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Cited by 114Prostate Cancer Treatment and ResearchCancer Immunotherapy and BiomarkersProstate Cancer Diagnosis and Treatment

Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies

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Graham, Laura S., Montgomery, Bruce, Cheng, Heather H., Yu, Evan Y., Nelson, Peter S., Pritchard, Colin, Erickson, Stephanie, Alva, Ajjai +1 more·2020·PLOS ONE
DOI 10.1371/journal.pone.0233260PMC PMC7250457
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Abstract

BACKGROUND: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment. METHODS: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported. RESULTS: 27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months). CONCLUSIONS: MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.

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  • With the exception of PD-1 blockade in patients with mCRPC harboring MSI-H/dMMR or TMB-H tumors, PD-1 blockade in PC has provided limited survival benefit.

    “With the exception of PD-1 blockade in patients with mCRPC harboring MSI-H/dMMR or TMB-H tumors, PD-1 blockade in PC has provided limited survival benefit, and ongoing strategies to understand immune evasion and increase the effectiveness of checkpoint blockade in mCRPC are needed [31, 68].”

    From Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey (2025) · cites this paper as [31]

    The Introduction (page unavailable) reports low response rates to PD-1 blockade in unselected mCRPC, while the Results report substantial pembrolizumab responses in patients with MMRd/MSI-H metastatic prostate cancer. The paper does not establish limited survival benefit from PD-1 blockade, and its Discussion treats high tumor mutational burden as a candidate predictor rather than a proven exception in mCRPC. (LLM, conf=0.87)

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  • In another retrospective series of 27 patients with dMMR/MSI-H metastatic PC, 8/17 (53.0%) pembrolizumab-treated patients experienced PSA responses ≥50%, of whom 7 (87.5%) remained on treatment without progression at 12 months median follow-up (range: 3-20 months).

    “In another retrospective series of 27 patients with dMMR/MSI-H metastatic PC, 8/17 (53.0%) pembrolizumab-treated patients experienced PSA responses ≥50%, of whom 7 (87.5%) remained on treatment without progression at 12 months median follow-up (range: 3–20 months) [31].”

    From Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey (2025) · cites this paper as [31]

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References 27 · Cited by 114

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  1. [1]Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol. 2017; 35(1): 40– 7. 10.1200/JCO.2016.69.1584 28034081 · DOI · Paper page
  2. [2]Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014; 15(7): 700– 12. 10.1016/S1470-2045(14)70189-5 24831977 PMC4418935 · DOI · Paper page
  3. [4]Sharma P, Pachynski RK, Narayan V, Flechon A, Gravis G, Galsky MD, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650) [abstract 142]. Presented in: ASCO Genitourinary Cancers Symposium. 2019.
  4. [5]Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017; 377(25): 2500– 1. 10.1056/NEJMc1713444 29262275 PMC6549688 · DOI · Paper page
  5. [6]Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA oncology. 2019; 5(4): 471– 8. 10.1001/jamaoncol.2018.5801 30589920 PMC6459218 · DOI · Paper page
  6. [7]Antonarakis ES, Shaukat F, Isaacsson Velho P, Kaur H, Shenderov E, Pardoll DM, et al Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations. Eur Urol. 2019; 75(3): 378– 82. 10.1016/j.eururo.2018.10.009 30337059 PMC6377812 · DOI
  7. [8]Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349): 409– 13. 10.1126/science.aan6733 28596308 PMC5576142 · DOI · Paper page
  8. [10]Pritchard CC, Morrissey C, Kumar A, Zhang X, Smith C, Coleman I, et al Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nature communications. 2014; 5: 4988 10.1038/ncomms5988 25255306 PMC4176888 · DOI
  9. [11]Rodrigues DN, Rescigno P, Liu D, Yuan W, Carreira S, Lambros MB, et al Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. The Journal of clinical investigation. 2018; 128(11): 5185. PMC6205373 30382943
  10. [12]Pritchard CC, Salipante SJ, Koehler K, Smith C, Scroggins S, Wood B, et al Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. The Journal of molecular diagnostics: JMD. 2014; 16(1): 56– 67. 10.1016/j.jmoldx.2013.08.004 24189654 PMC3873496 · DOI
  11. [13]Roychowdhury S, Iyer MK, Robinson DR, Lonigro RJ, Wu YM, Cao X, et al Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci Transl Med. 2011; 3(111):111ra21. PMC3476478 22133722
  12. [14]Ritch E, Fu SYF, Herberts C, Wang G, Warner EW, Schonlau E, et al Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer. Clin Cancer Res. 2019. 31744831
  13. [15]Guedes LB, Antonarakis ES, Schweizer MT, Mirkheshti N, Almutairi F, Park JC, et al MSH2 Loss in Primary Prostate Cancer. Clin Cancer Res. 2017; 23(22): 6863– 74. 10.1158/1078-0432.CCR-17-0955 28790115 PMC5690834 · DOI
  14. [16]James ND, Spears MR, Clarke NW, Dearnaley DP, De Bono JS, Gale J, et al Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). Eur Urol. 2015; 67(6): 1028– 38. 10.1016/j.eururo.2014.09.032 25301760 · DOI
  15. [17]Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371(5): 424– 33. 10.1056/NEJMoa1405095 24881730 PMC4418931 · DOI · Paper page
  16. [18]Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013; 368(2): 138– 48. 10.1056/NEJMoa1209096 23228172 PMC3683570 · DOI · Paper page
  17. [19]Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018; 7(3): 746– 56. 10.1002/cam4.1372 29436178 PMC5852359 · DOI
  18. [21]Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031): 1909– 20. 10.1016/S0140-6736(16)00561-4 26952546 PMC5480242 · DOI · Paper page
  19. [22]Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23): 2189– 99. 10.1056/NEJMoa1406498 25409260 PMC4315319 · DOI · Paper page
  20. [23]Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Molecular cancer therapeutics. 2017; 16(11): 2598– 608. 10.1158/1535-7163.MCT-17-0386 28835386 PMC5670009 · DOI · Paper page
  21. [24]Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, et al Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell. 2018; 33(5):853–61 e4. PMC6750707 29731394
  22. [25]Nakazawa M, Paller C, Kyprianou N. Mechanisms of Therapeutic Resistance in Prostate Cancer. Curr Oncol Rep. 2017; 19(2): 13 10.1007/s11912-017-0568-7 28229393 PMC5812366 · DOI

Authors
Graham, L. S., Montgomery, B., Cheng, H. H., Yu, E. Y., Nelson, P. S., Pritchard, C., Erickson, S., Alva, A., & Schweizer, M. T.
Affiliations
  • University of Washington (US)
  • University of Michigan (US)
Corresponding author
Schweizer, Michael T.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2020-05-26
Volume
15
Issue
5
Pages
e0233260
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0233260
PMC
PMC7250457
OpenAlex
W3031120515
Cited by
114
References
27
Citations by year
2026: 12 · 2025: 13 · 2024: 22 · 2023: 19 · 2022: 24 · 2021: 17 · 2020: 7
FWCI
9.44
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (W81XWH-16, PC170510, PC170503P2, W81XWH, W81XWH-18)
  • Prostate Cancer Foundation (P30 CA015704, W81XWH-16-1-0484, CA-097186, SU2C-AACR-DT0712)
  • Bristol-Myers Squibb
  • Pfizer (P30 CA015704)
  • AstraZeneca
  • Sanofi
  • Celgene
  • F. Hoffmann-La Roche
  • Clovis Oncology
  • BeiGene
  • Institute for Prostate Cancer Research
  • Daiichi-Sankyo
  • Astellas Pharma
  • Genentech
  • Stand Up To Cancer (SU2C-AACR-DT0712)
  • Pharmacyclics
  • National Cancer Institute (CA097186, CA015704, W81XWH-16, T32CA009515, P30CA015704)
  • Congressionally Directed Medical Research Programs (W81XWH-16-1-0484, W81XWH-18-1-0354, PC170510, PC170503P2)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
Keywords
mismatch repair deficiency, microsatellite instability, metastatic castration-resistant prostate cancer, anti-PD-1 therapy, pembrolizumab, immune checkpoint inhibitors, immunotherapy response, PSA response, progression-free survival, Gleason score, overall survival
MeSH terms
Aged, Aged, 80 and over, Antineoplastic Agents, Brain Neoplasms, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Neoplastic Syndromes, Hereditary, Prostatic Neoplasms, Retrospective Studies, Biomarkers, Tumor, Colorectal Neoplasms, Survival Analysis, Programmed Cell Death 1 Receptor

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