Upper Tract Research Articles

Comparison of Oncological Outcomes between Transperitoneal and Retroperitoneal Approaches in Laparoscopic Nephroureterectomies for Upper Tract Urothelial Carcinoma.

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs.

Reply to Jue et al. Overcoming Understaging and Undergrading in Upper Tract Urothelial Carcinoma. Comment on "Ghoreifi et al. Modern Kidney-Sparing Management of Upper Tract Urothelial Carcinoma. Cancers 2023, 15, 4495".

We appreciate the comments made by Jue et al [...].

Cumulative incidence and risk factors for recurrence of upper tract urothelial carcinoma in patients undergoing radical cystectomy

AbstractObjectivesThis study aimed to evaluate the cumulative incidence of upper tract urothelial carcinoma (UTUC) recurrence and identify its risk factors in patients who underwent radical cystectomy (RC).Patients and methodsWe performed RC on 385 patients between September 2002 and February 2020. After excluding 20 patients—13 with simultaneous nephroureterectomy, 6 with distal ureteral stump positivity and 1 with urachal cancer—365 patients were included in the analysis. To predict UTUC recurrence, we examined the cancer extension pattern in cystectomy specimens and categorized them into three types: cancer located only in the bladder (bladder‐only type), cancer extending to the urethra or distal ureter (one‐extension type) and cancer extending to both the urethra and distal ureter (both‐extension type). We determined hazard ratios for UTUC recurrence for each covariate, including this cancer extension pattern.ResultsOf the 365 patients, 60% had the bladder‐only type, 30% had the one‐extension type and 10% had the both‐extension type. During a median follow‐up period of 72 months for survivors, UTUC recurred in 25 of the 365 patients, with cumulative incidences of 3.7% at 5 years and 8.3% at 10 years. The median interval from cystectomy to recurrence was 65 months (interquartile range: 36–92 months). In the multivariate analysis, the extension pattern was a significant predictor of UTUC recurrence. The hazard ratios for UTUC recurrence were 3.12 (95% confidence interval [CI] = 1.15–8.43, p = 0.025) for the one‐extension type and 5.96 (95% CI = 1.98–17.91, p = 0.001) for the both‐extension type compared with the bladder‐only type.ConclusionsThe cancer extension pattern in cystectomy specimens is predictive of UTUC recurrence. A more extensive cancer extension in cystectomy specimens elevates the risk of subsequent UTUC recurrence. Intensive long‐term monitoring is essential, particularly for patients with the both‐extension type.

Overcoming Understaging and Undergrading in Upper Tract Urothelial Carcinoma. Comment on Ghoreifi et al. Modern Kidney-Sparing Management of Upper Tract Urothelial Carcinoma. Cancers 2023, 15, 4495.

Kidney-sparing management for upper tract urothelial carcinoma (UTUC) has become more common but is still most limited by inaccurate histopathologic diagnosis [...].

FGFR3 Mutations in Urothelial Carcinoma: A Single-Center Study Using Next-Generation Sequencing.

Background: Mutations of fibroblast growth factor receptor 3 (FGFR3) are associated with urothelial carcinoma (UC) oncogenesis and are considered an important therapeutic target. Therefore, we evaluated the FGFR3 mutation rate and its clinical significance in urothelial carcinoma (UC) using next-generation sequencing. Methods: A total of 123 patients with UC who were treated at Chonnam National University Hospital (Gwang-ju, Korea) from January 2018 to December 2020 were enrolled. We performed NGS using the Oncomine panel with tumor specimens and blood samples corresponding to each specimen. We analyzed the FGFR3 mutation results according to the type of UC and the effects on early recurrence and progression. Results: The mean age of the patients was 71.39 ± 9.33 years, and 103 patients (83.7%) were male. Overall, the FGFR3 mutation rate was 30.1% (37 patients). The FGFR3 mutation rate was the highest in the non-muscle-invasive bladder cancer (NMIBC) group (45.1%), followed by the muscle-invasive bladder cancer (22.7%) and upper tract UC (UTUC) (14.3%) groups. Patients with FGFR3 mutations had a significantly lower disease stage (p = 0.019) but a high-risk of NMIBC (p < 0.001). Conclusions: Our results revealed that FGFR3 mutations were more prevalent in patients with NMIBC and lower stage UC and associated with a high-risk of NMIBC. Large multicenter studies are needed to clarify the clinical significance of FGFR3 mutations in UC.

A preoperative magnetic resonance imaging can aid in staging and treatment choice for upper tract urothelial carcinoma

AbstractObjectivesThe aim was to investigate the predictive abilities of a preoperative diffusion‐weighted MRI (dwMRI) among patients with surgically treated upper tract urothelial carcinoma (UTUC).Materials and methodsWritten consent was obtained from all participants in this prospective and ethically approved study. Thirty‐five UTUC patients treated with radical surgery were examined with a preoperative dwMRI and prospectively included during 2017–2022. Two radiologists examined the CT scans and dwMRIs for radiological stage, and the apparent diffusion coefficient (ADC) in the tumours at the dwMRI was registered. The radiologists were blinded for patient history, final histopathology and the readings of the other radiologist. The radiological variables were analysed regarding their abilities to predict muscle‐invasive disease (MID, T2–T4) and tumour grade at final pathology after radical surgery. The predictive abilities were assessed using chi‐square tests, Student's t‐test and calculating the area under the curve in a receiver operating characteristic (ROC) curve. Correlation between the two radiologists was quantified calculating the intra‐class correlation coefficient. P‐values &lt;0.05 were considered statistically significant.ResultsMean age was 72 years, 20 had high‐grade tumour, and 13 patients had MID. The ADC values at the dwMRI were significantly lower among patients with MID compared to patients with non‐muscle‐invasive disease (930 vs 1189, p = &lt;0.001). The area under the ROC curve (AUC) in an ROC curve to predict MID was 0.88 (CI 0.77–0.99, p = &lt;0.001). The ADC values were significantly lower among patients with high‐grade tumours compared to low‐grade tumours (1005 vs 1210, p = 0.002). The correlation of the ADC measurements between the two radiologists was of 0.93 (CI 0.85–0.96, p &lt; 0.001).ConclusionTumour ADC at the MRI emerges as a potential biomarker for aggressive disease. The results are promising but should be validated in a larger, multicentre study.

Metastatic upper tract urothelial carcinoma with nest-like features presenting as malignant pleural effusion.

Metastatic urothelial carcinoma is a rare cause of pleural effusions. We report a case of urothelial carcinoma of the upper urinary tract in an oldest-old male patient, a smoker, with situs inversus totalis, that presented uniquely with malignant pleural effusion at presentation without evidence of a primary tumor on imaging. Cytological smears of the massive left pleural effusion revealed epithelioid neoplastic cells arranged in short cords, small-to-large clusters, and raspberry-like morules, mimicking mesothelioma; cell block preparations highlighted the presence of tubules and nest-like structures. The tumor cells showed a high nuclear-to-cytoplasmic ratio, nuclear grooves, and mitotic figures. Cytomorphologic features coupled with the immunophenotype of neoplastic cells (p63, GATA3, and uroplakin II positive) allowed the diagnosis of metastatic urothelial carcinoma and a possible nested subtype. These findings were supported by a total body computed tomography (CT) showing no evidence of a mass in the bladder or elsewhere in the urinary tract but a concentric parietal thickening of the proximal left ureter, suggesting malignancy. To our knowledge, a malignant effusion as a primary manifestation of urothelial carcinoma with nest-like features originating in the upper urinary tract has never been described previously. Our case focuses on the value of cell block in the working-up of neoplastic effusions by revealing the architectural pattern of an uncommon malignancy and the correlation between cytopathology and imaging gross findings to reach an accurate diagnosis.

Low rate of severe-end-stage kidney disease after SABR for localised primary kidney cancer

BackgroundStereotactic ablative body radiotherapy (SABR) is an emerging treatment for patients with primary renal cell carcinoma (RCC). However, its impact on renal function is unclear. This study aimed to evaluate incidence and clinical factors predictive of severe to end-stage chronic kidney disease (CKD) after SABR for RCC.Methods and materialsThis was a Single institutional retrospective analysis of patients with diagnosed primary RCC receiving SABR between 2012–2020. Adult patients with no metastatic disease, baseline estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73 m2, and at least one post-SABR eGFR at six months or later were included in this analysis. Patients with upper tract urothelial carcinoma were excluded. Primary outcome was freedom from severe to end-stage CKD, determined using the Kaplan–Meier estimator. The impact of baseline CKD, age, hypertension, diabetes, tumor size and fractionation schedule were assessed by Cox proportional hazard models.ResultsSeventy-eight consecutive patients were included, with median age of 77.8 years (IQR 70–83), tumor size of 4.5 cm (IQR 3.9–5.8) and follow-up of 42.2 months (IQR 23–60). Baseline median eGFR was 58 mls/min; 55% (n = 43) of patients had baseline CKD stage 3 and the remainder stage 1–2. By last follow-up, 1/35 (2.8%) of baseline CKD 1–2, 7/27 (25.9%) CKD 3a and 11/16 (68.8%) CKD 3b had developed CKD stage 4–5. The estimated probability of freedom from CKD stage 4–5 at 1 and 5 years was 89.6% (CI 83.0–97.6) and 65% (CI 51.4–81.7) respectively. On univariable analysis, worse baseline CKD (p < 0.0001) and multi-fraction SABR (p = 0.005) were predictive for development of stage 4–5 CKD though only the former remained significant in multivariable model.ConclusionIn this elderly cohort with pre-existing renal dysfunction, SABR achieved satisfactory nephron sparing with acceptable rates of severe to end-stage CKD. It can be an attractive option in patients who are medically inoperable.

Absence of GATA3/FOXA1 co-expression predicts poor prognosis in upper tract urothelial carcinoma.

GATA binding protein 3 (GATA3) and forkhead box A1 (FOXA1) have been individually implicated in the progression of upper tract urothelial carcinoma (UTUC). This study aims to evaluate the prognostic value of GATA3/FOXA1 co-expression in UTUC patients. We collected 108 UTUC pathological tissue samples with complete follow-up data and 24 normal control urothelial tissues. We created a 132-site microarray and performed immunohistochemistry (IHC) to measure GATA3 and FOXA1 expression levels. Kaplan-Meier survival and Cox regression analyses were conducted to assess UTUC prognosis. GATA3 expression was positively correlated with FOXA1 (P=0.031). Absence of GATA3/FOXA1 co-expression (GATA3-/FOXA1-) was associated with tumor extensive necrosis (P=0.001) after Bonferroni correction for multiple comparisons. GATA3-/FOXA1- was associated with shorter Disease-Free Survival (DFS) (P=0.001) and Cancer-Specific Survival (CSS) (P<0.001) than other combination groups. Multivariate analyses identified extensive necrosis as an independent prognostic factor for CSS (P=0.030). Our study revealed a positive correlation between GATA3 and FOXA1 expression in UTUC. GATA3-/FOXA1- is linked to tumor extensive necrosis and poor prognosis in UTUC and may serve as a potential biomarker for UTUC patients.

Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node-positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR) = 0.55 (95% CI, 0.38 to 0.80, P = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR = 0.68 (95% CI, 0.46 to 1.00, P = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.

The efficacy and safety of tislelizumab combined with gemcitabine plus cisplatin in the treatment of postoperative patients with muscle-invasive upper tract urothelial carcinoma

BackgroundA combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated excellent clinical efficacy and safety in treating a variety of cancers, including urothelial carcinoma (UC). However, its efficacy and safety in patients with muscle-invasive upper tract urothelial carcinoma (UTUC) who are undergoing radical surgery remain uncertain. The purpose of this retrospective study was to examine the effectiveness and safety of tislelizumab combined with gemcitabine plus cisplatin (TGC) as a first-line postoperative adjuvant treatment in this population.MethodsThis single-center, real-world study retrospectively analyzed the data from 71 patients with muscle-invasive UTUC who had radical nephroureterectomy (RNU) at the Affiliated Hospital of Xuzhou Medical University between November 1, 2020, and November 1, 2023. Among the 71 patients, 30 received adjuvant therapy of TGC within 90 days after RNU and 41 underwent surveillance. No patients receive preoperative neoadjuvant therapy. The TGC therapy group received adjuvant therapy every 3 weeks postoperatively until the first recurrence, first metastasis, or death due to any reason, whichever occurred first. The patients were followed up telephonically and through outpatient visits to record and evaluate their disease-free survival (DFS) and treatment-related adverse events (TRAEs).ResultsThis study assessed the DFS of 41 and 30 patients in the surveillance group and TGC therapy group, respectively. The median DFS of the surveillance group was 16.5 [95% confidence interval (CI), 14.7–18.3] months, while the median DFS of the TGC group has not yet reached [hazard ratio (HR) 0.367 (95% CI, 0.169–0.796); p = 0.008], with 21 patients still undergoing follow-up. Compared with the surveillance group, the TGC therapy group had dramatically improved DFS after RNU and reduced risk by 63.3%. Of the 30 patients receiving combination therapy, 28 experienced TRAEs; all TRAEs were consistent with the frequently reported events in the chemotherapy-alone regimens, and there were no treatment-related deaths.ConclusionThis study demonstrates that TGC therapy exhibits excellent clinical efficacy in patients undergoing radical surgery, significantly improving DFS and displaying great safety.

Diagnostic Value of Urine Cytology in Pharmacologically Forced Diuresis for Upper Tract Urothelial Carcinoma Diagnosis and Follow-Up.

We performed a urine cytology analysis of a pharmacologically induced diuresis for the diagnosis of upper tract urothelial carcinoma. To evaluate the diagnostic value of cytology of pharmacologically forced diuresis, an initial cohort of 77 consecutive patients with primary upper tract urothelial carcinoma treated via radical surgery was enrolled. To evaluate pharmacologically forced diuresis cytology as a follow-up procedure, a second cohort of 1250 patients who underwent a radical cystectomy for bladder cancer was selected. In the first cohort, the sensitivity of cytology of pharmacologically forced diuresis in patients with invasive, high-grade, low-grade, and concomitant carcinoma in situ was 8%, 9%, 0%, and 14%, respectively. In the second cohort, cytology of pharmacologically forced diuresis was positive in 30/689 (4.3%) patients, in whom upper urinary tract recurrence was present in 21/30 (70%) of cases, and urethral recurrence was present in 8/30 (26%) of cases. As a follow-up tool, cytology of pharmacologically forced diuresis showed a sensitivity, specificity, and positive and negative predictive values of 60%, 99%, 70%, and 98%, respectively. Overall, as a diagnostic tool, the sensitivity of cytology of pharmacologically forced diuresis is slightly better in patients with invasive upper tract urothelial carcinoma and concomitant carcinoma in situ. As a follow-up method, positive cytology of pharmacologically forced diuresis is strongly related to cancer recurrence and can reveal urethral recurrence. Cytology of pharmacologically forced diuresis might be useful in cases with contraindications for imaging or when achieving endoscopic access to the upper urinary tract is difficult.

Analysis of progression after elective distal ureterectomy and effects of salvage radical nephroureterectomy in patients with distal ureteral urothelial carcinoma

We compared the progression patterns after radical nephroureterectomy (RNU) and elective distal ureterectomy (DU) in patients with urothelial carcinoma of the distal ureter. Between Jan 2011 and Dec 2020, 127 patients who underwent RNU and 46 who underwent elective DU for distal ureteral cancer were enrolled in this study. The patterns of progression and upper tract recurrence were compared between the two groups. Progression was defined as a local recurrence and/or distant metastasis after surgery. Upper tract recurrence and subsequent treatment in patients with DU were analyzed. Progression occurred in 35 (27.6%) and 10 (21.7%) patients in the RNU and DU groups, respectively. The progression pattern was not significantly different (p = 0.441), and the most common progression site was the lymph nodes in both groups. Multivariate logistic regression analysis revealed that pT2 stage, concomitant lymphovascular invasion, and nodal stage were significant predictors of disease progression. Upper tract recurrence was observed in nine (19.6%) patients with DU, and six (66.7%) patients had a prior history of bladder tumor. All patients with upper tract recurrence after DU were managed with salvage RNU. Elective DU with or without salvage treatment was not a risk factor for disease progression (p = 0.736), overall survival (p = 0.457), cancer-specific survival (p = 0.169), or intravesical recurrence-free survival (p = 0.921). In terms of progression patterns and oncological outcomes, there was no difference between patients who underwent RNU and elective DU with/without salvage treatment. Elective DU should be considered as a therapeutic option for distal ureter tumor.

Urine cytology in the detection of renal cell carcinomas - a territory-wide multi-institutional retrospective review of more than 2 decades.

Compared with urothelial lesions of the upper urinary tract, the diagnostic performance of urine cytology in detection of renal cell carcinomas is underreported. This study aims to establish the role of urine cytology in the assessment of renal carcinomas by a multi-institute review of urine cytology from nephrectomy confirmed renal cell carcinomas, referenced against renal urothelial and squamous cell carcinomas. Records of nephrectomy performed from the 1990s to 2020s at three hospitals were retrieved and matched to urine cytology specimens collected within 1year prior. Patient demographics, specimen descriptors, and histology and staging parameters were reviewed and compared against cytologic diagnoses. There were 1147 cases of urine cytology matched with renal cell carcinomas, with 666 renal urothelial/squamous carcinomas for comparison. The detection rate for urothelial/squamous (atypia or above [C3+]: 63.1%; suspicious or above [C4+]: 24.0%) were higher than renal cell carcinoma (C3+: 13.1%; C4+: 1.5%) (p<0.001). The positive rate for upper tract urine exceeded other collection methods at 45.0% (C3+) and 10.0% (C4+) (p<.01). Other factors associated with increased positive rates were male sex, collecting duct carcinoma histology, nuclear grade, and renal/sinus involvement (p<.05). Multivariate analysis revealed additional positive correlations with presence of sarcomatoid tumor cells, lymphovascular invasion, and perinephric fat involvement (p<.05). Larger lesion size and higher urine volume did not improve detection rates (p<.05). The detection rate of renal cell carcinomas is suboptimal compared with urothelial carcinomas, although urine samples collected from cystoscopy or percutaneous nephrostomy significantly outperformed voided urine specimens.

Changes in the Perioperative Management and Outcomes of Patients With Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy at Memorial Sloan Kettering Cancer Center: Over 20 Years of Experience.

We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period. Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models. Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable. We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

FGFR3 mutated (FGFR3mut+) urothelial carcinoma of bladder (UCB) or upper tract (UTUC): A comparative genomic landscape study.

540 Background: Activating DNA sequence genomic alterations (GA) in the FGFR3 gene including short variant (SV) mutations and kinase domain activating gene rearrangements/fusions (RE-FUS) are known drivers and relevant precision treatment targets for pts with UC. THOR trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs (taxane or vinflunine) in patients (pts) with advanced UCB or UTUC. PROOF-302 trial showed higher frequency of FGFR3 GA in UTUC (30%) vs UCB (13%). We sought to explore differences in frequency of FGFR3 alterations and the genomic landscapes of FGFR3-altered UCB and UTUC. Methods: 10,402 UCB and 2,325 UTUC (combined ureter and renal pelvis) underwent hybrid capture-based comprehensive genomic profiling (CGP) using a hybrid capture-based to assess all classes of GA and measure MSI status, TMB level, genomic ancestry, genomic signature, germline mutations and HRD score. PD-L1 was determined by IHC (Dako 22C3 using the TPS system. Results were compared using the Fisher Exact method with the Benjamini-Hochberg adjustment. Results: FGFR3mut+ status was significantly more frequent in UTUC than in UBC (24.9% vs 17.7%; p&lt;.0001) (Table). UCB pts were more often male than UTUC (P=.0003). Age (71-72 yrs), EUR ancestry (85%) and GA/tumor (8.9-9.0) were similar. The number of GA/case and the frequency of EUR ancestry were similar. Targetable GA in ERBB2 and PIK3CA were more frequent in FGFR3mut+ UBC vs FGFR3mut+ UTUC. GA in PTEN, TSC1 and MTAP currently associated with clinical trials were similar in UBC and UTUC. The KEGG ERBB and VEGF signaling pathways were more frequently identified in UCB (p=0.036) and the MMR pathway more frequently identified in UTUC (p=0.014). The HRD signature was similar in both groups (2.3-3.1%). Anti-PD(L)1 putative biomarkers included a significantly higher frequency of MSI-high status in UTUC vs UCB but no significant difference in TMB or PD-L1 expression levels. Conclusions: Although histologically similar, the genomic landscape of FGFR3mut+ UTUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation. The findings may impact of clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents. [Table: see text]

WUTSUP-02-II-Neo-Dis-Tis: Investigating the efficacy and safety of neoadjuvant tislelizumab plus disitamab vedotin with adjuvant tislelizumab in upper urinary tract carcinoma—A phase II multi-center study.

TPS718 Background: Upper tract urothelial carcinoma (UTUC) and urothelial bladder cancer (UBC) are frequently referred to as “disparate twins” despite their common tissue origin. They exhibit varying biological behaviors, prognostic outcomes, and responses to treatment. It is crucial to conduct dedicated clinical trials for UTUC as a separate entity rather than relying solely on UBC study results, giving that UTUC lags in evidence quantity and quality compared to UBC. Despite the superior outcomes of neoadjuvant treatment over adjuvant treatment in UBC trials, the currently available evidence for neoadjuvant therapy of UTUC remains limited in quantity and diversity, as the largest trial, POUT, is focused on adjuvant therapy. Additionally, the limited number of neoadjuvant trials for UTUC primarily utilize chemotherapy-based regimens, with little investigation into combination therapies. Of note, UTUC patients frequently have impaired renal functions, making a chemotherapy-independent approach a desirable alternative. On the other hand, given the short duration of neoadjuvant therapy, a combination therapy strategy appears to be necessary, especially with the increasing interest in immune therapy maintenance after surgery. Tislelizumab has demonstrated efficacy in patients with advanced or metastatic urothelial carcinoma. Disitamab Vedotin, a HER2-targeting antibody-drug conjugate (ADC), has demonstrated robust clinical efficacy in metastatic urothelial carcinoma patients with HER2 2+ or 3+ expression. Disitamab Vedotin in combination with PD-1 immunotherapy has shown remarkable results in locally advanced or metastatic urothelial carcinoma, regardless of HER2 expression, indicative of a synergistic effect between ADC and PD-1 immunotherapy. In this study, we aim to conduct a prospective phase II trial to investigate the efficacy and safety of neoadjuvant tislelizumab plus Disitamab Vedotin followed by adjuvant tislelizumab in patients with high-risk UTUC. Methods: This multi-center phase II trial aims to enroll 45 patients with histologically confirmed UTUC at clinical stage cT2-4N0M0 or cT1-4N1-2M0. Neoadjuvant therapy includes 4 cycles of Tislelizumab (200mg for each 3-week cycle) in combination with Disitamab Vedotin (2.0mg/kg for each 3-week cycle). Radical nephroureterectomy (including bladder cuff resection and regional lymph node dissection if indicated) will be performed if there is no obvious contraindication within 3-6 weeks after the final neoadjuvant therapy administration. Postoperative adjuvant treatment with 8 cycles of tislelizumab will be provided. The primary endpoint is pathological complete response rate. Secondary endpoints include overall survival, local recurrence free survival, distant metastasis free survival, FACT–G. Clinical trial information: ChiCTR2300067836 .

AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation.

LBA531 Background: Muscle-invasive urothelial carcinoma (MIUC) is an aggressive disease with high relapse rates. Neoadjuvant platinum-based chemotherapy (NAC) is the standard of care in patients (pts) who are cisplatin (Cis)-eligible. However, many pts are Cis-ineligible or have persistent muscle-invasive disease after NAC and surgery. We evaluated pembrolizumab (Pembro) as adjuvant therapy in pts with high-risk MIUC following surgical resection. Methods: The AMBASSADOR study is an open-label, randomized, phase III trial that enrolled pts with histologically confirmed MIUC of the bladder, upper tract, or urethra who (1) had ≥ pT2 and/or pN+ or margins+ at surgery (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy) following NAC or (2) ≥ pT3 and/or pN+ or margins+ at surgery without NAC and were either Cis-ineligible or declined adjuvant Cis-based therapy. Pts were registered ≥4 to 16 weeks after surgery and randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or observation (Obs). Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC. The dual primary endpoints were disease-free survival (DFS) and overall survival (OS) with a target sample size of 739 pts and required 387 DFS and 320 OS events for final analysis. Secondary objectives included evaluation of DFS and OS in PD-L1-positive and -negative pts and assessing safety. Here we present the interim DFS and OS results. Results: Between 09/2017 and 08/2021 a total of 702 pts were randomized prior to early closure due to US FDA approval of nivolumab for MIUC pts: 354 pts to Pembro and 348 pts to Obs; 13.0% vs 21.6% withdrew from study without event in the Pembro vs Obs arms, respectively. 74 pts (21%) in the Obs arm received an immune checkpoint inhibitor. Median follow-up was 22.3 months (mos) for DFS and 36.9 mos for OS. The DFS endpoint (based on 319 events needed for interim analysis) crossed the efficacy boundary. Median DFS was 29.0 months (95% confidence interval (CI) 21.8‒not evaluable (NE)) with Pembro and 14.0 months (95% CI 9.7‒20.20) with Obs (hazard ratio (HR) 0.69 [95% CI 0.55–0.87]; p=0.0013). At the interim analysis (n = 257 events), median OS was 50.9 months (95% CI 43.9‒NE) with Pembro and 55.8 months (95% CI 53.3‒NE) with Obs (HR 0.98 [95% CI 0.76–1.26]; p=0.88). Grade 3+ adverse events occurred in 48.4% and 31.8% of pts in the Pembro and Obs arms, respectively. Conclusions: Adjuvant Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs Obs for high-risk MIUC pts after radical surgery. The OS endpoint may have been impacted by pts on the Obs arm receiving a checkpoint inhibitor. Pembro was tolerable with no new safety signals. These results support adjuvant Pembro as a new therapeutic option for pts with MIUC with high risk for recurrence. Additional follow-up is ongoing for the final DFS/OS, PD-L1 subgroups, and ctDNA analyses. Clinical trial information: NCT03244384 .

Defining molecular features associated with microsatellite instability and response to immune checkpoint blockade in urothelial carcinoma.

536 Background: Microsatellite instability (MSI) and deficient mismatch repair (dMMR) are associated with sensitivity to immune checkpoint blockade (ICB) in urothelial carcinoma (UC). MSI status may only partially explain this sensitivity, and the molecular features that distinguish MSI-high (MSI-H) UC are not well described. Methods: Retrospective review of UC patients having undergone targeted exome sequencing of up to 505 genes was performed. Using the previously validated MSIsensor score, we identified MSI-H (score ≥10) and MSI stable (MSS) (score &lt;3) UC tumors. Tumor mutational burden (TMB) was quantified. Gene alterations enriched in MSI-H UC were evaluated using the false discovery method with q&lt;0.05 considered statistically significant. Mutational process signatures (MPS) were characterized using COSMIC v3.3. Survival analysis was performed using the Kaplan-Meier method with Cox proportional-hazards to determine progression-free (PFS) and overall survival (OS) based on molecular features. Results: Targeted exome sequencing data were available for 3,811 UC specimens representing 2,608 patients, of which 471 carried a diagnosis of upper tract UC. Of the total, 60 (1.6%) MSI-H tumors from 55 (2.1%) patients were identified. Germline testing (n=52) revealed dMMR mutations in 24 cases (46.2%) with MSH2 (59.6%) being most common. Median MSIsensor score was 19.8 (IQR 15.5, 27) and median TMB was 52.7 mut/Mb (IQR 39.7, 63.2). Notable gene alterations enriched in MSI-H tumors are summarized in Table 1. Dominant MPS in MSI-H UC included dMMR (85.0%), APOBEC (8.3%), and Aging (6.7%). MSI-H tumors clustered with dMMR mutational signatures SBS6 and SBS44. A total of 21 MSI-H and 160 MSS patients having received ICB for metastatic disease were identified for survival analysis. Median follow-up was 18.4 months (IQR 6.6, 58.5). MSI-H UC demonstrated superior PFS (HR 0.34, 95% CI 0.22-0.55) and OS (HR 0.48, 95% CI 0.28-0.80) following ICB. There was no association between TMB or MPS and survival following ICB in MSI-H UC. In MSS UC, TMB ≥10 mut/mB was associated with improved PFS (HR 0.56, 95% CI 0.40-0.79) and OS (HR 0.71, 95% CI 0.50-1.0). Conclusions: Targeted sequencing reveals distinct genomic features of MSI-H UC. The findings from this relatively large clinical cohort of MSI-H UC patients affirm previous associations between MSI status, TMB, and response to ICB in metastatic UC. [Table: see text]

Neoadjuvant nivolumab (N) + ipilimumab (I) in cisplatin-ineligible patients with upper tract urothelial cancer (UTUC): Updated results.

645 Background: Perioperative platinum-based chemotherapy for UTUC improves pathologic responses and disease-free survival (DFS). We report the updated results from our on-going phase II neoadjuvant trial of N+I for cisplatin-ineligible patients (pts) with UTUC (NCT03520491). Methods: Cisplatin-ineligible pts with histologically confirmed high-grade UTUC and/or radiographically invasive UTUC with positive selective urine cytology were eligible. Pts were treated with I 3mg/kg + N 1mg/kg (weeks 0, 6), and “N” 3mg/kg (week 3) prior to radical nephroureterectomy (NU). The primary endpoint (EP) was pathologic complete response (pCR, ypT0pN0) and secondary EPs included &lt;ypT2pN0 rate, DFS, and toxicity. Next generation sequencing of pre-treatment tumors was correlated with pathologic response. Results: Seventeen pts (76% male) were enrolled between 2/2021-6/2023 with median age 73 (range 59-85). Primary sites included ureter in 10 pts, renal pelvis in 5 and both in 2. Median tumor diameter was 3.0 cm, (range: 1.5 - 4.2 cm), with 8 pts (47%) having hydronephrosis. To date, 11 pts (65%) have received all planned treatment, 6 pts had N+/-I stopped early due to treatment-related toxicities, 2 pts are pending NU, 13 pts have undergone NU, 1 declined surgery, and another progressed on N+I. A pCR was seen in 4/15 pts (27%) and &lt;ypT2pN0 in 9/15 (60%). Median time from last treatment to NU was 1.6 months (range 0.5-4.9). Three pts developed metastatic recurrence at 3.9, 10.3 and 15.6 months after treatment initiation. CTCAE grade ≥3 treatment-related adverse events occurred in 5 pts (29%). Four pts died during follow up: two of metastatic disease, one of complications related to a bowel leak (7.2 months after N+I initiation and 4.7 months after NU), and one from complications of a fall unrelated to disease or treatment (9.2 months after N+I initiation and 4.7 months after NU). Median tumor mutational burden (TMB) in 9 pts with pre-treatment sequencing was 13.2 mutations/mb (range 4.1-106.3), with 4/5 pts with TMB&gt;10 &lt;ypT2pN0 at NU. Pathogenic germline variants in mismatch repair genes were confirmed in 4 pts (MSH2 in 3, MLH1 in 1) and MSI-high tumors without germline alterations in 2 pts, with 5 of 6 completing NU (1 pending surgery); all 5 achieved pCR (n=3) or ypTaN0 (n=2) and remain alive and disease-free at last follow-up (6, 13.4, 17, 17.9 and 31 months). Conclusions: Updated findings from an on-going phase II trial of cisplatin-ineligible pts with UTUC receiving neoadjuvant N+I shows clinical activity in line with our initial results. All pts with pathogenic germline variants in mismatch repair genes or MSI-high tumors without germline alteration who underwent NU achieved &lt;ypT2pN0 and remain free of disease. Clinical trial information: NCT03520491 .