Effect of Genomic Subtypes of Urothelial Carcinoma on Response to Immune Checkpoint Inhibitors - Expert Commentary

While immune checkpoint inhibitors (ICI) have revolutionized treatment for bladder cancer patients, studies have shown that not all patients achieve a response. To identify potential genetic predictors of ICI treatment response, Sarfaty et al. investigated the link between specific subtypes based on genomic alterations in ICI-treated patients with advanced urothelial carcinoma and survival outcomes.

The study cohort consisted of 88 patients with advanced urothelial carcinoma treated with ICI therapy, for whom high-quality pretreatment tumor samples were available. Most patients were male (70%) and had a smoking history (65%). The disease originated in the bladder in 65% of patients, in the upper tract in 30%, and in the urethra in 5% of patients. The median age at treatment initiation was 69 years. 65% of patients exhibited visceral metastases, and 73% had previously been treated with platinum-based chemotherapy. PD-1 inhibitor was used in 45% of patients, while PD-L1 inhibitor was used in 55%. The median progression-free survival (PFS) time was 3.4 months, and the median overall survival (OS) time was 11.2 months.

Whole-exome sequencing of patient tumors revealed high concordance between commonly mutated genes in this cohort and those reported in The Cancer Genome Atlas (TCGA), which were TP53, ARID1A, KM2D/C, KDM6A, FGFR3, and RB1. There was a strong and significant association between ARID1A mutation and enhanced survival after treatment (PFS, p = 0.002; OS, p = 0.025). The authors subsequently analyzed the effect of TMB on outcomes using a pre-defined cut-off point (>10 mut/Mbp), and the result was non-significant (p = 0.15). To investigate this further, they performed an analysis to determine the optimal threshold, which was found to be > 3 mut/Mbp, which was significantly associated with PFS (p = 0.003) and OS (p = 0.08). Patients with a higher ratio of nonsynonymous to synonymous mutations, dN/dS in the immunopeptidome, had superior PFS after treatment (p = 0.029). Similarly, there was a strong association between high tumor cell purity and poor PFS (p = 0.022). ┬ČIn addition, the neutrophil-to-lymphocyte (NLR) ratio was strongly predictive of OS (p = 0.018), and the neutrophil-to-eosinophil ratio further outperformed NLR in predicting negative OS (p = 0.001). The authors subsequently classified patients into molecular subtypes to determine whether they exhibited distinct outcomes. The four subtypes were as follows: tumors with low TMB (subtype 1); tumors with high TMB and high tumor cell purity (subtype 2); tumors with high TMB, low tumor cell purity, and ARID1A mutation (subtype 3); and tumors with high TMB, low tumor cell purity, and wild-type ARID1A (subtype 4). Subtype 1 represented the worst clinical outcome, with a median PFS of less than 6 months. Subtype 3 had the longest PFS, while subtype 2 had poor survival despite a high mutational load. The relevance and predictive power of these subtypes were subsequently validated on whole-exome sequencing data from external cohorts.

This study shows that specific genomic subclasses of urothelial cancers are associated with higher response rates to immunotherapy.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine


  1. Sarfaty M, Golkaram M, Funt SA, et al. Novel Genetic Subtypes of Urothelial Carcinoma With Differential Outcomes on Immune Checkpoint Blockade. J Clin Oncol. 2023;JCO2202144. 
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