IBCN 2018: Combining DNA-Repair Gene Mutations and Molecular Subtyping for More Accurate Prediction of Outcome after Neoadjuvant
Recent publications have suggested that mutations in DNA damage repair genes (DDRG) and molecular subtyping of bladder cancer are predictive of outcome after NAC. Dr. Seiler combined these markers in a multicenter cohort of patients to determine the interaction and complementary value of both biomarkers. Whole exome sequencing and transcriptome microarray analysis were performed on pre-NAC MIBC samples. Any mutation in ERCC2, FANCC, RB1 or ATM that was predicted to be deleterious was considered a DDRG mutation. Molecular subtype was assigned with a previously reported single patient classifier. Response to NAC was defined as the absence of MIBC in the cystectomy sample. Of 106 patients with a median follow-up of 2.3 years included 69 (65%) non-responders (23% with DDRG mutation) and 37 (35%) responders (57% with DDRG mutation). The 3 year OS was 77.8% and 50.8% for patients with and without a DDRG mutation, respectively (p<0.01). With the caveats of small sample size in each subtype, OS could be further sub-stratified by DDRG mutation status in basal tumors but had no impact on outcome in the other subtypes. In summary, Both DDRG mutations and molecular subtypes predict survival after NAC for MIBC. This is the largest NAC cohort to date with DDRG mutation results and the first to incorporate also subtyping. Both markers appear to provide complementary predictive information. In summary, tumors likely to respond to NAC are basal-like subtype and alteration in DDR. Less likely to respond to NAC are luminal-like subtype and wild-type DDR. Further external validation of these results is needed in larger cohorts to understand DDRG mutations and molecular subtypes in the development of classifiers to aid in clinical decision-making. As we move towards understanding the molecular underpinnings of bladder carcinogenesis, we need to make these systems clinically useful and easy to use.
Presented by: Professor Roland Seiler, MD, The University of Bern, Bern, Switzerland
Written by: Stephen B. Williams, M.D., Associate Professor, Division of Urology, The University of Texas Medical Branch, Galveston, TX. and Ashish M. Kamat, M.D. Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 16th Annual Meeting of the International Bladder Cancer Network (IBCN) October 11-13, 2018 - the Inntel Hotels Rotterdam Centre, Rotterdam, The Netherlands