Novel Genetic Subtypes of Urothelial Carcinoma With Differential Outcomes on Immune Checkpoint Blockade
Michal Sarfaty1,2,3, Mahdi Golkaram4, Samuel A Funt1
1Genitourinary Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Purpose:
Immune 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.
Methods:
To 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.
Results:
We 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.
Conclusion:
Together, our study defines molecular subgroups of bladder cancer that influence benefit from ICB.
Insights
Identifying genetic factors like ARID1A mutations and tumor mutational burden can predict bladder cancer patient response to immune checkpoint blockade (ICB) therapy, defining molecular subtypes for personalized treatment.
Area of Science:
- Genomics and Precision Oncology
- Immunotherapy Research
- Bladder Cancer Therapeutics
Background:
- Immune checkpoint blockade (ICB) therapy offers significant clinical benefits for advanced bladder cancer.
- Selecting patients who will benefit from ICB requires identifying reliable biomarkers.
Purpose of the Study:
- To identify genetic variables associated with patient benefit from ICB in advanced bladder cancer.
- To define molecular subtypes of bladder cancer based on genetic factors influencing ICB response.
Main Methods:
- Whole-exome sequencing of tumor specimens from 88 advanced bladder cancer patients treated with ICB.
- Analysis of genetic factors including ARID1A mutation, tumor mutational burden, and immune dN/dS.
- Validation in an independent cohort (IMvigor210) and comparison with The Cancer Genome Atlas (TCGA) bladder cancer cohort.
Main Results:
- Identified ARID1A mutation, tumor mutational burden, intratumoral heterogeneity, immune dN/dS, and tumor purity as correlates of progression-free and overall survival after ICB.
- Defined four molecular subtypes of bladder cancer with differential sensitivity to ICB, validated in an independent cohort.
- Demonstrated correlation of subtypes with outcomes in non-ICB treated patients and with immune infiltration/inflammation.
Conclusions:
- The study defines distinct molecular subgroups of bladder cancer that significantly influence benefit from ICB therapy.
- These findings support the development of personalized treatment strategies for bladder cancer based on molecular profiling.
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