Altered Expression of the Transcription Factor Forkhead Box A1 (FOXA1) Is Associated With Poor Prognosis in Urothelial Carcinoma of the Upper Urinary Tract

Objective To determine the prognostic significance of Forkhead Box A1 (FOXA1) expression in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). Materials and Methods A retrospective analysis of 566 patients undergoing RNU at seven academic medical centers was performed. Tissue microarrays were subjected to immunohistochemistry using a commercially available polyclonal FOXA1 antibody. Logistic regression determined the association of FOXA1 expression with pathologic features and survival outcomes. Results Three hundred twenty-two men and 244 women were included. The pathologic distribution of specimens included 53% muscle-invasive or greater (≥pT2), 74% high-grade, 16% with flat architecture, 13% with necrosis, 21% with lymphovascular invasion, 18% with concomitant carcinoma in situ, and 8% with positive lymph nodes. The median FOXA1 score was 5.0 (range: 0-8). Lower FOXA1 expression was significantly correlated with advanced pathologic stage (≥pT3) (P = .02), concomitant carcinoma in situ (P = .006), and renal pelvis (vs ureter) location (P < .0001). At a median follow-up of 27.0 months (range: 3-196), 139 patients (25%) experienced disease recurrence and 121 (21%) died from the disease. In a multivariate model, lower FOXA1 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.05-1.62, P = .04), cancer-specific mortality (HR: 1.17, 95% CI: 1.03-1.92, P = .04), and all-cause mortality (HR: 1.08, 95% CI: 1.02-1.18, P = .05). Conclusion Lower FOXA1 expression is associated with adverse pathologic features and inferior survival outcomes for UTUC patients undergoing RNU. These data indicate lower FOXA1 expression may be a marker of aggressive disease in UTUC.