Using Molecular Subtyping to Predict Response to Immunotherapy in Urothelial Cancer

By: Joseph Fanelli
Posted: Thursday, May 4, 2023

According to findings presented in the Journal of Clinical Oncology, novel molecular subtyping of bladder cancer, which can be quantified using DNA, may be used as a more clinically applicable predictor of response to immune checkpoint blockade therapy for patients with urothelial cancer. This approach may be adapted to targeted-sequencing panels and clinical whole-exome sequencing, concluded Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues.

“The stability of DNA enhances the feasibility of our approach in clinical environments,” the authors said. “Although RNA-based signatures may further enhance the predictive value of our model, clinical implementation of RNA-based assays has historically been challenging.”

In this investigation, the authors performed whole-exome sequencing on tumor specimens from 88 patients with advanced urothelial cancer who were treated with immune checkpoint blockade therapy. Several genetic factors seemed to correlate with progression-free and overall survival after immune checkpoint blockade therapy, including ARID1A mutation, tumor mutational burden, intratumoral heterogeneity, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, and tumor cell purity. Neutrophil-to-lymphocyte ratio and patients’ smoking history were negatively associated with overall survival, according to the investigators. These genetic characteristics defined four molecular subtypes with differential sensitivity to immune checkpoint blockade therapy.

Additionally, the authors found that these molecular subtypes also correlated with patient outcome, although with distinct relationships among patients not treated with immune checkpoint blockade therapy. Via parallel RNA-sequencing data, the subtypes were also shown to correlate with immune infiltration and inflammation.

Disclosure: For full disclosures of the study authors, visit ascopubs.org.

Journal of Clinical Oncology