ASCO GU 2018: Update on The Cancer Genome Atlas

San Francisco, CA (UroToday.com) Dr. Lerner provided the second Urothelial Carcinoma Keynote Lecture and provided an 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. Specifically he focused on the updates to TCGA data.

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, 31% N+, 2.4% M+, 13% with divergent histology. 406 of them had complete clinical data. Obtained for 36 tissue source sites. No prior systemic therapy. Every pathology specimen was re-reviewed by 4 GU pathology experts. Median follow-up was 17.5 months, 143 recurrences (35%) and 183 deaths (44%). Unlike original study, some mixed histologies and variants were included. 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!

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

He provided a 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
As Dr. Black previously mentioned though, the importance lies in a single-patient classified. Dr. Lerner noted that his group is working on a single patient classified with the TCGA dataset, with early promising results. He also briefly reviewed some work by other groups that have begun to examine single-patient classifiers, as the clinical implications are much greater – no need for a large dataset to help a single patient determine treatment.

More importantly, he ended with a plea to begin consolidation of the many different molecular classification schemes in advanced bladder cancer. He highlighted the work on a “metagenomics classifier” being completed by a group from France. They have made progress towards a consensus classification.

Presented by: Seth Lerner, Baylor College of Medicine

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA  

Reference: 

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, et al. 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]
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