A Genomic Classifier for Predicting Clinically Aggressive Luminal Bladder Tumors with Higher Rates of Pathological Up Staging.

PURPOSE: Urothelial carcinoma of the luminal molecular subtype is associated with lower rates of pathological up staging from clinical stage T1-T2 to nonorgan confined (pT3 or greater and/or pN+) disease at radical cystectomy. However, approximately a third of luminal urothelial carcinoma cases were up staged to nonorgan confined disease, and these may be under treated if neoadjuvant chemotherapy is withheld. In this study we trained a genomic classifier to predict luminal nonorgan confined disease in patients diagnosed with clinically organ confined (cT1/T2) disease. MATERIALS AND METHODS: Specimens from transurethral resected high grade cT1-T2N0M0 urothelial carcinoma of the bladder that belonged to the luminal subtype (Seiler 2017) were randomly split into training (75) and testing (25) sets for the development of a single sample luminal up staging classifier using lasso/ridge-penalized logistic regression. All patients underwent radical cystectomy without neoadjuvant chemotherapy and the primary end point was up staging to nonorgan confined disease. A radical cystectomy cohort and a platinum treated neoadjuvant chemotherapy cohort were used to evaluate the luminal up staging classifier. RESULTS: Up staging to nonorgan confined disease occurred in 34% of luminal cases. The luminal up staging classifier predicted up staging in 32 of 34 cases, with 6 false-positives (AUC 0.96). The sensitivity for detection of luminal pN+ disease was 95% (20 of 21). Patients with predicted nonorgan confined luminal tumors had worse survival than those with organ confined luminal tumors (p=0.001). On multivariable analysis the luminal up staging classifier was a significant predictor of overall survival after adjusting for clinical variables available at transurethral resection. The luminal up staging classifier also predicted overall survival for aggressive luminal TCGA (The Cancer Genome Atlas) cases (n=83, p=0.043). In the neoadjuvant chemotherapy cohort the luminal up staging classifier predicted 9 up staging cases, all of which had excellent prognosis. CONCLUSIONS: A luminal up staging classifier was developed that distinguishes a subset of cT1-T2N0M0 luminal urothelial carcinoma cases at high risk for up staging to nonorgan confined disease at radical cystectomy and of death. Validation of this model in an independent, large patient cohort is necessary to determine how molecular stratification of luminal tumors could be used to guide treatment of these patients.