Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with...

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Prostate cancer patients with MSI-H/dMMR and TMB-H are candidates for pembrolizumab.
• Characterizing genomic features and clinical outcomes in MSI-H/dMMR and TMB-H/MSS prostate cancers is crucial for understanding treatment responses.

Purpose of the Study:

• To define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H/MSS prostate cancers.

Main Methods:

• Sequenced 3,244 prostate tumors from 2,257 patients.
• Defined MSI-H/dMMR (MSIsensor score ≥10 or ≥3 with MMR alteration) and TMB-H (≥10 mutations/megabase).
• Assessed PSA50 and RECIST responses; compared overall survival and radiographic progression-free survival (rPFS) using log-rank test.

Main Results:

• Identified 63 (2.8%) MSI-H/dMMR and 33 (1.5%) TMB-H/MSS prostate cancers.
• MSI-H/dMMR and TMB-H/MSS tumors more frequently presented with high grade and metastatic disease.
• MSI-H/dMMR tumors exhibited higher TMB, indel, and neoantigen burden compared to TMB-H/MSS.
• 45% of MSI-H/dMMR patients had RECIST response; 65% had PSA50 response.
• 50% of TMB-H/MSS patients had PSA50 response, with no RECIST response.
• rPFS was longer in MSI-H/dMMR patients receiving immunotherapy compared to TMB-H/MSS patients.

Conclusions:

• MSI-H/dMMR prostate cancers possess greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers.
• These genomic distinctions may contribute to profound and durable responses to ICB.
• Further investigation into these differences can optimize immunotherapy strategies for prostate cancer.