Clinical implications of mismatch repair deficiency in prostate cancer

Immune checkpoint blockade holds great promise in the treatment of solid tumors but has not yet been approved for use in advanced prostate cancer. This is largely due to the relatively modest response in clinical trials in unselected patients and the lack of available biomarkers to predict clinical benefit. Germline and somatic mismatch repair (MMR) gene deficiencies are more prevalent than previously thought, especially in the metastatic setting, in patients with high-grade Gleason scores and in patients with variant histologies. An early signal suggests that patients with deficiency in MMR may respond well to immunotherapy. Both germline and somatic genetic testing are recommended, yet questions remain on the best modality for testing given lack of standardization and false-negative results in patients with complex genomic structural rearrangements. Expanded panels, such as next generation sequencing may increase the sensitivity without compromising specificity. Future studies are still needed to explore the relationships of hypermutation, tumor mutational burden, tumor-infiltrating lymphocytes and microsatellite instability-H status as predictors of response to immunotherapy. The drivers of variable response is largely unknown, and a more mature understanding of the mechanisms of resistance in deficiencies in MMR tumors may help to more precisely inform use of immunotherapy in prostate cancer.