Introduction: Mutations in the TP53 gene are indicative of worse outcome in bladder cancer and are usually assessed by immunohistochemistry. To define p53-overexpression, a threshold of >10% is most commonly used (cut-off1). Recently, a novel cut-off (aberrant = 0% or ≥50%) (cut-off2) showed better correlation to clinical outcome. In this study, we evaluate the association between p53-immunohistochemistry cut-offs, clinico-pathological variables and disease-specific survival (DSS). Methods: Seven-hundred-fifty chemotherapy-naïve patients who underwent radical cystectomy were included (92% muscle-invasive bladder cancer. In addition to cut-off1 and cut-off2, a third cut-off (cut-off3) was determined based on the highest Youden-index value. Cut-off values were associated with clinico-pathological variables and FGFR3 mutation status. The Kaplan-Meier method was used to estimate DSS. Results: Aberrant p53-expression was found in 489 (65%) (cut-off1) and 466 (62%) (cut-off2) tumors. Cut-off3 was determined at 25% and aberrant p53-expression in 410 cases (55%) (cutoff3). p53-expression levels were significantly associated with higher pT-stage (cut-off1/2/3: P = 0.047, P = 0.006 and P = 0.0002, respectively), higher grade (all, P < 0.0001), and FGFR3 wild-type (cut-off1: P = 0.02, cut-offs2&3: P = 0.001). Median follow-up was 5.3 years (interquartile range, 4.0-6.0 years). p53-expression was not associated with DSS for any of the three cut-offs (cut-off1/2/3: P-log-rank = 0.566, 0.77 and 0.50, respectively). If we only considered locally advanced bladder cancer, results on DSS remained non-significant. Conclusion: This multi-center, multi-laboratory study showed that, regardless of the cut-off used, p53-immunohistochemistry did not enable selection of patients with worse outcome. Our results suggest that p53-immunohistochemistry alone is not suitable to guide clinical decision making after radical cystectomy.

Core Facility Molecular Pathology and Biobank Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Laboratory Medicine and Pathobiology 7938University of Toronto Toronto ON Canada

Department of Medical Oncology Claudius Regaud Institute Toulouse University Cancer Center Oncopole Toulouse France

Department of Pathology Institute Curie Paris France

Department of Pathology University Health Network Princess Margaret Cancer Center 7938University of Toronto Toronto ON Canada

Department of Surgery and Surgical Oncology University Health Network Princess Margaret Cancer Center University of Toronto Toronto ON Canada

Department of Surgical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Caritas St Josef Medical Center 9147University of Regensburg Regensburg Germany

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Hôpital Foch UVSQ Paris Saclay University Suresnes France

Department of Urology University of Texas Southwestern Medical center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Dept Pathology University Medical Center Regensburg Regensburg Germany

Division of Anatomic Pathology Department of Laboratory Medicine and Molecular Diagnostics Sunnybrook Health Sciences Centre Toronto ON Canada

Institut Curie CNRS UMR144 Molecular Oncology team PSL Research University Paris France

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

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