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-papillary --- Favorable survival
- Neuronal --- Unfavorable survival
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
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
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]