SIU 2017: Translational Observations from Mutation Profiling of Muscle Invasive Bladder Cancer

Lisbon, Portugal (UroToday.com)  Dr. Lerner provided a very informative update on the current status of translational observations from mutational profiling of muscle invasive bladder cancer (MIBC). There has been significant much-publicized work in this field, and it hoping will lead to prime-time decision-making tools in the near future.

He began by introducing us back to his original work, published in 2014 Nature.1 In the study, they analyzed patients with MIBC – pT2-4, any N, any M, <50% variant histology. Established mean (7.7) and median (5.5) somatic mutation rate. 69% of tumors had potentially actionable mutations in a variety of pathways. There were 32 significantly mutated genes, 9 never previously identified in bladder cancer. They found 4 distinct molecular subtypes, similar to other malignancies.

In a recently published update,2 they have a complete cohort of 412 patients – 61% cT3-4, 33% N+, 2.7% M+. Obtained for 36 tissue source sites. No prior systemic therapy. Every pathology specimen was re-reviewed by 4 GU pathology experts. Unlike original study, some mixed histologies and variants were included. It was just put in print today. He highlighted some key points below

  1. Up to 56 significantly mutated genes
            - Bladder cancer has some of the highest somatic mutation rates of all cancers
            - Mean somatic mutation rate 8.2 now, median 5.8
            - 34 of these were not in prior paper!

  1. 2. 5 mutation signatures
    - vast majority related to APOBEC – endogenous mutagen – unique signature in both MIBC and NMIBC
    - Mutational burden, mutation process, APOBEC mutation load and neoantigen load were all associated with survival outcomes
                - High APOBEC == high mutation load == best prognosis

    - APOBEC is important in the mutation signatures
    - 5 new mutation signatures = TAKE HOME MESSAGE
                - Luminal
                - Luminal-Infiltrated
                - Luminal-papillary --- Favorable survival
                - Neuronal --- Unfavorable survival
                - Basal-squamous

    3. HLA and neoantigen analysis
    4. Update expression subtypes
    5. Integrated non-coding RNA analysis
    6. Univariate and MV survival analysis
                - Luminal-papillary strongly favors better survival
                - Neuronal associated with worse survival

    A nice summary slide with the 5 subtypes and proposed paradigm for management – though much too early to affect clinical practice.

    Basal-squamous – perhaps best to be treated with chemotherapy

    Luminal-infiltrated – may best be treated with immunotherapy

    REFERENCES:

    1. TCGA RESEARCH Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Cancer Genome Atlas Research Network. Nature. 2014 Mar 20;507(7492):315-22. doi: 10.1038/nature12965. Epub 2014 Jan 29.

    2. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, Castro MAA, Gibb EA, Kanchi RS, Gordenin DA, Shukla SA, Sanchez-Vega F, Hansel DE, Czerniak BA, Reuter VE, Su X, de Sa Carvalho B, Chagas VS, Mungall KL, Sadeghi S, Pedamallu CS, Lu Y, Klimczak LJ, Zhang J, Choo C, Ojesina AI, Bullman S, Leraas KM, Lichtenberg TM, Wu CJ, Schultz N, Getz G, Meyerson M, Mills GB, McConkey DJ; TCGA Research Network, Weinstein JN, Kwiatkowski DJ, Lerner SP. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017 Oct 4. pii: S0092-8674(17)31056-5. doi: 10.1016/j.cell.2017.09.007. [Epub ahead of print]

    Presented by: Sether Lerner

    Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal

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