Over the weekend, a number of impactful abstracts on bladder cancer were presented, each contributing to our understanding of this complex disease.
Non-Muscle Invasive Bladder Cancer
Guiding adjuvant instillation in intermediate-risk NMIBC by drug screens in patient-derived organoids.Egger et al. presented an update on a Phase II clinical trial aimed at guiding adjuvant instillation in IR-NMIBC using patient-derived organoids to determine tumor response to four chemotherapeutic agents (epirubicin, mitomycin C, gemcitabine, and docetaxel). Thirteen patients have enrolled with successful model and drug screen outcomes in all cases. Recruitment for the trial is ongoing. From a resource standpoint, the use of PDOs may not be practical for all IR-NMIBC cases, but it offers a promising individualized approach for patients with recalcitrant tumors and frequent recurrences. The final results are eagerly awaited.
Reducing the number of flexible cystoscopies in patients undergoing follow-up for non-muscle invasive bladder cancer with either flexible cystoscopy or the urinary biomarker test Bladder Cancer Monitor: A secondary outcome from a randomized clinical trial.
Dreyer et al. presented an update from the DaBlaCa-15 non-inferiority RCT, comparing the number of cystoscopies in patients with HG-NMIBC undergoing cystoscopy q4 mos. vs urinary biomarker test Xpert® Bladder Cancer Monitor surveillance q4 mos. with one annual cystoscopy (n=313). Importantly, this study enrolled patients with high-grade tumors at various stages of their disease trajectory, including at the time of diagnosis, while receiving maintenance intravesical therapy, or up to two years after diagnosis. Patients with UTUC within 5 years and HGT1 tumor without re-resection were excluded. The intervention arm required significantly fewer cystoscopies (345) than the control arm (740). The authors suggest non-inferior RFS in the intervention arm and low risk of progression in the total study population, with data forthcoming later this year. Is the level-one evidence we need for routine clinical use of urinary markers on the horizon?
The impact of centralized uropathology review in the management of bladder cancer patients at the time of transurethral resection of the bladder.
Robersti et al. presented data examining 272 TURBT specimens from 231 patients seeking a pathologic second opinion from a fellowship-trained uropathologist. Major discordance with changes in management according to European Association of Urology (EAU) guidelines was observed in 28% of cases. These findings support centralized pathologic review by an expert uropathologist in all cases; at the very least, patients should be informed of the option and its implications. Considering feasibility challenges and current resource limitations, we need to identify which patients benefit more precisely from a second opinion; perhaps future integration of AI for quality control and flagging specimens for central review could streamline this process.
Muscle Invasive Bladder Cancer
Clinical outcomes in patients with high-risk, post-cystectomy muscle-invasive bladder cancer (MIBC) with persistent circulating tumour DNA-negative (ctDNA-) status on serial testing: surveillance analysis from the IMvigor011 studyPowles et al. presented an analysis from the IMvigor011 surveillance cohort, focusing on high-risk post-cystectomy MIBC with persistent ctDNA negative status on serial testing. Over a median follow-up of 16 months, 17 DFS events occurred out of 171 patients. Serially negative ctDNA status demonstrated strong prognostic value, with an 18-month DFS rate of 88%. However, 10% of patients relapsed radiographically despite negative ctDNA, suggesting the inability to replace radiographic surveillance completely.
Extended follow-up from CheckMate 274 including the first report of overall survival outcomes.
Galsky et al. presented extended follow-up data from CheckMate 274 evaluating adjuvant nivolumab versus placebo after surgery for patients with ypT2-4a or pT3-pT4a or (y)pN+ MIBC. The trial previously met both its primary endpoints, DFS in the ITT population and patients with tumor PD-L1 expression ≥ 1%. With extended follow-up, the study continues to show DFS benefits. New interim OS data favors adjuvant nivolumab with a median OS of 70 months vs 50 months HR 0.76 (0.61-0.96). This is in contrast to trials evaluating pembrolizumab (OS HR 0.98) and atezolizumab (OS HR 0.85).
Positive ctDNA status before radical cystectomy predicts lymph node status and pathological upstaging.
Ben-David et al. presented a retrospective study of serial tumor-informed ctDNA (Signatera) in 112 patients undergoing RC with a median follow-up of 8 months. Positive preoperative ctDNA status was associated with an increased risk of node-positive disease, variant histology, and locally advanced disease (≥ pT3). While prognostic, the clinical utility of preoperative ctDNA in guiding neoadjuvant treatment is not yet known. Notably, the tumor-informed ctDNA approach requires an adequate TURBT specimen and initial specimen processing takes 3-6 weeks.
The role of androgen response pathway in association with tumor biology and response to neoadjuvant ICI in MIBC.
Tateo et al. presented a retrospective transcriptome-wide expression profiling (Decipher) focusing on AR gene expression of 102 TURBT samples from patients in the PURE-01 study. The AR gene expression and androgen response signature were highly expressed in luminal tumors vs other subtypes (p=0.005 and p<0.001). Androgen response signature scores were significantly lower in ypT0N0 responders (p=0.03). While AR signaling is known to promote CD8 T cell exhaustion and impair the efficacy of ICI in preclinical models, this is the first study to report the androgen response pathway as a potential biomarker of ICI benefit in MIBC. Nonetheless, these results require cautious interpretation without a comparator group not treated with ICI.
Metastatic Invasive Bladder Cancer
Enfortumab vedotin and pembrolizumab (EV+P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Results from the global phase 3 EV-302/KEYNOTE-A39 study.Powles et al. presented a subgroup analysis from the EV-302/KEYNOTE-A39 study. The PFS and OS benefit was consistent with the overall population in all pre-specified subgroups, including upper tract and lower tract disease groups, reaffirming EV+P as the standard first line treatment in both groups. For upper tract with EV+P vs chemo, mPFS was 12.7 mos vs 6.2 mos HR 0.50 (0.35–0.71), and mOS NR vs 18.4 mos HR 0.53 (0.34–0.83). For lower tract disease, mPFS was 12.5 mos vs 6.3 mos HR 0.44 (0.35–0.54), and mOS was 31.5 mos vs 15.6 mos HR 0.46 (0.36–0.59).
Membranous NECTIN-4 expression in metastasis versus matched primary tumor more accurately predicts enfortumab vedotin response.
Büttner et al. conducted a follow-up study to their previous investigation, examining NECTIN-4 expression in primary tumors versus distant metastatic sites. Their initial research revealed decreased NECTIN-4 expression in metastatic sites vs primary tumors. In this retrospective sample of 26 patients with metastatic UC treated with EV, they explored the predictive value of membranous NECTIN-4 expression in primary tumors versus distant metastasis. NECTIN-4 expression correlated with improved PFS, particularly when analyzing tissue from metastatic sites compared to primary tumors. Utilizing NECTIN-4 expression from metastatic tissue biopsies as a predictive biomarker has the potential to aid in treatment decision-making, potentially avoiding unnecessary costs and drug toxicity in patients unlikely to benefit from EV.
All Stages
Development of the Bladder Utility Symptom Scale (BUSS utility): A novel tool to measure utilities and quality of life in bladder cancer patients.Kulkarni et al. presented the development of the Bladder Utility Symptom Scale (BUSS utility). Patient utilities critically impact comparative effectiveness and cost-effectiveness analyses. The previously validated BUSS-P tool was utilized to elicit time tradeoff utilities. This is the first instrument to provide utilities derived from both patients (n=200) and the general public (n=200). These data in all phases of BCa will facilitate robust cost-effectiveness and decision-modeling work.
A patient-derived bladder cancer organoid biobank for translational research and precision oncology.
Garioni et al. aimed to establish an expandable living biobank of patient-derived organoid models. 95 samples were collected and processed from 52 patients with MIBC and 38 patients with NMIBC to generate organoids and tumor/organoid pairs. Of the 18 samples maintained for more than five passages, 10 PDO lines from different bladder cancer subtypes were selected and phenotypically characterized. Selected lines highly resembled their original tumors. PDOs displayed either a pure luminal (CK8+), a pure basal (CK5+), a mixed basal-luminal (CK5+ and CK8+ cells), or a sarcomatoid (Vimentin+) phenotype. Preliminary in vitro drug screens revealed significant differences in the response of each PDO line toward various therapeutics. This PDO biobank will serve as a valuable resource for translational research and precision oncology applications, offering insights into tumor response to therapeutics and potential biomarkers of drug sensitivity.
Written by: Amanda Myers, MD, Fellow of Urologic Oncology, MD Anderson Cancer Center, Houston, Texas
Adapted from the International Bladder Cancer Group (IBCG) Newsletter 2024 Vol 2