Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer.
Publication/Presentation Date
7-1-2024
Abstract
PURPOSE: Patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI (TMB-H/MSS).
METHODS: We sequenced 3,244 tumors from 2,257 prostate cancer patients. MSI-H/dMMR prostate cancer was defined as MSIsensor score ≥10 or MSIsensor score ≥3 and≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival (OS) and radiographic progression-free survival (rPFS) were compared using log rank test.
RESULTS: 63 (2.8%) men had MSI-H/dMMR and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel and neoantigen burden compared with TMB-H/MSS. 27 patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored POLE mutations. 45% of MSI-H/dMMR patients had a RECIST response and 65% had a PSA50 response. No TMB-H/MSS patient had a RECIST response and 50% had a PSA50 response. rPFS tended to be longer in MSI-H/dMMR patients than in TMB-H/MSS patients who received immunotherapy. Pronounced differences in genomics, TMB or MSIsensor score were not detected between MSI-H/dMMR responders and non-responders.
CONCLUSIONS: MSI-H/dMMR prostate cancers have greater TMB, indel and neoantigen burden compared with TMB-H/MSS prostate cancers, and these differences may contribute to more profound and durable responses to ICB.
ISSN
1557-3265
Published In/Presented At
Lenis, A. T., Ravichandran, V., Brown, S., Alam, S. M., Katims, A., Truong, H., Reisz, P. A., Vasselman, S., Nweji, B., Autio, K. A., Morris, M. J., Slovin, S. F., Rathkopf, D., Danila, D., Scher, H. I., Woo, S., Vargas, H. A., Laudone, V. P., Ehdaie, B., Reuter, V., … Abida, W. (2024). Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 10.1158/1078-0432.CCR-23-3403. Advance online publication. https://doi.org/10.1158/1078-0432.CCR-23-3403
Disciplines
Medicine and Health Sciences
PubMedID
38949888
Department(s)
Department of Medicine
Document Type
Article