TY - JOUR
T1 - Novel Genetic Subtypes of Urothelial Carcinoma with Differential Outcomes on Immune Checkpoint Blockade
AU - Sarfaty, Michal
AU - Golkaram, Mahdi
AU - Funt, Samuel A.
AU - Al-Ahmadie, Hikmat
AU - Kaplan, Shannon
AU - Song, Fan
AU - Regazzi, Ashley
AU - Makarov, Vladimir
AU - Kuo, Fengshen
AU - Ostrovnaya, Irina
AU - Seshan, Venkatraman
AU - Zhao, Chen
AU - Greenbaum, Benjamin
AU - Liu, Li
AU - Rosenberg, Jonathan E.
AU - Chan, Timothy A.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/6/10
Y1 - 2023/6/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85163240612&partnerID=8YFLogxK
U2 - 10.1200/JCO.22.02144
DO - 10.1200/JCO.22.02144
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C2 - 36927002
AN - SCOPUS:85163240612
SN - 0732-183X
VL - 41
SP - 3225
EP - 3235
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 17
ER -