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

Abstract

Background: 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. Objective: To validate the prognostic impact of common genomic alterations in NMIBC pretreatment and define somatic changes present in post-BCG relapses. Design, setting, and participants: 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. Outcome measurements and statistical analysis: Associations between clinical outcomes and genomics were determined using Cox proportional hazard models. Results and limitations: 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. Conclusions: 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.

Somatic Mutation of the Non-Muscle-Invasive Bladder Cancer Associated with Early Recurrence

“…In the present study, the median incidence of genetic variations in 43 tumour samples was 56 variations per sample, and a high TMB was associated with tumour recurrence, which is consistent with previous reports. In addition, previous studies reported that patients with a high TMB had better overall survival and response to immunotherapy compared with those with a low TMB [19,20]. However, in the present study, overall survival was not analysed because NMIBC has a high cancer-specific survival rate.…”

Urinary comprehensive genomic profiling predicts urothelial carcinoma recurrence and identifies responders to intravesical therapy

“…2E ). Finally, we assessed ARID1A mutations which were previously shown to be more prevalent in patients with BCG recurrence [ 39 , 40 ]. We observed ARID1A mutation enrichment of 1.7‐fold in IVT Refractory versus IVT Responder patients.…”

“…The limited cohort size also restricted our ability to assess individual molecular relationships. For example, previous studies have identified ARID1A mutations as indicators of BCG failure [ 39 , 40 ]. We see a similar pattern emerge, but the cohort size constrains statistical confidence.…”

Novel sequential treatment strategy for patients with muscle-invasive bladder cancer (MIBC): intravesical recombinant BCG, followed by neoadjuvant chemoimmunotherapy, radical cystectomy plus pelvic lymphadenectomy and adjuvant immunotherapy – protocol of a multicentre, single arm phase 2 trial (SAKK 06/19)

“…Resistance mechanisms to BCG are not entirely understood but interestingly, granulomata found in patients not responding to BCG were found to be highly expressing PD-L128 suggesting a T-cell exhaustion resulting from checkpoint activation. Patients with ARIDA1A mutation and CCNE1 amplification also appear to be at higher risk of relapse after BCG treatment 33. The immune response induced by intravesical BCG is, however, not solely restricted to the superficial urothelial layer but affects the whole bladder wall and also induces a systemic immune response 20.…”

“…Patients with ARIDA1A mutation and CCNE1 amplification also appear to be at higher risk of relapse after BCG treatment. 33 The immune response induced by intravesical BCG is, however, not solely restricted to the superficial urothelial layer but affects the whole bladder wall and also induces a systemic immune response. 20 Therefore, the next logical step appears to use intravesical BCG also in patients with MIBC as an adjuvant to prime and boost the immune response (both innate and adaptive) when using systemic immunotherapy with checkpoint inhibitors (figure 2).…”