Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade Journal Article


Authors: Abida, W.; Cheng, M. L.; Armenia, J.; Middha, S.; Autio, K. A.; Vargas, H. A.; Rathkopf, D.; Morris, M. J.; Danila, D. C.; Slovin, S. F.; Carbone, E.; Barnett, E. S.; Hullings, M.; Hechtman, J. F.; Zehir, A.; Shia, J.; Jonsson, P.; Stadler, Z. K.; Srinivasan, P.; Laudone, V. P.; Reuter, V.; Wolchok, J. D.; Socci, N. D.; Taylor, B. S.; Berger, M. F.; Kantoff, P. W.; Sawyers, C. L.; Schultz, N.; Solit, D. B.; Gopalan, A.; Scher, H. I.
Article Title: Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade
Abstract: Importance: The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. Objective: To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. Design, Setting, and Participants: In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. Main Outcomes and Measures: Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. Results: Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. Conclusions and Relevance: The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance. © 2019 American Medical Association. All rights reserved.
Journal Title: JAMA Oncology
Volume: 5
Issue: 4
ISSN: 2374-2437
Publisher: American Medical Association  
Date Published: 2019-04-01
Start Page: 471
End Page: 478
Language: English
DOI: 10.1001/jamaoncol.2018.5801
PROVIDER: scopus
PUBMED: 30589920
PMCID: PMC6459218
DOI/URL:
Notes: Article -- Export Date: 1 May 2019 -- Source: Scopus
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MSK Authors
  1. Charles L Sawyers
    199 Sawyers
  2. Vincent Laudone
    86 Laudone
  3. Susan Slovin
    226 Slovin
  4. Michael Morris
    395 Morris
  5. Jedd D Wolchok
    811 Wolchok
  6. David Solit
    627 Solit
  7. Karen Anne Autio
    93 Autio
  8. Zsofia Kinga Stadler
    254 Stadler
  9. Anuradha Gopalan
    347 Gopalan
  10. Jinru Shia
    583 Shia
  11. Dana Elizabeth Rathkopf
    199 Rathkopf
  12. Ahmet Zehir
    276 Zehir
  13. Nicholas D Socci
    209 Socci
  14. Michael Forman Berger
    568 Berger
  15. Victor Reuter
    1128 Reuter
  16. Howard Scher
    1042 Scher
  17. Daniel C Danila
    123 Danila
  18. Wassim Abida
    103 Abida
  19. Barry Stephen Taylor
    225 Taylor
  20. Nikolaus D Schultz
    312 Schultz
  21. Jaclyn Frances Hechtman
    194 Hechtman
  22. Sumit   Middha
    81 Middha
  23. Karl Philip Jonsson
    47 Jonsson
  24. Philip Wayne Kantoff
    160 Kantoff
  25. Joshua   Armenia
    46 Armenia
  26. Ethan Sean Barnett
    20 Barnett
  27. Michael Lain Cheng
    14 Cheng
  28. Emily Ann Carbone
    17 Carbone