Clinical implications of mismatch repair deficiency in prostate cancer

Research output: Contribution to journalReview articlepeer-review

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2395-2411
Number of pages17
JournalFuture Oncology
Volume15
Issue number20
DOIs
StatePublished - Jul 2019
Externally publishedYes

Bibliographical note

Funding Information:
ES Antonarakis: Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Amgen, Clovis, Merck (consulting/advisory), Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol-Myers Squibb, AstraZeneca, Celgene, Clovis, Merck (research funding), Qiagen (intellectual property). Consulting/advisory relationship; research funding; employment; expert testimony; honoraria received; ownership interests; intellectual property rights/inventor/patent holder; scientific advisory board. This work was partially supported by NIH Cancer Center Support Grant P30 CA006973, and Department of Defense grant W81XWH-16-PCRP-CCRSA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Publisher Copyright:
© 2019 Future Medicine Ltd.

Keywords

  • germline mutations
  • immunotherapy
  • mismatch repair defects
  • prostate cancer
  • somatic mutations

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