SUO 2018: Genomics of Upper Tract Disease

Phoenix, Arizona  ( Dr. Coleman reviewed the contemporary understanding of genomics of upper tract disease and implications for future targeted therapies. It is presently understood that cancers arising from the urothelium of the bladder and upper tract are morphologically similar, yet clinical findings also reveal important biological differences. Compared to bladder urothelial carcinoma (UC), upper tract urothelial carcinoma (UTUC) is more often high grade (70% vs 30%), associated with environmental exposures to toxins (aristolochic acid, phenacetin, blackfoot disease), associated with hereditary patterns (Lynch Syndrome, MSH mutations) and with better cancer-specific mortality.

Supporting the notion that bladder UC and UTUC are disparate diseases, Dr. Coleman reviewed a study published by Catto et al in The Journal of Urology in 2007 which showed that tumor stage and grade, not location (bladder, ureter, renal pelvis) were associated with tumor behavior. Studies showing disparate clinical behavior were briefly reviewed by Dr. Coleman, but he further ascertained that there are likely multiple factors that lead to clinical disparities between upper and lower tract disease. Diagnostic differences may play a role as UTUC is diagnosed endoscopically with less accurate grading and particularly staging. Anatomic differences such as a thinner muscularis stroma, egress to renal parenchyma, and embryologic origin may additionally play important roles. There are clear local therapy limitations for UTUC as endoscopic and topical therapies for UTUC are just emerging, and consequences of actual treatment for UTUC such as loss of renal function after nephroureterectomy that may limit adjuvant therapy options (he briefly discusses the POUT trial).

In addition to diagnostic, anatomic, and patient factor differences that may lead to disparities, genomics has been found to play a role. Indeed, comparative genomic studies in UTUC have served to demonstrate significant differences compared to bladder UC, suggesting a different set of future therapeutic strategies. Prior studies have shown that high-grade bladder UC without upper tract involvement is associated with mutations in p53 and KDM6A; only a small fraction of such patients have mutations in FGFR3. Conversely, Dr. Coleman reviewed work from his institution which showed that genomics of patients with pure UTUC are associated with a high proportion of FGFR3 mutations (54%), and furthermore, analyses have demonstrated mutual exclusivity for FGFR3 and p53 (i.e. if a patient has a mutation in one, they don’t have a mutation in the other). One additional important finding is that while Rb mutations are present in 20% of bladder UC, they are absent in UTUC. Corroborative work by Moss et al published in European Urology in 2017 reported similar findings as the MSKCC group, and additionally evaluated RNA expression analyses which allowed tumors to be separated into four groups with clear prognostic differences. This and similar work by Bagrodia et al from 2017 support that patients can be risk stratified based on genomic profiles, and offered tailored targeted therapies. Work is currently underway for patients with Lynch Syndrome, in which an activating mutation in R248C has been identified, and may represent a target for future research.

Dr. Coleman concluded his talk by summarizing that the importance of genomics in UTUC particularly in the setting of variable diagnostic reliability for the disease. He reinforced that differences in survival may be explained by differences in genetic mutation frequencies and that there is a potential for risk stratification based on genomic profiles. In addition to risk stratification, sequencing data suggests that there are various susceptibilities and targetable pathways (e.g. FGFR3, MSI-H, ERCC2, PIK3CA) that may optimize treatment in the future.

Presented by: Jonathan A. Coleman, MD, Memorial Sloan Kettering Cancer Center, New York, New York

Written By: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, Philadelphia, Pennsylvania, @selmasic, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona