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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.

journal_name

JAMA Oncol

journal_title

JAMA oncology

authors

Abida W,Cheng ML,Armenia J,Middha S,Autio KA,Vargas HA,Rathkopf D,Morris MJ,Danila DC,Slovin SF,Carbone E,Barnett ES,Hullings M,Hechtman JF,Zehir A,Shia J,Jonsson P,Stadler ZK,Srinivasan P,Laudone VP,Reuter V,Wo

doi

10.1001/jamaoncol.2018.5801

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

471-478

issue

eissn

2374-2437

issn

2374-2445

pii

2718924

journal_volume

pub_type

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Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade.