In a study reported in JAMA Oncology, Abida et al found that approximately 3% of patients with prostate cancer had microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) tumors and that some of these patients exhibited durable responses to treatment with immune checkpoint inhibitors.
The study involved analysis of 1,551 tumors from 1,346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center from January 2015 through January 2018. Patients consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. Tumor mutational burden and MSIsensor score (quantitative measure of MSI) were assessed.
Prevalence of MSI-H/dMMR Tumors
Among 1,033 patients with adequate tumor quality for MSIsensor analysis, 32 (3.1%) had MSI-H/dMMR prostate cancer; of these, 23 (2.2%) had tumors with high MSIsensor scores and 9 (0.9%) had indeterminate scores with evidence of dMMR. A pathogenic germline mutation in a Lynch syndrome–associated gene was identified in 7 (21.9%) of the 32 patients. Among 6 patients with more than 1 tumor analyzed, 2 exhibited an acquired MSI-H phenotype later in the disease course.
Anti–programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) treatment was given to 11 patients with MSI-H/dMMR castration-resistant prostate cancer. In 6 (54.5%), more than a 50% decline in prostate-specific antigen levels was observed, with 4 of these patients having radiographic responses. As of May 2018, 5 of the 6 responders remained on treatment, with the longest ongoing response at the time of analysis being 89 weeks.
The investigators concluded, “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.”
Wassim Abida, MD, PhD, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: This study was supported by the Prostate Cancer Foundation, National Cancer Institute, Department of Defense, and others. The study authors’ full disclosures can be found at jamanetwork.com.
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