SPTAN1, APC, and FGFR3 Mutation Status and APOBEC Mutation Signatures are Predictive of Mitomycin C Response in Non-muscle-invasive Bladder Cancer

Abstract

BackgroundCurrently, no biomarkers of response to mitomycin C have been identified in non–muscle-invasive bladder cancer patients. Predictive biomarkers could improve the treatment outcome and eliminate adverse events from unnecessary treatment. ObjectiveTo identify and validate predictive biomarkers of chemoresection with mitomycin C. Design, setting, and participantsThe intervention group of a randomised controlled trial was identified for analyses. The study was conducted between January 2018 and June 2019 in two major urological departments in Denmark. Patients had a history of Ta low-grade/high-grade disease and were included upon recurrence. The intervention group (58 patients) received chemoresection with mitomycin C. Tumour and reference germline DNA from prior tumours were analysed by whole exome sequencing. Predictive biomarkers were validated in the context of Ta low-grade tumours from the UROMOL study. Outcome measurements and statistical analysisResponse to chemotherapy (intervention group from the randomised controlled trial) and recurrence-free survival (UROMOL cohort) were measured. Groups were compared using Fisher’s exact test and Wilcoxon rank sum test. Results and limitationsChemoresponse was associated with the mutation status of SPTAN1, APC, and FGFR3, and the level of APOBEC signature contribution (p = 0.035, p = 0.034, p = 0.055, and p = 0.035, respectively). The main limitations include no biopsy for biomarker discovery immediately prior to chemoresection and the unmatched validation cohort. ConclusionsMutation status of APC, SPTAN1, and FGFR3 and the level of mutational contribution from APOBEC-related signatures were identified as potential predictive biomarkers for chemoresection with mitomycin C in non–muscle-invasive bladder cancer patients. A prospective validation study is however needed. Patient summaryWe investigated DNA from noninvasive bladder tumours in order to predict treatment response to chemotherapy. Four biomarkers showed promising results, which should be tested in future studies.