Clinical outcomes with <i>ERBB2</i> gene amplification and activating mutations in muscle-invasive bladder cancer patients treated with neoadjuvant chemotherapy.

4595 Background: Activating ERBB2 mutations (mut) are associated with improved pathologic response (pCR) to neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). However, the impact of ERBB2 gene amplification (amp) on pCR and of aggregate ERBB2 gene variants (amp and mut) on relapse and survival is unknown. We previously reported that high tumor mutational burden (TMB) is associated with improved pCR and relapse-free survival (RFS) in a cohort of MIBC patients treated with cisplatin-based NAC followed by cystectomy (Burgess et al. GU ASCO ‘26). In the current analysis, we assessed the impact of ERBB2 gene variants on clinical outcomes in the previously reported cohort. Methods: 91 patients with MIBC who received cisplatin-based NAC followed by radical cystectomy underwent genomic analysis of diagnostic transurethral resection of bladder tumor specimens with the Tempus xT platform. Sample size was prespecified by statistical design. Correlation of ERBB2 gene variants with TMB and clinical outcomes was performed using logistic regression, Cox proportional hazards models, and Kaplan-Meier techniques. Results: Median follow for the cohort was 63.6 months. pCR was achieved in 31.9%. Thirty-eight (41.8%) patients relapsed. Only 4 (4.4%) received adjuvant immune checkpoint inhibition (ICI). ERBB2 mut and amp were exclusively found in 4 (4.4%) and 13 (14.3%) patients, respectively. All ERBB2 mut were p.S310F. pCR occurred in 3 (75%) patients with mut and 6 (46.2%) patients with amp. In those with amp and no pCR (7), 4 were ypTaN0 or ypT1N0. In aggregate, the presence of ERBB2 gene variants (mut + amp, n = 17) was associated with an improved pCR rate compared to no ERBB2 gene variant (OR = 3.038, p = 0.048). ERBB2 variants (mut + amp) were not clearly associated with a TMB &gt; 10 Mut/Mb (OR = 2.217, p = 0.178). Five patients with ERBB2 gene variants relapsed (29.4%, OR = 0.518, p = 0.288). Three (75%) mut and ten (76.9%) amp patients remain alive. The median RFS for patients with and without ERBB2 gene variants in aggregate is 124.1 and 54.7 months (HR = 0.460, p=0.094). The median overall survival (OS) for patients with and without ERBB2 gene variants is Not Reached and 107.6 months (HR = 0.381, p=0.098). Conclusions: The impact of ERBB2 gene variants (mut + amp) on survival in MIBC-patients treated with NAC has not been previously reported. In this cohort collected before widespread use of peri-operative ICI, the presence of ERBB2 gene variants was associated with improved pCR rates and showed strong trends for improved RFS and OS but not clearly associated with high TMB. These findings establish a prognostic role for ERBB2 amp in addition to previously reported ERBB2 mut in patients with MIBC. Whether peri-operative use of ICI or ERBB2-targeted agents may influence these findings warrants further investigation.