Molecular Subtyping of Clinically Localized Urothelial Carcinoma Reveals Lower Rates of Pathological Upstaging at Radical Cystectomy Among Luminal Tumors

Background: Upstaging of clinical T1-T2 urothelial carcinoma (UC) to non-organ-confined (NOC) pathological stage ≥T3 or N+ at radical cystectomy (RC) is common. Tools for stratifying patients who may have NOC disease are limited. Objective: To determine an association of a genomic subtyping classifier (GSC) with pathological upstaging in multi-institutional cohort of patients with cT1-T2 UC treated with RC. Design, setting, and participants: Precystectomy transurethral specimens from 206 patients with high-grade, cT1-T2, N0M0 UC, who underwent RC without neoadjuvant chemotherapy, underwent GSC testing. Outcome measurements and statistical analysis: Uni- and multivariable logistic regression analyses evaluated GSC for upstaging, defined as pT3/T4 and/or pTanyN1–3 disease at RC. Results and limitations: Pathological upstaging occurred in 23% of cT1 and 57% of cT2 cases. Lower rates of upstaging to NOC was seen for luminal versus nonluminal tumors (34% vs 51%, p = 0.02). The differences in upstaging were confined to T stage, with no difference in node positivity for luminal versus nonluminal patients (cT1: 13% for both [p > 0.9], cT2: 15% and 23% [p = 0.6], respectively). Fewer patients with luminal tumors were upstaged to ≥pT3Nany compared with nonluminal tumors (Mantel-Haenszel p = 0.002; cT1: 13% vs 30%, cT2: 34% vs 58%). On multivariable logistic regression analysis, nonluminal patients were more likely to be upstaged to ≥pT3 at RC (p < 0.001). Limitations include retrospective design and sample size. Conclusions: Molecular subtyping of clinically localized UC demonstrated that luminal tumors have lower rates of upstaging to non-organ-confined disease compared with nonluminal tumors. If validated, these data can help inform which patients may need multimodal therapy. Patient summary: Determining whether bladder cancer has spread beyond the bladder is challenging at diagnosis. In this paper, genomics helped identify patients who were more likely to have aggressive disease that has spread outside the bladder. These patients may benefit from chemotherapy prior to surgery. Upstaging of bladder cancer from precystectomy clinical stage ≤T2 to non-organ-confined (NOC) pathological stage ≥T3 or N+ at radical cystectomy is common. Molecular subtyping determined that luminal tumors have lower rates of upstaging to NOC disease than nonluminal tumors.