The Cancer Genome Atlas (TCGA), a joint research effort of the National Cancer Institute and the National Human Genome Research Institute, has provided a “complete genomic roadmap” of muscle-invasive bladder cancer, according to Seth P. Lerner, MD, co-chair of the Analysis Working Group of the TCGA program for muscle-invasive bladder cancer. Dr. Lerner, of Baylor College of Medicine in Houston, talks to Urology Times about the clinical relevance of the TCGA’s findings, possible implications for upper tract disease, and what further research is needed.
Give us a high-level view of what the Cancer Genome Atlas has taught us about bladder cancer.
This was a great team science project where we did integrative genomic analysis of DNA, RNA, and protein. Essentially it gave us a complete genomic roadmap of the target population, which was individuals with muscle-invasive bladder cancer. We didn't have a lot of patients who had had prior chemotherapy, so we can't say much about genomic biomarkers predicting response to chemotherapy. But we learned a lot about the genomic landscape.
Not surprisingly, p53 was the most commonly mutated gene. We've probably known that for a long time. But right behind that were a whole series of chromatin-modifying genes, which was a news story that was emerging in bladder cancer. That takes us down a whole path of research. We learned a lot about certain amplifications, deletions, and fusion events, but it's really this integrated genomic analysis that gives us a pretty complete picture of muscle-invasive bladder cancer.
How have data from the Cancer Genome Atlas translated into clinical practice?
I'll give an example of that. We learned a lot about a type of genes called DNA damage repair gene alterations, ERCC2 being the headliner. Other groups have taken that information and they've interrogated it in their phase II clinical trials of neoadjuvant chemotherapy. We now have two trials going on that are asking a question about patients who have an alteration in one or more DNA damage repair genes in this pathway and have a complete clinical response to chemotherapy: Are they cured without additional surgery or radiation? These trials are really important. They're ongoing, and they may end up telling us about a certain part of the patient population that can be cured with chemotherapy alone. Very exciting stuff.
What has the Cancer Genome Atlas taught us about upper urinary tract carcinoma?
Just to be clear, the only patients that were included in the TCGA project were patients with muscle-invasive cancer of the bladder. But the Memorial Sloan Kettering group and our group, in collaboration with MD Anderson, have published this data, and we took a similar approach in our collaboration to look at DNA, RNA, and protein in upper urinary tract disease and do the same integrative genomic analysis. We found, as others have found, some striking differences in the mutation profile comparing upper tract cancer to bladder cancer, most notably a much higher incidence of alterations in FGFR3 and a lower incidence of alterations in p53.
In metastatic muscle-invasive bladder cancer, we now have an approved agent targeting FGFR3, and with this knowledge we have about a upper tract disease, you're going to see trials looking at targeting FGFR3 in that disease. It may not be a direct correlation, but a nice correlation.
What are some of the limitations of the Cancer Genome Atlas?
There are some limitations of the project. People have asked, what about tumor heterogeneity? We know that, within a particular tumor, it's not identical across that tumor. There may be areas of variant histology, for instance, and we now know genomically that there may be multiple different clones that have different genomic alterations that may have different biologic aspects. So the TCGA, which by definition was bulk tumor analysis, tells us a lot, but we need to get more granular and understand the impact of tumor heterogeneity on the ultimate biology in response to our therapies.
Disclosures: Dr. Lerner conducts clinical trials for Endo, FKD Therapies, JBL (SWOG), Roche/Genentech (SWOG), Urogen, Vaxiion Therapeutics, and Viventia Bio; is a consultant/advisory board member for Archiano Therapeutics, Ferring, Merck, QED Therapeutics, Roche/Genentech, UroGen, Vaxiion, and Verity Pharmaceuticals; receives speaker honoraria from Nucleix; and has a patent pending on a TCGA classifier.