tract urothelial carcinoma but evidence of their benefit in UTUCs is lacking. New optical and image enhancement techniques are being developed to facilitate real-time diagnostics with increased accuracy. A new diagnostic algorithm for patients with suspected UTUC that integrates the diagnosis, treatment and clinical risk stratification is required.

Impact of squamous and glandular differentiation on oncologic outcomes in upper and lower tract urothelial carcinoma.

PurposeTo investigate the prognostic significance of squamous and/or glandular differentiation in urothelial carcinoma (UC).Materials and MethodsAmong 800 consecutive patients who underwent radical cystectomy or nephroureterectomy at our institution from January 1990 to December 2010, 696 patients were included for the analysis. Clinicopathologic variables were compared according to the presence of squamous and/or glandular differentiation and the tumor location.ResultsA total of 51 (7.3%) patients had squamous and/or glandular differentiation. Patients with squamous and/or glandular differentiation had higher pathological T stage (p<0.001) and grade (p<0.001) than those with pure form of UC. After the median follow-up of 55.2 months, 84 (24.6%) and 82 (23.1%) died of upper urinary tract UC and UC of bladder, respectively. Patients with squamous and/or glandular differentiation in upper urinary tract UC showed poorer cancer-specific survival (CSS) (p<0.001) and overall survival (OS) (p<0.001) than those with pure form in upper urinary tract UC (p<0.001), but not in UC of bladder (p = 0.178 for CSS and p = 0.172 for OS). On multivariate Cox regression analysis, squamous and/or glandular differentiation was an independent predictor of CSS (hazard ratio [HR] 1.76; 95% confidence interval [CI] 1.08–2.85, p = 0.023), but it was not associated with OS (HR 1.52; 95% CI 1.00–2.32, p = 0.051).ConclusionsThe presence of variant histology could be associated with poorer survival outcome in patients with UC. Squamous and/or glandular differentiation is associated with features of biologically aggressive disease and an independent predictor of CSS.

Increased upper and lower tract urothelial carcinoma in patients with end-stage renal disease: a nationwide cohort study in Taiwan during 1997-2008.

Background. Urothelial cancer (UC) is the leading cancer of patients with end-stage renal disease (ESRD) in Taiwan. The aims of this study were to explore the time trends of UC incidences and propose possible etiologic factors. Methods. ing from the National Health Insurance Research Database (NHIRD), there were 90,477 newly diagnosed cases of ESRD between 1997 and 2008 covering the patients aged 40–85. Among them, 2,708 had developed UC after diagnosis of ESRD. The CIR40–85 (cumulative incidence rate) of upper tract UC (UTUC) and lower tract UC (LTUC) were calculated for ESRD patients and general population, as well as SIR40–85 (standardized incidence ratio) for comparison. Results. Female ESRD patients were found to have 9–18 times of elevated risks of UC, while those of males were increased up to 4–14 times. The time trends of CIR40–84 and SIR40–84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA associated herbal products after 1998. Conclusions. Patients with ESRD are at increased risks for both LTUC and UTUC in Taiwan. We hypothesize that the time trends associate with the consumption of aristolochic acid in Chinese herbal products (female predominant).

Stage-Specific Impact of Tumor Location on Oncologic Outcomes in Patients With Upper and Lower Tract Urothelial Carcinoma Following Radical Surgery

BackgroundDissimilarities in management and outcomes exist between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB). ObjectiveThe aim of this study was to analyze the stage-specific impact of upper or lower urinary tract tumor location on oncologic outcomes. Design, setting, and participantsData were collected from 4335 patients with UCB treated with radical cystectomy (RC) and bilateral pelvic lymphadenectomy (PLND), 877 patients with ureteral UTUC, and 1615 with pelvicalyceal UTUC treated with radical nephroureterectomy (RNU). No patient received preoperative chemotherapy or radiation therapy. InterventionsPatients were treated with RC and bilateral PLND or RNU. MeasurementsOutcomes were assessed according to primary tumor location. Results and limitationsCompared to UTUC patients, UCB patients had more advanced tumor stage and higher grade, and they were more likely to harbor lymphovascular invasion (LVI) and lymph node metastasis (p<0.001). In non–muscle-invasive tumor stages, UCB patients were more likely to experience disease recurrence and mortality compared to renal pelvicalyceal tumor patients (p<0.002) but not ureteral tumors (p>0.05). In pT2 and pT3 tumors, there was no difference in outcomes between the three tumor locations. In pT4 tumors, patients with ureteral and pelvicalyceal tumors were more likely to experience disease recurrence and mortality compared to UCB patients (p<0.004). These stage-specific findings were unchanged after adjustment for the effects of age, gender, tumor grade, LVI, lymph node status, and adjuvant chemotherapy. This study is limited by its retrospective and multicenter nature. ConclusionsStage-specific differences in outcomes exist between UCB and UTUC. The differentially worse outcomes by stage between UCB and UTUC patients underline the differences between both cancer entities and the need for individualized stage-specific management for each patient.