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Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer

Lenis, Andrew T., Ravichandran, Vignesh, Brown, Samantha, Alam, Syed M., Katims, Andrew, Truong, Hong, Reisz, Peter A., Vasselman, Samantha +22 more·2024·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-23-3403PMC PMC11371520

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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/microsatellite stable (MSS)]. Experimental Design: We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test. Results: Sixty-three (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. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders. Conclusions: MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB.

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  • Germline, somatic, and liquid biopsy-based approaches are increasingly indispensable in advanced disease, particularly when they identify actionable alterations such as HRD or dMMR.

    “In contrast, germline, somatic, and liquid biopsy–based approaches are increasingly indispensable in advanced disease, particularly when they identify actionable alterations such as homologous recombination repair deficiency or mismatch repair deficiency [8–10, 18].”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [10]

    The Introduction (page not available) identifies MSI-H/dMMR prostate cancer as eligible for pembrolizumab, and the Results show that tumor sequencing identified MSI-H/dMMR in a patient who then received immune checkpoint blockade. The Methods describe tumor sequencing with blood as a germline reference, while the Discussion describes liquid biopsy as a possible alternative for detecting MSI-H. The paper does not establish that all three approaches are increasingly indispensable in advanced disease or address homologous recombination repair deficiency as an actionable finding. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In advanced prostate cancer, germline and somatic testing identify predictive biomarkers linked to therapy selection.

    “in advanced disease, germline and somatic testing identify predictive biomarkers linked to therapy selection”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [10]

    The Methods (Study cohort and Genomic sequencing; page unavailable) describe sequencing tumor and germline DNA and using germline or somatic mismatch-repair alterations to help classify tumors. The Discussion (page unavailable) explicitly supports somatic tumor testing in locally advanced and metastatic prostate cancer to guide immune-checkpoint therapy selection, but does not make the same treatment-selection recommendation for germline testing as a separate test. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Mismatch repair deficiency and MSI-H status represent a predictive axis in prostate cancer; although relatively uncommon, these tumors may derive substantial benefit from immune checkpoint inhibitors, particularly pembrolizumab.

    “Mismatch repair deficiency and MSI-H status represent another predictive axis. Although relatively uncommon, these tumors may derive substantial benefit from immune checkpoint inhibitors, particularly pembrolizumab [10].”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [10]

  • In metastatic disease, germline and somatic sequencing are recommended to identify actionable alterations such as HRD and dMMR/MSI-H, which have direct implications for PARP inhibitor therapy and immune checkpoint blockade.

    “In metastatic disease, genomic testing shifts toward predictive biomarkers. Germline and somatic sequencing are recommended to identify actionable alterations such as homologous recombination repair deficiency (HRD) and mismatch repair deficiency (dMMR/MSI-H), which have direct implications for PARP inhibitor therapy and immune checkpoint blockade [2, 8–10].”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [10]

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Authors
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., Woo, S., Vargas, H. A., Laudone, V. P., Ehdaie, B., Reuter, V., Arcila, M., Berger, M. F., Viale, A., Scher, H. I., Schultz, N., Gopalan, A., Donoghue, M. T. A., Ostrovnaya, I., Stopsack, K. H., Solit, D. B., & Abida, W.
Affiliations
  • Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 1
  • Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. 2
  • Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 3
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 4
  • Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. 5
  • Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 6
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2024-07-01
Volume
30
Issue
17
Pages
3894-3903
ISSN
  • 1078-0432
  • 1557-3265
DOI
10.1158/1078-0432.ccr-23-3403
PMC
PMC11371520
Cited by
79
References
2
Language
en
Funders
National Cancer Institute (P50-CA092629, P01 CA228696, P30-CA008748)

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