How Do Novel Genetic Subtypes of Urothelial Carcinoma Respond to Immune Checkpoint Blockade?

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In a study reported in the Journal of Clinical Oncology, Sarfaty et al identified novel genetic subtypes of urothelial carcinoma exhibiting different responses to immune checkpoint blockade.

Study Details

In the multicenter study, whole-exome sequencing was performed on tumor specimens from 88 patients with advanced bladder cancer treated with immune checkpoint blockade therapy.

Four genetic subtypes were identified that discriminated outcomes with immune checkpoint blockade therapy:

  • Subtype 1 = low tumor mutational burden (TMB)
  • Subtype 2 = high TMB and high tumor cell purity (low immune infiltration)
  • Subtype 3 = high TMB, low tumor cell purity, and ARID1A mutation
  • Subtype 4 = high TMB, low tumor cell purity, and wild-type ARID1A.

Key Findings

In the initial cohort, compared with subtype 1 (n = 32), hazard ratios for progression-free survival were 0.75 for subtype 2 (n = 11), 0.25 for subtype 3 (n = 18), and 0.5 for subtype 4 (n = 27; overall P < .001). Hazard ratios for overall survival vs subtype 1 were 0.67 for subtype 2, 0.37 for subtype 3, and 0.66 for subtype 4 (overall P = .047).

In an independent cohort of patients receiving immune checkpoint blockade treatment in the IMvigor210 trial, compared with subtype 1 (n = 90), hazard ratios for overall survival were 0.76 for subtype 2 (n = 20), 0.52 for subtype 3 (n = 39), and 0.63 for subtype 4 (n = 94; overall P = .017).

In a cohort of patients who did not receive immune checkpoint blockade treatment from the Cancer Genome Atlas (TCGA) bladder cancer cohort, compared with subtype 1 (n = 99), hazard ratios for overall survival were 0.56 for subtype 2 (n = 135), 0.81 for subtype 3 (n = 89), and 0.86 for subtype 4 (n = 72; overall P = .036).

Parallel RNA sequencing data showed that the subtypes were correlated with immune infiltration in the IMvigor210 cohort and inflammation in the TCGA bladder cancer cohort.

The investigators concluded, “Together, our study defines molecular subgroups of bladder cancer that influence benefit from immune checkpoint blockade.”

Jonathan E. Rosenberg, MD, of the Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Illumina, the MSK Coleman Immunogenomics Initiative, National Cancer Institute, and others. For full disclosures of the study authors, visit

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