MSI-H/dMMR Is Clinically Meaningful, Despite Being Uncommon in Prostate Cancer

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Biomarkers of PD-1/PD-L1 checkpoint inhibitor response in prostate cancer could help stratify patients by response.
Biomarkers of PD-1/PD-L1 checkpoint inhibitor response in prostate cancer could help stratify patients by response.

Appearance of a microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) molecular phenotype is uncommon in prostate cancer, but may have clinical implications when it comes to the use of immune checkpoint inhibitors, according to a case series published online December 27, 2018, in JAMA Oncology.1

To determine the prevalence and clinical relevance of MSI-H or dMMR, study researchers evaluated 1551 tumors from 1346 patients with prostate cancer who were receiving treatment at Memorial Sloan Kettering Cancer Center, New York, New York. Tumor molecular profiling was performed on tumor biopsies or archival tissue using a targeted sequencing assay. Tumor mutation burden and MSIsensor score (low, indeterminate, or high) was assessed in evaluable patients. 

A total of 1033 patients had adequate tumor quality to determine MSIsensor score. Of these, 23 patients (2.2%) had tumors with high MSIsensor scores and 9 patients (<1%) had tumors with indeterminate scores and evidence of dMMR. In sum, 32 patients (3.1%) had a MSI-H/dMMR molecular phenotype. Of these 32 patients, 7 individuals (21.9%) had a pathogenic germline mutation in a Lynch syndrome–associated gene.

Six of 11 patients with MSI-H/dMMR castration-resistant prostate cancer (CRPC) responded to anti–PD-1/PD-L1 therapy, and was linked to a more than 50% reduction in prostate-specific antigen levels. Four patients had radiographic responses. At follow-up in May 2018, 5 of the 6 patients who responded remained on treatment for up to 89 weeks. 

“The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer,” the study authors wrote, in conclusion.

The analysis “demonstrates that treatment with an anti–PD-1 or anti–PD-L1 checkpoint inhibitor — either [US] Food and Drug Administration–approved pembrolizumab or another anti–PD-1 or anti–PD-L1 checkpoint inhibitor through a clinical trial—should be considered in patients with prostate cancer whose tumors harbor MSI,” wrote authors of an invited commentary.2

References

  1. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade [published online December 27, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.5801
  2. Reichert ZR, Urrutia J, and Alumkal JJ. Microsatellite Instability as an emerging biomarker for checkpoint inhibitor response in advanced prostate cancer [published online December 27, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.5789

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