#EAU15 - Molecular profiling in bladder cancer: The Cancer Genome Atlas (TCGA) project - Session Highlights

MADRID, SPAIN (UroToday.com) - Dr. Seth Lerner presented on the potential impact on TCGA on genomic profiling in bladder cancer and its implications in treatment and molecular subtyping.

The TCGA project started in 2006 and was implemented in bladder cancer starting in 2010. It uses all genomic data (DNA, RNA, and protein) and integrates it via informatics. Data is public so that it is available to researchers. For bladder cancer, there are 19 tissue-source sites sending pathology to the genome characterization center.

eauThe TCGA project shows 3 clusters of bladder cancer with no association with smoking, papillary morphology, gender, and stage. Mean and median somatic mutation rate per tumor is 7.7. This corresponds to one of the highest genomic instabilities among cancers. Data from increasing numbers of patients would give the highest chance of finding significantly mutated genes. The P53 gene corresponds to the most commonly mutated gene, corresponding to about 49%. Other commonly mutated genes include RB1 (17%), MLL2 (27%), ARID1A (25%), KDM6A (24%), PIK3CA (19%), and EGFR3 (12%).

A majority of these genes correspond to altered cell cycle regulatory pathways. P53/RB pathway is altered in a total of 93%. RTK/RAS is altered in 39%. Clinical implications of these are immense as molecular inhibitors are present targeting these pathways. Many of these drugs have been FDA approved in other cancers. Many are being investigated within bladder cancer now as a result of TCGA. For example, FGFR3 is altered in bladder cancer in 15% of TCGA cases. A drug, BGJ398, has been investigated in 5 patients and showed an overall response rate of 40% and disease control rate in all patients.

Currently, we understand the role of these new drugs retrospectively via genomic sequencing. However, in future, we need to able to personalize treatment per patient. Dr. Lerner highlighted a phase II trial using everolimus in urothelial carcinoma. The trial was a negative study. However, in those who responded, whole genome sequencing revealed TSC1 and NF2 inactivating mutations where in vitro evaluation showed that TSC1 sensitized urothelial cancer cells to mTOR inhibition. Dr. Lerner suggests that currently we are using phenotype-to-genotype approach to understanding treatment (genomic alterations provide explanation of why treatment worked for that one patient). However, we need to start a genotype-to-phenotype approach where we match actionable molecular alteration to targeted agent. Genomic based trial design, however, has its own hurdles with respect to biomarker validity, Next-Gen sequencing CLIA approved lab, FDA regulatory process, collaboration of pharma and biotech industry, and prioritization of target/pathway. Dr. Lerner highlighted an ongoing clinical trial, NCI MATCH, which uses genomic sequencing to provide a specific study agent based on actionable mutation.

In addition to implications in therapeutics and clinical trials, TCGA data also has implications in molecular subtyping of bladder cancer. TCGA data suggest that there are at least 3 clusters, if not 4, of molecular subtypes—papillary, luminal, and basal/squamous-like. Luminal subtype comprises 41%, male prominent, and has FGFR3 mutations. Basal subtype comprises 29%, female prominent, and has squamous histology. Basal phenotype is also associated with worse prognosis. However, immunotherapeutic genes are more enriched in this subtype and can be molecularly targeted. However, the molecular subtyping is still being investigated and integrated. This will also be a topic of discussion in the Bladder Cancer Molecular Taxonomy Consensus Meeting scheduled by the Spanish National Cancer Center.

Currently, within the TCGA, there are 412 samples in final cohort with mean follow up of 1.6 years (0-154 months) and a 26% death rate.

In summary, TCGA data show that bladder cancer has a high mutation rate, a high percentage of potentially targetable pathways, and a high frequency of mutations in chromatic modifying genes. The hope is that the knowledge gained from comprehensive analysis will lead to better patient outcomes through continuing translational research.

Presented by Seth Lerner, MD at the 30th Annual European Association of Urology (EAU) Congress - March 20 - 24, 2015 - IFEMA - Feria de Madrid - Madrid, Spain

Reported by Mohammed Haseebuddin, MD, medical writer for UroToday.com