MP54-07: A urine-based molecular assay refines the risk stratification of the recent American Urological Association Guideline on Hematuria

Joep de Jong*, Olga Pijpers, Kim van Kessel, Joost Boormans, Rotterdam, Netherlands, Wim van Criekinge, Ghent, Belgium, Ellen Zwarthoff, Rotterdam, Netherlands, Yair Lotan, Dallas, TX

Introduction: According to the recent American Urological Association (AUA) Guideline on Hematuria, patients are stratified into low, intermediate and high-risk groups. These risk groups are based on clinical risk factors and do not incorporate urine-based tumor markers. Previously, we validated a urine-based molecular assay in a large prospective cohort of patients referred for gross- or microscopic hematuria. Here, we applied the updated AUA guidelines onto this prospective cohort, integrating both clinical and molecular parameters for refined urothelial cancer risk prediction.

Methods: We selected all patients with complete biomarker status from a previously published prospective Dutch hematuria cohort, including 838 patients of whom 112 were diagnosed with urothelial cancer. Patients were stratified into AUA risk category low, intermediate or high risk based on sex, age and type of hematuria. Biomarker status included mutation status of the FGFR3, TERT and HRAS genes and methylation status of the OTX1, ONECUT2 and TWIST1 genes, as assessed on urinary patient DNA. The primary end point was the diagnostic model performance for different hematuria risk groups as indicated by the AUC. Further analyses assessed the pre- and post-test cancer probability within hematuria subgroups using Fagan’s nomograms.

Results: Overall, 65 patients (7.8%) were classified as low risk, 106 (12.6%) patients intermediate risk, and 667 patients (79.6%) were classified as high risk. The urothelial cancer incidence differed significantly between gross (21%, 98/457) and microscopic (4%, 14/381) hematuria subgroups (P <0.001). Notably, all cancer cases were among the high risk AUA category with an incidence of 16.8% (112/667). Application of the diagnostic model revealed robust performance among all evaluated hematuria risk groups (AUC’s 0.929-0.971), showing consistent sensitivities of >90%. However, specificity of the assay was only 53% for gross hematuria patients, while microscopic hematuria risk groups had consistent specificities of >90%. Depending on the evaluated hematuria risk group, a negative urine assay was associated with a post-test cancer probability of 0.3-2% and a positive urine assay was associated with a post-test cancer probability of 31-42%.

Conclusions: This study suggests efficiency for incorporating a urine-based molecular assay after AUA guideline stratification based on clinical risk factors for evaluation of hematuria patients. The AUA high risk stratification is accurate and detects all urothelial cancer cases. In AUA low/intermediate risk categories, patients with a negative assay may be able to safely avoid cystoscopy. Furthermore, AUA high risk patients with a positive assay should have expedite evaluation.

Source of Funding: Supported by MDxHealth and powered by Health Holland, Top Sector Life Sciences & Health