Urinary comprehensive genomic profiling predicts urothelial carcinoma recurrence and identifies responders to intravesical therapy.

Intravesical therapy (IVT) is the standard of care to decrease risk of recurrence and progression for high-grade nonmuscle-invasive bladder cancer. However, post-IVT recurrence remains common and the ability to risk-stratify patients before or after IVT is limited. In this prospectively designed and accrued cohort study, we examine the utility of urinary comprehensive genomic profiling (uCGP) for predicting recurrence risk following transurethral resection of bladder tumor (TURBT) and evaluating longitudinal IVT response. Urine was collected before and after IVT instillation and uCGP testing was done using the UroAmp™ platform. Baseline uCGP following TURBT identified patients with high (61%) and low (39%) recurrence risk. At 24 months, recurrence-free survival (RFS) was 100% for low-risk and 45% for high-risk patients with a hazard ratio (HR) of 9.3. Longitudinal uCGP classified patients as minimal residual disease (MRD) Negative, IVT Responder, or IVT Refractory with 24-month RFS of 100%, 50%, and 32%, respectively. Compared with MRD Negative patients, IVT Refractory patients had a HR of 10.5. Collectively, uCGP enables noninvasive risk assessment of patients following TURBT and induction IVT. uCGP could inform surveillance cystoscopy schedules and identify high-risk patients in need of additional therapy.

Development and Multicenter Case-Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction.

PURPOSE: Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. EXPERIMENTAL DESIGN: This is a multicenter case-control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology. RESULTS: uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%. CONCLUSIONS: uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients.

Urinary Comprehensive Genomic Profiling Correlates Urothelial Carcinoma Mutations with Clinical Risk and Efficacy of Intervention.

The clinical standard of care for urothelial carcinoma (UC) relies on invasive procedures with suboptimal performance. To enhance UC treatment, we developed a urinary comprehensive genomic profiling (uCGP) test, UroAmplitude, that measures mutations from tumor DNA present in urine. In this study, we performed a blinded, prospective validation of technical sensitivity and positive predictive value (PPV) using reference standards, and found at 1% allele frequency, mutation detection performs at 97.4% sensitivity and 80.4% PPV. We then prospectively compared the mutation profiles of urine-extracted DNA to those of matched tumor tissue to validate clinical performance. Here, we found tumor single-nucleotide variants were observed in the urine with a median concordance of 91.7% and uCGP revealed distinct patterns of genomic lesions enriched in low- and high-grade disease. Finally, we retrospectively explored longitudinal case studies to quantify residual disease following bladder-sparing treatments, and found uCGP detected residual disease in patients receiving bladder-sparing treatment and predicted recurrence and disease progression. These findings demonstrate the potential of the UroAmplitude platform to reliably identify and track mutations associated with UC at each stage of disease: diagnosis, treatment, and surveillance. Multiple case studies demonstrate utility for patient risk classification to guide both surgical and therapeutic interventions.

Decreasing need for artificial urinary sphincter revision surgery by precise cuff sizing in men with spongiosal atrophy.

PURPOSE: Many patients with persistent incontinence after an artificial urinary sphincter procedure gain improved continence after cuff downsizing. In 2010 a new, smaller (3.5 cm) artificial urinary sphincter cuff was introduced. We hypothesized that men with spongiosal atrophy previously treated with a 4.0 cm cuff would now show a decreased rate of revision surgery due to more accurate cuff sizing. MATERIALS AND METHODS: We evaluated the outcome in men who received identical 4.0 cm cuff sizes in 2 eras, before (2007 to 2009) and after (2010 to 2013) the introduction of the 3.5 cm artificial urinary sphincter cuff. Patients with a history of cuff erosion or those undergoing tandem, transcorporal, or 4.5 cm or greater cuff placement were excluded from analysis. We validated our institutional results using the nationwide AMS® PIF (Patient Information Form) database from identical time frames. RESULTS: Of 236 men who underwent artificial urinary sphincter placement at our institution during the study period 170 with a mean age of 67 years met study inclusion criteria, of whom 88 (52%) received a 4.0 cm artificial urinary sphincter cuff. Mean followup was 34 months. Ten of 45 patients (22.2%) who had a 4.0 cm cuff placed from 2007 to 2009 required cuff downsizing for persistent incontinence while only 2 of 43 (4.7%) who received a 4.0 cm cuff from 2010 to 2013 required revision (p <0.001). Nationally patients with a 4.0 cm cuff underwent fewer revisions during the latter era (16.2% vs 7.5%, p = 0.001). In local and national cohorts Kaplan-Meier analysis revealed improved survival of the 4.0 cm cuff after the introduction of the 3.5 cm cuff (p <0.05). CONCLUSIONS: The incidence of artificial urinary sphincter revision surgery in patients with a 4.0 cm cuff has decreased since the availability of the 3.5 cm cuff. This suggests that precise cuff sizing appears to be beneficial in men with spongiosal atrophy.