Abida W, et al. - Using a targeted sequencing assay from January 1, 2015, through January 31, 2018, researchers defined the prevalence of microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) prostate cancer and the clinical benefit of anti–PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this case series of 1346 patients with prostate cancer who had paired tumor and germline sequencing. Results of this study suggested that the MSI-H/dMMR molecular phenotype is uncommon but therapeutically significant in prostate cancer and can be somatically acquired during disease development. These findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR in view of the potential for durable responses to anti–PD-1/PD-L1 therapy.

Methods

• One thousand, five hundred fifty-one tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed in this case series.
• Patients had a prostate cancer diagnosis and consented to molecular tumor profiling when a tumor biopsy was planned or archival tissue was available.
• Clinical outcomes were reported with follow-up until May 31, 2018 for each patient.
• For this investigation, researchers calculated tumor mutation burden and MSIsensor score, a quantitative measure of MSI.
• In select cases, mutational signature analysis and immunohistochemistry for MMR protein expression were performed.

Results

• Of the 1033 patients with adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer.
• They found that 23 of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR.
• In a Lynch syndrome–associated gene, 7 of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation.
• It was noted that 6 patients had more than 1 tumor analyzed, 2 of whom showed an acquired MSI-H phenotype later in their disease course.
• They observed that 11 patients with MSI-H/dMMR castration-resistant prostate cancer received anti–PD-1/PD-L1 therapy.
• Findings revealed that 6 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%]) had been on treatment for 89 weeks.