ESMO 2017: Comparison of tumor mutational burden in relevant molecular subsets of metastatic urothelial cancer 

Madrid, Spain (  Dr. Sumanta Pal and colleagues presented their study assessing tumor mutational burden in molecular subsets of metastatic urothelial carcinoma at ESMO 2017.  Previous phase I and II studies suggest a potential benefit with targeted therapy (e.g., FGFR3, ERBB2/3 and CDK4/6 inhibitors) in certain molecular subsets of metastatic urothelial carcinoma. Combined with increasing data supporting PD-1/PD-L1 inhibitors in metastatic urothelial carcinoma, there is interest in combining targeted therapy and immunotherapy agents. Since tumor mutation burden is a putative biomarker of immunotherapy response [1], the objective of this study was to investigate differences in tumor mutation burden in relevant molecular subsets of metastatic urothelial carcinoma.

Among 2,024 patients with metastatic urothelial carcinoma, DNA was extracted from 40 microns of FFPE sections. Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The comprehensive genomic profiling assay included base substitutions, INDELs, copy number alterations, and fusions/rearrangements. Tumor mutation burden was determined on 1.2 million Mb of sequenced DNA. The results were reported for the overall cohort and in subsets segregated separately by presence or absence of FGFR3, ERBB2/3, PIK3CA and CDKN2A/B alteration. In this cohort 72.0% of patients were male and the median age was 67 years. Median tumor mutation burden in the overall cohort was 7.2 mutations/Mb. FGFR3, ERBB2, ERBB3, PIK3CA, and CDKN2A/B alteration were identified in 23%, 14%, 4%, 19% and 37% of patients, respectively. Tumor mutation burden was significantly different in patients stratified based on ERBB2 alteration (p<0.0001), PIK3CA alteration (p<0.0001) and ERBB3 mutation (p = 0.01). ERBB2 and FGFR3 genomic alterations were significantly mutually exclusive, while FGFR3 genomic alterations significantly co-occurred with PIK3CA and CDKN2A/B mutations.  

In conclusion, given the proposed correlation between tumor mutation burden and immunotherapy response, this data may inform the utility of combination strategies. Specifically, given the higher tumor mutation burden in patients with ERBB2/ERBB3 or PIK3CA alteration, combination studies exploring immunotherapy and targeted therapy directed at these molecular targets may be warranted. 

Speaker: Sumanta K. Pal, City of Hope Comprehensive Cancer Center, Duarte, United States of America

Co-Authors: N. Agarwal (Salt Lake City, United States of America) T. K. Choueiri (Boston, United States of America) P. J. Stephens (Cambridge, United States of America) J. S. Ross (Albany, United States of America) V. A. Miller (Cambridge, United States of America), S. M. Ali (Cambridge, United States of America) J. Chung (Cambridge, United States of America) P. Grivas (Cleveland, United States of America)

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md


1. Galsky MD, Saci A, Szabo PM, et al. Impact of Tumor Mutation Burden on Nivolumab Efficacy in Second-Line Urothelial Carcinoma Patients: Exploratory Analysis of the Phase II CheckMate 275 Study. ESMO 2017 Abstr 848.