Somatic Features of Response and Relapse in Non–muscle-invasive Bladder Cancer Treated with Bacillus Calmette-Guérin Immunotherapy

High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with bacillus Calmette-Guérin (BCG), but relapse is common. Improvement of patient outcomes requires better understanding of links between BCG resistance and genomic driver alterations.To validate the prognostic impact of common genomic alterations in NMIBC pretreatment and define somatic changes present in post-BCG relapses.We retrieved tumour tissues and outcomes for 90 patients with BCG-naive NMIBC initiating BCG monotherapy. Post-BCG tissue was available from 34 patients. All tissues underwent targeted sequencing of tumour and matched normal.Associations between clinical outcomes and genomics were determined using Cox proportional hazard models.Of the patients, 58% were relapse free at data cut-off, 24% had NMIBC recurrence, and 18% experienced muscle-invasive progression. The risk of relapse was associated with ARID1A mutation (hazard ratio [HR] = 2.00; p = 0.04) and CCNE1 amplification (HR = 2.61; p = 0.02). Pre- and post-BCG tumours shared truncal driver alterations, with mutations in TERT and chromatin remodelling genes particularly conserved. However, shifts in somatic profiles were common and clinically relevant alterations in FGFR3, PIK3CA, TSC1, and TP53 were temporally variable, despite apparent clonal prevalence at one time point. Limitations include the difficulty of resolving the relative impact of BCG therapy versus surgery on genomics at relapse and biopsy bias.Somatic hypermutation and alterations in CCNE1 and ARID1A should be incorporated into future models predicting NMIBC BCG outcomes. Changes in tumour genomics over time highlight the importance of recent biopsy when considering targeted therapies, and suggest that relapse after BCG is due to persisting and evolving precursor populations.Changes in key cancer genes can predict bladder cancer relapse after treatment with bacillus Calmette-Guérin. Relapses after treatment can be driven by large-scale genetic changes within the cancer. These genetic changes help us understand how superficial bladder cancer can progress to be treatment resistant.