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

Reference:

  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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