IBCN 2020: Molecular Correlates of Cisplatin-Based Chemotherapy Response In Muscle-Invasive Bladder Cancer by Integrated Multi-Omics Analysis

(UroToday.com) While cisplatin-based chemotherapy is a mainstay for neoadjuvant and adjuvant treatment of patients with muscle-invasive bladder cancer (MIBC), and none of the reported biomarkers for predicting response have been implemented in the clinic thus far.

Dr. Ann Taber presented data from researchers at the Aarhus University Hospital, Denmark, where they performed comprehensive genomic, transcriptomic, epigenomic, and proteomic analysis of 300 MIBC patients treated with cisplatin-based chemotherapy to identify molecular changes associated with treatment response. Based on mutational signatures, they identified two patient groups: those characterized by mutations in a tri-nucleotide signature 5 context (SBS5) that are related to ERCC2 mutations, and those related to APOBEC mutations.

Expression data identified the basal/squamous gene expression subtype to be associated with poor cisplatin-based treatment response. Immune cell infiltration and high PD-1 protein expression was also significantly associated with treatment response; they identified a unique subset that corresponds to an “immune desert”, which was associated with poor treatment response (Figure 1).

Figure 1: Association of immune cell infiltration and cisplatin-based treatment response.


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The authors then assigned patients to high and low genomic instability groups based on SBS5 mutations, indels, allelic imbalance and BRCA2 mutation status. Patients with high genomic instability had a response rate of 71% versus 49% for patients with low genomic instability (p = 0.007). Through further integration, they identified a group of patients with a very high response rate (80%) characterized by high genomic instability and non-basal/squamous gene expression subtype and a group of patients with a very low response rate (25%) characterized by low genomic instability and basal/squamous gene expression subtype (p<0.001, Figure 2).

Figure 2: Patient subclassification based on genomic instability and basal/squamous gene expression subtype.
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The results highlight several molecular correlates of chemotherapy response. These findings are now the basis of a new clinical trial for the treatment of metastatic bladder cancer following radical cystectomy.1

Presented by: Ann Taber, Ph.D., Department of Molecular Medicine (MOMA), Aarhus University Hospital, Denmark.

Written by: Anirban P. Mitra, MD, Ph.D., Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter:@UroDocAsh, at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.

References:
1. Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy (TOMBOLA). ClinicalTrials.gov identifier NCT04138628.

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