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Attend this session at the
2017 ASCO Annual Meeting!


Session: Genitourinary (Nonprostate) Cancer

Type: Oral Abstract Session

Time: Monday June 5, 8:00 AM to 11:00 AM

Location: Arie Crown Theater

Comprehensive molecular characterization and analysis of muscle-invasive urothelial carcinomas.

Sub-category:
Bladder Cancer

Category:
Genitourinary (Nonprostate) Cancer

Meeting:
2017 ASCO Annual Meeting

Abstract No:
4500

Citation:
J Clin Oncol 35, 2017 (suppl; abstr 4500)

Author(s): Seth P. Lerner, Gordon Robertson, Jaegil Kim, Andrew Cherniack, Guangwu Guo, Rehan Akbani, Rupa S Kanchi, Katherine A. Hoadley, Toshinori Hinoue, Peter W. Laird, Hikmat Al-Ahmadie, Joaquim Bellmunt, Mauro Castro, Dmitry Gordenin, Gordon B. Mills, Francisco Sanchez-Vega, Sachet A Shukla, Ewan A Gibb, John N. Weinstein, David J. Kwiatkowski, TCGA Network; Baylor College of Medicine, Houston, TX; BC Cancer Agency, Vancouver, BC, Canada; Broad Institute of MIT and Harvard, Cambridge, MA; Broad Institute, Cambridge, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Cancer Center, Houston, TX; University of North Carolina, Chapel Hill, NC; Van Andel Institute, Grand Rapids, MI; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Federal University of Paraná Polytechnic Center, Curitiba, Brazil; National Institute of Environmental Health Sciences, Research Triangle Park, NC

Abstract Disclosures

Abstract:

Background: We reported the integrated molecular analysis of 131 tumors in 2014 (Nature 507:315, 2014) and now report on the entire cohort of 412 tumors from the TCGA project in chemotherapy-naïve, muscle-invasive urothelial bladder cancer. Methods: Following strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations (WES), DNA methylation, mRNA, non-coding RNA (lncRNA and miRNA) and (phospho-) protein expression, gene fusions, viral integration, pathway perturbation, clinical correlates, outcomes, and histopathology. Results: There was a high overall somatic mutation rate (8.2/Mb), as previously reported. There were 58 significantly mutated genes (SMGs) (MutSig_2CV), increased from 32 in the original report. We identified 5 mutation signatures including APOBEC-a and b, ERCC2, C > T_CpG, and a single ultra-mutated sample with a functional POLE mutation. APOBEC mutagenesis explained 70% of the mutation burden and was associated with survival (p = 0.0013). High mutation burden and neoantigen load were also associated with improved outcome (p = 0.00014 and 0.00078). The previously identified four mRNA subtypes were predicted on the larger set and also identified a novel poor-survival ‘neuronal’ subtype that nevertheless lacked small cell or neuroendocrine histology. Clustering converged for mRNA, lncRNA and miRNA expression, and for inferred activity of gene sets associated with regulator expression. We identified subsets with differential epithelial-mesenchymal transition scores, carcinoma-in-situ scores, and survival, with implications for distinct therapeutic potential. Conclusions: This integrated analysis of 412 TCGA patient samples validates and extends observations from the first 131 patients and significantly increases our power to detect additional low-frequency aberrations. The results provide unique insights into mechanisms of bladder cancer development, and identify novel subsets of MIBC that may benefit from differential treatment approaches.

 
Other Abstracts in this Sub-Category:

 

1. Planned survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC).

Meeting: 2017 ASCO Annual Meeting Abstract No: 4501 First Author: Dean F. Bajorin
Category: Genitourinary (Nonprostate) Cancer - Bladder Cancer

 

2. Biomarker findings and mature clinical results from KEYNOTE-052: First-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).

Meeting: 2017 ASCO Annual Meeting Abstract No: 4502 First Author: Peter H. O'Donnell
Category: Genitourinary (Nonprostate) Cancer - Bladder Cancer

 

3. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

Meeting: 2017 ASCO Annual Meeting Abstract No: 4503 First Author: David C. Smith
Category: Genitourinary (Nonprostate) Cancer - Bladder Cancer

 

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