Molecular Correlates of Cisplatin-based Chemotherapy Response in Muscle Invasive Bladder Cancer by Integrated Multi-omics Analysis

Abstract

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic Here we performed a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converged on genomic instability driven by a high number of chromosomal alterations, indels, mutations in a tri-nucleotide signature 5 context and/or BRCA2 mutations. Expression data identified the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression was also significantly associated with treatment response. We assigned patients to high and low genomic instability groups based on tri-nucleotide signature 5 mutations, indels, allelic imbalance and BRCA2 mutation status. Patients with high genomic instability had a response rate of 71% vs. 49% for patients with low genomic instability (p = 0.007). Through further integration of genomic and transcriptomic data, we identified a group of patients with a very high response rate (80%) characterized by high genomic instability and non-Ba/Sq gene expression subtype and a group of patients with a very low response rate (25%) characterized by low genomic instability and Ba/Sq gene expression subtype (p<0.001). Our results highlight several molecular correlates of chemotherapy response and importantly, the integration of genomic instability and gene expression subtypes identified patient groups with vastly different response rates. This could pave the way for future patient selection following validation in prospective clinical trials.