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.

Figure 1.. Tumor Mutation Burden (TMB) and Microsatellite Instability (MSI) in Prostate Cancer

A, Tumor mutation burden in mutations per megabase (mut/Mb) and MSIsensor score, a measure of microsatellite instability derived from sequencing data, are given for 1167 tumors from 1033 patients. B, MSIsensor scores were classified as high (≥10), indeterminate (≥3 to <10), or low (<3). Tumors with high MSIsensor scores invariably had high TMB and were considered to have high MSI (MSI-H) (orange). Tumors with MSIsensor indeterminate scores were classified as MSI-H or mismatch repair deficient (dMMR) if they had deleterious MMR gene alterations or MMR protein loss on immunohistochemical analysis (orange). Tumors with MSIsensor low scores typically had lower TMBs, with 1 exception that harbored a hotspot mutation in POLE (cyan).

Figure 2.. Integrative Analysis of Microsatellite Instability (MSI), Tumor Mutation Burden (TMB), Mutational Signature Decomposition, and Mismatch Repair (MMR) Gene and Protein Status

Tumors with the highest TMB (in mutations per megabase [mut/Mb]) and indeterminate (≥3 to <10) and high (≥10) MSIsensor scores are shown. Mutation signatures with a contribution of at least 20% are shown, including MMR/MSI signatures 6, 15, 20 and 26; signature 1, which is associated with aging; and signatures 12 and 28.^, The oncoprint (left) shows genomic alterations in MMR genes, and immunohistochemical analysis (IHC) for MMR proteins (MSH2, MSH6, MLH1, and PMS2).

Figure 3.. Longitudinal Assessment of Microsatellite Instability–High and Mismatch Repair–Deficient Status (MSI-H/dMMR) in Matched Tumors

Six patients with MSI-H/dMMR prostate cancer had more than 1 tumor profiled. The time of acquisition of these tumors is indicated relative to the time of acquisition of the first profiled tumor (month 0). Two of the 6 patients (P-0000964 and P-0007143) had evidence of somatically acquired MSI in the latter metastatic castration–resistant tumors. For patient P-0007143, the earlier tumor was a prostate sample acquired at his diagnosis, at which time he had de novo metastatic noncastrate disease. This tumor had a very low MSIsensor score and tumor mutation burden (TMB). One patient (P-0000449) with a germline PMS2 mutation displayed MSI in both matched tumors. IHC indicates immunohistochemical analysis.

Figure 4.. Responses to Immune Checkpoint Blockade in Microsatellite Instability–High and Mismatch Repair Deficient (MSI-H/dMMR) Prostate Cancer

Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received an anti–programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agent. Best prostate-specific antigen (PSA) response from baseline to date, and radiographic responses (partial response [PR], stable disease [SD], progressive disease [PD]) are noted. As of May 31, 2018, 5 patients continued to receive treatment with greater than 50% declines in PSA levels, 4 of whom had objective radiographic responses (eFigure 5 in the Supplement). One patient (eFigure 5B in the Supplement) had an initial radiographic PR, progressed in the prostate and by PSA, underwent palliative radiotherapy to the prostate, and continued to receive immune therapy with further clinical benefit. One patient had stable disease (SD) for approximately 6 months. Five patients showed no benefit, one of whom died, possibly owing to drug-related toxic effects.