Novel genetic subtypes of urothelial carcinoma with differential outcomes on immune checkpoint blockade Journal Article
| Authors: | Sarfaty, M.; Golkaram, M.; Funt, S. A.; Al-Ahmadie, H.; Kaplan, S.; Song, F.; Regazzi, A.; Makarov, V.; Kuo, F.; Ostrovnaya, I.; Seshan, V.; Zhao, C.; Greenbaum, B.; Liu, L.; Rosenberg, J. E.; Chan, T. A. |
| Article Title: | Novel genetic subtypes of urothelial carcinoma with differential outcomes on immune checkpoint blockade |
| Abstract: | PURPOSEImmune checkpoint blockade (ICB) therapy has significantly improved clinical outcomes in bladder cancer. Identification of correlates of benefit is critical to select appropriate therapy for individual patients.METHODSTo reveal genetic variables associated with benefit from ICB, we performed whole-exome sequencing on tumor specimens from 88 patients with advanced bladder cancer treated with ICB.RESULTSWe identified several genetic factors that correlated with progression-free and overall survival after ICB therapy including ARID1A mutation, tumor mutational burden, intratumoral heterogeneity, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome (immune dN/dS), and tumor cell purity. In addition, we noted that neutrophil-to-lymphocyte ratio and smoking history were negatively associated with overall survival. These genetic characteristics define four molecular subtypes demonstrating differential sensitivity to ICB. We validated the association of these four subtypes with clinical benefit from ICB in an independent cohort (IMvigor210). Finally, we showed that these molecular subtypes also correlate with outcome, although with distinct relationships, among patients not treated with ICB using The Cancer Genome Atlas (TCGA) bladder cancer cohort. Using parallel RNA sequencing data, the subtypes were also shown to correlate with immune infiltration and inflammation, respectively, in the IMvigor210 and TCGA cohorts.CONCLUSIONTogether, our study defines molecular subgroups of bladder cancer that influence benefit from ICB. © American Society of Clinical Oncology. |
| Keywords: | adult; cancer chemotherapy; controlled study; human tissue; unclassified drug; gene mutation; major clinical study; overall survival; genetics; mutation; unspecified side effect; cancer patient; heredity; cancer immunotherapy; progression free survival; antineoplastic metal complex; cohort analysis; genetic association; smoking; pathology; fibroblast growth factor receptor 3; protein p53; tumor marker; bladder tumor; urinary bladder neoplasms; cancer genetics; oncogene; genomic instability; immunophenotyping; mutation rate; carcinoma, transitional cell; transitional cell carcinoma; genetic heterogeneity; mucin; mucin 4; clinical outcome; immune checkpoint inhibitor; arid1a gene; kdm6a protein; humans; human; male; female; article; rna sequencing; pembrolizumab; neutrophil lymphocyte ratio; whole exome sequencing; rb1 protein; immune checkpoint inhibitors; biomarkers, tumor; tumor mutational burden; kmt2d protein; kmt2c protein; pd 1 inhibitor; cgref1 protein; elf3 protein; mucin 19; pd l1 inhibitor; prb4 protein'; ptprf protein; ryanodine receptor 1; ryanodine receptor 2; vps13b protein; genetic purity; transitional cell carcinoma of the bladder |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 41 |
| Issue: | 17 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2023-06-10 |
| Start Page: | 3225 |
| End Page: | 3235 |
| Language: | English |
| DOI: | 10.1200/jco.22.02144 |
| PUBMED: | 36927002 |
| PROVIDER: | scopus |
| PMCID: | PMC10256354 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding author is MSK author Jonathan E. Rosenberg -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
-
382Seshan -
196Ostrovnaya -
660Al-Ahmadie -
89Regazzi -
510Rosenberg -
135Funt -
81Kuo -
11Sarfaty -
57Greenbaum
Related MSK Work