Clinical Implications of Mismatch Repair Deficiency in Prostate Cancer

Abstract

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.

Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

“…This inspired the development of ICIs or blockades that led to the revolutionary treatment of many cancer types and earned both James P Allison and Tasuku Honjo a 2018 Nobel Prize in Physiology or Medicine. Patients with melanoma, bladder and kidney cancers that exhibit mismatch repair deficiency (dMMR), cyclin dependent kinase 12 (CDK12) loss and high tumour mutational burden characterised by good T cell infiltration tend to respond well to ICIs as compared to patients with PCa [ 63 , 64 ]. PCa is generally immunologically “cold” associated with low tumour mutational burden around tumour microenvironment and enriched with poor T cell infiltration and myeloid cells that are immunosuppressive [ 65 , 66 ].…”

Molecular Characterization of Prostate Cancers in the Precision Medicine Era

“…Concerning prostate cancer, MMRd has been identified in about 5% of metastatic patients and the most frequently mutated genes are MSH2 and MSH6 [ 73 ]. Only a small percentage of MMR gene mutations are inherited (germline), with Lynch syndrome being rarely associated with prostate cancer, thus meaning that MMRd could be acquired by prostate cancer cells during disease evolution [ 74 ].…”

Genetic Contributions to Prostate Cancer Disparities in Men of West African Descent

“…Mutations in MMR genes including MSH2 (MutS Homolog 2), MLH1 (MutL homolog 1), PMS1 (PMS1 homolog 1), PMS2 (PMS homolog 2) or MSH6 (MutS Homolog 6) subsequently give rise to a highly penetrant autosomal dominant predisposition cancer known as Lynch syndrome that increase risk for colon, endometrial, prostate, and other cancers. Several studies have shown deleterious mutations in these genes are causal of cancer development across populations ( 112 ). Matejcic and colleagues performed targeted gene sequencing, using a panel composed of 19 MMR precancer disposition genes, in 2,453 AA and 1,151 Ugandan Cases and Controls with prostate cancer.…”