BACKGROUND: There might be differential sensitivity to neoadjuvant chemotherapy (NAC) in patients with primary muscle-invasive bladder cancer (MIBC) in comparison to patients with secondary MIBC after a history of non-muscle-invasive disease. OBJECTIVE: To investigate pathologic response rates and survival associated with primary versus secondary MIBC among patients treated with cisplatin-based NAC for cT2-4N0M0 MIBC. DESIGN SETTING AND PARTICIPANTS: Oncologic outcomes were compared for 350 patients with primary MIBC and 64 with secondary MIBC treated with NAC and radical cystectomy between 1992 and 2021 at 11 academic centers. Genomic analyses were performed for 476 patients from the Memorial Sloan Kettering/The Cancer Genome Atlas cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome measures were pathologic objective response (pOR; ≤ypT1 N0), pathologic complete response (pCR; ypT0 N0), overall mortality, and cancer-specific mortality. RESULTS AND LIMITATIONS: The primary MIBC group had higher pOR (51% vs 34%; p = 0.02) and pCR (33% vs 17%; p = 0.01) rates in comparison to the secondary MIBC group. On multivariable logistic regression analysis, primary MIBC was independently associated with both pOR (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.26-0.87; p = 0.02) and pCR (OR 0.41, 95% CI 0.19-0.82; p = 0.02). However, on multivariable Cox regression analysis, primary MIBC was not associated with overall mortality (hazard ratio 1.70, 95% CI 0.84-3.44; p = 0.14) or cancer-specific mortality (hazard ratio 1.50, 95% CI 0.66-3.40; p = 0.3). Genomic analyses revealed a significantly higher ERCC2 mutation rate in primary MIBC than in secondary MIBC (12.4% vs 1.3%; p < 0.001). CONCLUSIONS: Patients with primary MIBC have better pathologic response rates to NAC in comparison to patients with secondary MIBC. Chemoresistance might be related to the different genomic profile of primary versus secondary MIBC. PATIENT SUMMARY: We investigated the treatment response to neoadjuvant chemotherapy (NAC; chemotherapy received before the primary course of treatment) and survival for patients with a primary diagnosis of muscle-invasive bladder cancer (MIBC) in comparison to patients with a history of non-muscle-invasive bladder cancer that progressed to MIBC. Patients with primary MIBC had a better response to NAC but this did not translate to better survival after accounting for other tumor characteristics.

Department of Cancer Medicine Institut Gustave Roussy Villejuif France

Department of Experimental and Clinical Medicine University of Florence Oncologic Minimally Invasive Urology and Andrology Unit Careggi Hospital Florence Italy

Department of Internal Medicine 2 University Hospital Krems Karl Landsteiner University of Health Sciences Krems an der Donau Austria

Department of Maternal Infant and Urologic Sciences Sapienza University of Rome Policlinico Umberto 1 Hospital Rome Italy

Department of Minimally Invasive and Robotic Urology University Center of Excellence in Urology Wrocław Medical University Wrocław Poland

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

Department of Urology AOU Città della Salute e della Scienza Torino School of Medicine Turin Italy

Department of Urology European Institute of Oncology IRCCS Milan Italy

Department of Urology Hospital Universitario La Paz Madrid Spain

Department of Urology IRCCS Ospedale San Raffaele and Vita Salute San Raffaele University Milan Italy

Department of Urology Medical University Innsbruck Austria

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology Torrejon University Hospital Madrid Spain

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

Department of Urology Weill Cornell Medical College New York NY USA

Francisco de Vitoria University Madrid Spain

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

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

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